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CHAPTER TITLE

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Acknowledgements

I would like to express my gratitude for the continuous help and critical remarks of all those who made this work
possible, especially Peter Bakker Afra van den Berg, Ronald Bleys, George Bruyn, Ruud Buijs, Liesbeth Dubelaar,
Frank van Eerdenburg, Tini Eikelboom, Bart Fisser, Eric Fliers, Bas Gabrels, Tony Goldstone, Louis Gooren, Valeri
Goncharuk, Joop van Heerikhuize, Michel Hofman, Witte Hoogendijk, Inge Huitinga, Tatjana Ishunina, Marina
Kahlmann, Dries Kalsbeek, Wouter Kamphorst, Michiel Kooreman, Berry Kremer, Frank Kruijver, Jenneke Kruisbrink,
Gert Jan Lammers, Fred van Leeuwen, Rong-Yu Liu, Paul Lucassen, Gerben van der Meulen, Gerben Meynen, Jan
van de Nes, Elly de Nijs, Willeke van Ockenburg, Sebastiaan Overeem, Maria Panayotacopoulou, Joris van der Post,
Chris Pool, Rivka Ravid, Erik Scherder, Eus van Someren, Henk Stoffels, Elly Tjoa, Suzanne Trottier, Unga Unmehopa,
Paul van der Valk, Wilma Verweij, Ronald Verwer, Jos Wouda, Jiang-Ning Zhou, all other participants of the
Netherlands Brain Bank team, and all staff members, students, and guest workers of the Netherlands Institute for
Brain Research. The persons who kept me from working on this book are too numerous too mention.

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vii

CONTENTS

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List of abbreviations

A
AADC
AC
AD
ACTH
ADHD
AGRP
AIDS
AIP
ALD
ALS
AM
AMPA
AMDLX
ANP
APOE
AT
ATD
AVP
BDNF
BMI
BST
BSTdspm/
BNSTdspm
BSTc
BSTm
CAG
CAH
CART
CCK
CDC
CG
ChAT
CM
CMV
CNS
CRH
CSF
CT
DII

amygdala
aromatic L-amino acid decarboxylase
anterior commissure
Alzheimers disease
corticotropin
attention deficit hyperactivity disorder
agouti-related peptide
acquired immune deficiency syndrome
acute intermittent porphyria
adrenoleukodystrophy
amyotrophic lateral sclerosis
anteromedial subnucleus of the basal nucleus
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
adhesion molecule-like X
atrial natriuretic peptide
apolipoprotein E
angiotensin
1,4,6-androstratriene-3,17-dione (aromatase
inhibitor)
arginine vasopressin
brain-derived neurotropic factor
body mass index
bed nucleus of the stria terminalis
darkly staining posteromedial
component of the bed nucleus of the stria
terminalis
central nucleus of the bed nucleus of the
stria terminalis
medial nucleus of the bed nucleus of the
stria terminalis
DNA sequence that codes for glutamine
repeats. An expanded sequence is found
in Huntingtons disease
congenital adrenal hyperplasia
cocaine- and amphetamine-regulated
transcript
cholecystokinin
center for disease control and prevention
chiasmal gray
choline acetyltransferase
corpora mamillaria
cytomegalovirus
central nervous system
corticotropin-releasing hormone
cerebrospinal fluid
computer tomography
deiodinase type II

DAX-1
DA
DB/DBB
DDAVP
DES
DHEA
DHEAS
DM/DMN/
DMH
DMI
DMV
DNA
DSM-III R/IV

DYN
EAE
ECT
EEG
EM
ER-/
ERT
FAI
FO/Fx
FSH
GA
GABA
GAD
GAP
GFAP
GHRH
GnRH
HCG
Hcrt1-2
HD
H&E
HMPG
5-HIAA
HIOMT
HITF
HIV
HLA
HNS
HPA-axis

dosage-sensitive sex-reversal, adrenal


hypoplasia, congenital, X-chromosome-1
dopamine
diagonal band of Broca
1-desamine-8-D-arginine vasopressin
(= desmopressin)
diethylstilbestrol
dehydroepiandrosterone
dehydroepiandrosterone sulfate
dorsomedial nucleus of the hypothalamus
desmethylimipramine
dorsal motor nucleus of the nervus vagus
deoxyribonucleic acid
diagnostic and statistical manual mental
disorders (American Psychiatric
Association), third revised edition/fourth
edition
dynorphin
experimental allergic encephalomyelitis
electroconvulsive therapy
electroencephalogram
electron microscope
estrogen receptor-/
estrogen replacement therapy
free androgen index
fornix
follicle-stimulating hormone
Golgi apparatus
gamma-aminobutyric acid
glutamic acid decarboxylase
gonadotropin hormone-releasing hormoneassociated peptide
glial fibrillary acidic protein
growth hormone-releasing hormone
gonadotropin-releasing hormone (= LHRH)
human chorionic gonadotropin
hypocretin (orexin) 1-2
Huntingtons disease
hematoxylineosin staining
3-methoxy-4-hydroxyphenylglycol
5-hydroxyindoleacetic acid
hydroxyindole-O-methyltransferase
human intestinal trefoil factor
human immunodeficiency virus
human leukocyte antigen
hypothalamoneurohypophysial system
hypothalamopituitaryadrenal axis

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HVA
5-HT
I
III
ICC
icv
IF
IFN
IGF
IHA
IL-1
INAH1-4
INSP4
KALIG-1
LC
LCA
LH
LHA
LHRH
LPH
LV
LVP
MAO
MAP(A/B)
MCH
MCR1-4
MDMA
ME
MEN
MELAS
MHPG
MHC
MPN
MRI
MS
()MSH
(m)RNA
NA
NADPH
NAPH
NAT
NBB
NBM
N-CAM
NEI
NFT
NGF
NKB
NMDA
NOS
NP

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LIST OF ABBREVIATIONS

homovanillic acid
(= serotonin (5-hydroxytryptamine)
infundibulum
third ventricle
immunocytochemistry
intracerebroventricularly
infundibular nucleus
interferon 
insulin-like growth factor
intermediate hypothalamic area
interleukin-1
interstitial nucleus of the anterior
hypothalamus 1-4
inositol-(1,3,4,5)-tetrakisphosphate
Kallmans syndrome interval gene-1
locus ceruleus
leukocyte common antigen
luteinizing hormone
lateral hypothalamic area
luteinizing hormone-releasing hormone
(= gonadotropin-releasing hormone,
GnRH)
lipotropic hormone
lateral ventricle
lysine vasopressin
monoamine oxidase
microtubule-associated protein (A/B)
melanin-concentrating hormone
melanocortin1-4 receptor
3,4-methylenedioxymethamphetamine
(= ecstasy)
median eminence
multiple endocrine neoplasia
mitochondrial encephalopathy, lactic
acidosis and stroke-like episode syndrome
3-methoxy-4-hydroxyphenylglycol
major histocompatibility complex
medial preoptic nucleus
magnetic resonance imaging (fMRI =
functional MRI)
multiple sclerosis
-melanotropin
(messenger) ribonucleic acid
norepinephrine
nicotinamide adenine dinucleotide
nicotinamide adenine dinucleotide, reduced
form
N-acetyl-transferase
Netherlands Brain Bank
nucleus basalis of Meynert
neural cell adhesion molecule
neuropeptide glutamic acid isoleucine
neurofibrillary tangles
nerve growth factor
neurokinin B
N-methyl-D-aspartate
nitric oxide synthase
neuritic plaque

NPAF
NPY-IR
NSM
NST/NTS
NT
NT-3, 4/5
NTI
NTL
OC
ORL1
OT
OVLT
OXT
P
p75
PACAP
PAP
PBN
PC
PCR
PD
PDD
PDYN
PENK
PET
PHM
PNS
POAH
POMC
PSP
PVA
PVN
PWS
REM
RHT
RIA
RT-PCR
SAD
SCN
SDN(-POA)
SHBG
SIADH
SIDS
SN
SNP
SNRPN
SON
SOREMPS
SPECT
SRY
SSRI
SWS

neuropeptide AF
neuropeptide-Y-like immunoreactivity
nucleus septalis medialis
nucleus of the solitary tract
neurotensin
neurotrophin-3, 4/5
nonthyroidal illness
lateral tuberal nucleus/nucleus tuberalis
lateralis
optic chiasm
opioid receptor-like receptor
optic tract
organum vasculosum lamina terminalis
oxytocin
perikarya
low-affinity neurotrophin receptor
pituitary adenylcyclase-activating
polypeptide
peroxidase-anti-peroxidase
parabrachial nucleus
prohormone convertase
polymerase chain reaction
Parkinsons disease
pregna-4,20-diene-3,6-dione
prodynorphin
proenkephalin
positron emission tomography
peptide methionine amine
peripheral nervous system
preoptic anterior hypothalamic area
pro-opiomelanocortin
progressive supranuclear palsy
periventricular area
paraventricular nucleus
PraderWilli syndrome
rapid eye movement
retinohypothalamic tract
radioimmunoassay
real-time polymerase chain reaction
seasonal affective disorder
suprachiasmatic nucleus
sexually dimorphic nucleus (of the preoptic
area) = INAH-1
sex hormone-binding globulin
syndrome of inappropriate secretion
antidiuretic hormone
sudden infant death syndrome
substantia nigra
single nucleotide polymorphism
small nuclear riboprotein-associated
polypeptide
supraoptic nucleus
REM sleep onset periods
single-photon emission computed
tomography
sex-determining region Y
selective serotonin reuptake inhibitor
slow-wave sleep

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LIST OF ABBREVIATIONS

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T3
T4
TBS
TENS
TG
TH
THA
TH-IR
TMN
TR
TRH

triiodothyronine
thyroxine
Tris-buffered saline
transcutaneous electrical nerve stimulation
tuberal gray
tyrosine hydroxylase
tetrahydroaminoacrine
tyrosine hydroxylase-immunoreactive
tuberomamillary nucleus
thyroid hormone receptor
thyrotropin-releasing hormone

Trk A, B, C
TSH
VR1,2,3
VEP
VIP
VLPO
VMN/VMH
VP

tyrosine kinase neurotrophin receptor A,


B or C
thyrotropin
vasopressin receptor 1, 2 or 3
visual evoked potential
vasoactive intestinal polypeptide
ventrolateral preoptic region of the
hypothalamus
ventromedial nucleus
vasopressin

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)


The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved

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CHAPTER 17

Vascular supply and vascular disorders

. . . the vital spirit in the blood from the heart is changed


into animal spirit in the rete mirabile . . . (Anderson and
Haymaker, 1974)

from the internal carotid artery, the fetal configuration.


In the majority of cases, the P2 segment obtains its blood
primarily from the basilar artery, the adult configuration.
Multiple anomalies are found in 13% of the circles. The
incidence of all varieties of anomalous vessels is higher
in brains with infarcts than in control cases (Alpers
et al., 1959; Riggs and Rupp, 1963; Battacharji et al.,
1967), indicating that they are a risk factor for
pathological changes. The hypothalamic vessels the
anterior, middle and posterior groups receive their
blood supply both from perforating branches (Figs. 17.1,
17.3, 24.1, 24.2) derived from the circle of Willis and
from stems of cerebral arteries (see Chapter 17.1g; Table
17.1).
The preoptic and anterior parts of the hypothalamus
and the septal area are supplied mainly by the anterior
cerebral and anterior communicating artery. The tuberal
region and the posterior region extending backward to
the rostral part of the mamillary body, together with the
thalamus in its lower anterior quarter, are mainly supplied
by the posterior communicating artery. The posterior
portion of the hypothalamus is supplied with blood by
branches arising from the bifurcation of the basilar, posterior, cerebral and neighboring parts of the posterior
communicating artery. These vessels reach the hypothalamus mainly by way of the posterior perforated
substance and supply mamillary bodies, posterior and
lateral hypothalamic nuclei, and the subthalamus (Figs.
17.1, 17.3).
Venous drainage of the human hypothalamus takes
place via the anterior cerebral vein, the basal vein of
Rosenthal (Fig. 17.1) and the internal cerebral vein
(Fig. 17.3). These channels lead into the great cerebral
vein of Galen (for details, see Haymaker et al., 1969,
Chapter 5).

. . . the central nervous system regulates the activity of the


adenohypophysis by means of a humoral relay through
the hypophysial portal vessels (Green and Harris, 1947)

17.1. Blood supply to the hypothalamus and


pituitary
Arterial blood supply to the human hypothalamus is
derived from terminal branches of the internal carotid and
basilar arteries and from the anastomoses between them,
which form the arterial circle of Willis or circulus arteriosis ceribri (Fig. 17.1). Willis never claimed to be the
first to describe the circle, but he is still honored every
year on St. Martins day, the day he died in 1675
(Wolpert, 1997). In addition, the anastomotic arterial
circuminfundibular plexus and a prechiasmal anastomotic
arteriocapillary plexus can be considered as a source of
spare blood supply to the hypothalamus, should any of
the branches be occluded. There are many variations in
the pattern of the circle of Willis (Fig. 17.2). A normal
configuration of the circle of Willis occurs in less than
50% of subjects. The most frequent anomaly is a filiform
caliber of one of the component vessels in 27% of the
circles, most frequently localized in the posterior communicating arteries. A duplication of vessels is observed in
19%, the anterior communicating artery being the favorite
site for such accessory vessels. In 8% of the circles, a
midline, persistent corpus callosum branch is present. In
15% of cases, the supply to the postcommunicating part
(P2 segment) of the posterior cerebral artery is mainly
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Fig. 17.1. Hypothalamic and related vessels as viewed from the basal aspect of the brain: the circle of Willis. (From Haymaker et al., 1969,
Fig. 5.1 with permission.)

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Fig. 17.2. Anatomical variations in the circle of Willis. (From Alpers et al., 1959, Figs. 19 with permission.)

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D.F. SWAAB

Fig. 17.3. Arteries (red) of the hypothalamus and adjacent structures as viewed medially. Veins (blue) draining the superior and rostral parts of
the hypothalamus are illustrated. (From Haymaker et al., 1969, Fig. 5.2 with permission.)

(a) Stalk/median eminence region


After describing the origin of the portal vessels in the
median eminence in 1933, Popa and Fielding erroneously
deduced that blood in the portal vessels flowed upwards,
from the pituitary to the hypothalamus. On the basis of

histological observations Wislocki and King, in 1936,


proposed that the blood flow in the portal vessels (see
Chapter 17.1c) was downwards. In 1947 and 1949, using
a combination of india ink perfusion techniques and direct
microscopic observations in the living rat, Green and
Harris subsequently demonstrated that this was indeed

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TABLE 17.1
Arterial supply of the hypothalamus.
Anterior group of arteries
(from internal carotid,
anterior cerebral and
posterior communicating)

Intermediate group of arteries


(from posterior communicating

Posterior group of arteries


(from posterior communicating,
posterior cerebral and basilar)

Periventricular system
Suprachiasmatic nucleus
Medial preoptic area
Anterior area
Supraoptic nucleus
Paraventricular nucleus

Periventricular system
Lateral hypothalamic area

Infundibular nucleus
Ventromedial nucleus
Dorsomedial nucleus
Nuclei tuberis laterales
Posterior nucleus
Lateral mamillary nucleus
Medial mamillary nucleus
Supramamillary area

Periventricular system
Lateral hypothalamic area

Posterior nucleus
Lateral mamillary nucleus
Medial mamillary nucleus
Supramamillary area

From Haymaker, 1969, table 51, with permission.

rodents. One can, however, distinguish an upper


infundibular stem, located in the suprasellar region, which
contains the portal system, and a lower infundibular stem,
which contains the fibers running to the infundibular
process or neurohypophysis. The pars tuberalis of the
pituitary forms the most rostral boundary of the median
eminence (McKinley and Oldfield, 1990). The median
eminence gets its blood supply from the superior
hypophysial arteries that spring from the internal carotid
artery (Fig. 17.6; Daniel and Prichard, 1975). The portal
system is described in Chapter 17.1).

the case (for historical references, see Meites, 1992;


Raisman, 1997).
The median eminence is separated from the neighboring tuber by the sulcus infundibularis (Fig. 17.4) and
it is continued by the infundibular stem/stalk toward the
neural lobe. Thus the median eminence is made up of
the proximal segment of the neurohypophysis, attached
to the tuber, and this constitutes the walls of the
hypophysial recess (Duvernoy, 1972). The median
eminence is the site of neurosecretion of a number of
releasing and inhibiting hormones that are synthesized in
the hypothalamus and act on the adenohypophysis (see,
e.g. Chapter 11 for the infundibular nucleus and Chapter
8.5 for CRH and vasopressin from the paraventricular
nucleus). The neuropeptides are transported to the anterior pituitary gland by the portal system. On the other
hand, peptides produced by the supraoptic nuclei (SON)
and paraventricular nuclei (PVN), such as vasopressin
and oxytocin, are for the largest part transported to the
most distal part of the neurohypophysis, the infundibular
process, which is also known as the pars nervosa or the
posterior pituitary. At the outer surface of the human
hypothalamus, the median eminence is no longer evident,
since it is incorporated into the upper part of the
infundibular stem. There is also no strict delineation
between an internal and external zone as observed in, e.g.

(b) Pituitary
The pituitary derives its blood supply, directly or indirectly, from two main sources, one above and the other
below the level of the diaphragm sellae, i.e. the superior
and inferior hypophysial arteries, respectively (for review,
see Daniel and Prichard, 1975; Figs. 17.5 and 17.6).
Radiographic microvascular injections showed that the
inferior hypophysial artery is, in most cases, the dominant supply to both the neurohypophysis and the portal
system (Gebarski, 1993). The superior and inferior
hypophysial arteries are both paired vessels and spring
from the internal carotid artery on each side, the inferior
artery arising from the cavernous segment of the internal
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Fig. 17.4. Floor of the diencephalon in man. 1 = optic chiasm,


2 = posterior side of the median eminence and of the stalk crossed by
the portal vessels. The arrows indicate the sulcus infundibularis. 3 = postinfundibular eminence or posterior tuber, 4 = mamillary bodies, 5 =
optic tracts. (From Duvernoy, 1972, Fig. 24 with permission.)

carotid, and the superior artery having its origin shortly


after the carotid has emerged from the cavernous sinus
and passed through the dura mater, the supraclinoid part.
Both the superior and inferior hypophysial arteries anastomose with their contralateral counterparts. There is also
a substantial anastomotic channel which runs through the
pituitary gland and connects a branch of the superior
hypophysial artery with a branch of the inferior one, i.e.
the artery of the trabecula (Figs. 17.5, 17.6; Daniel and
Prichard, 1975).
(c) Portal system
The primary plexus of the portal system is made up of
two vascular systems that are intricately linked: the
surface network (the rete mirabile of Galenus) and the
deep network. The surface network (or mantel plexus)
covers the surface of the median eminence. From this
network stem numerous short capillary loops that penetrate into the median eminence, where neurosecretory
substances are released into them (Duvernoy, 1972). Cajal
has already described hypothalamic nerve fibers that
terminate on the capillaries of the median eminence, while

Fig. 17.5. Blood supply of the human pituitary gland and hypothalamus
(sagittal sections). The sinusoids of the pars distalis are supplied by
two types of portal vessels: (i) long portal vessels (LPV) draining capillary loops (C) in the upper infundibular stem (i.e. neural tissue of the
stalk); and (ii) short portal vessels (SPV) draining capillary loops in
the lower infundibular stem. Cap, capillary bed; H, hypothalamic
neurons; IHA, inferior hypophysia artery; P, primary capillary bed;
SHA, superior hypophysial artery. For other details see legend to Fig.
17.6. (From Daniel and Prichard, 1975, Fig. 36 with permission.)

Harris and Campbell (1966) have shown that these capillaries are of the specialized fenestrated type also found
in other secretory and absorptive organs. Here, the
bloodbrain barrier is permeable to larger molecules.
The deep network is divided into a long capillary loop
and a huge subependymal capillary network connected
to the rest of the primary portal plexus (Duvernoy,
1972). The deep network is made up of voluminous
twisted capillaries. These capillaries are often situated
transversally under the ependyma, which lines the pars
caudalis tuberis (Fig. 17.7). Those situated near the posterior insertion of the median eminence are drained
exclusively into the portal system. However, most of the
posterior capillary formations are drained both toward
the portal system and towards the lateral hypothalamic
veins (Fig. 17.8). The capillaries near the mamillary
bodies have a blood supply and drainage that are
exclusively in the direction of the hypothalamus and independent of the portal system (Duvernoy, 1972). The main
feature of the deep network is the large number of coiled

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Fig. 17.6ad. Neoprene latex-injected preparations of the human pituitary gland which show some of the main features of the vascular arrangements. (a) The pituitary gland and neighboring structures are viewed from the front. The superior hypophysial artery (SH) is seen springing from
the internal carotid artery (IC) on each side, anastomosing in front of the pituitary stalk (S), and giving off branches to supply a primary capillary bed (not visible here) within the stalk. The long portal vessels which drain this bed and run down the stalk into the pars distalis are better
seen in (b). The artery of the trabecula (AT), seen also in (b), although plunging into the pars distalis, does not deliver blood directly to this lobe,
which has a purely portal venous blood supply. O, ophthalmic artery; OC, optic chiasma. (b) A similar preparation, partially macerated to show
the long portal vessels (LPV) running down the stalk (S) and breaking up into the sinusoids (Si) of the pars distalis. AT, artery of the trabecula.
(c) Sagittal section of a stalk (anterior surface on right) in which the blood vessels have been displayed by a red cell staining method (benzidine).
Note the convoluted capillary loops (C), which are typical of the primary capillary bed in the stalk, draining into a long portal vessel (LPV). One
of these capillary complexes is elongated into a spike (Sp) such as the one seen in (d). (d) Neoprene cast of a long spike of convoluted capillaries (C) taken from an injected stalk (all tissue has been macerated). The afferent artery (A) to this capillary complex, and the long portal vessel
(LPV) into which it drains, are both seen. (From Daniel and Prichard, 1975, Fig. 18 with permission.)

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Fig. 17.7. Vascularization of the floor of the diencephalon in human. cho, optic chiasm; bo, optic tracts; pc, section of the mesencephalon; cm,
mamillary bodies; t, hypophysial stalk; si, sulcus infundibularis. A dotted line surrounds the place occupied by the postinfundibular eminence (PIE).
Only the deep network is shown in this drawing. 1 and 19, arterioles which supply the PIE; 2, deep network exclusively drained by tuberal veins
(39); 4 and 49, deep capillary network with mixed drainage via lateral tuberal veins and via long posterior portal vessels (5); 59, branch of a
portal vessel draining the surface network; this network is not shown in this drawing; 6, deep network exclusively drained toward the hypophysis
by portal vessels (5); 7, branch of the superior hypophysial arteries which bend over and reach the deep network of the median emincence
(8); this network is drained by deep portal vessels (9). (From Duvernoy, 1972, Fig. 25 with permission.)

capillary loops of characteristic form and varying degree


of complexity which are seen in the neural tissue of the
upper infundibular stem (Fig. 17.8). Fed by terminal
branches of the superior hypophysial artery, these capillary loops form a 12 mm long and 50100 m wide
corkscrew of capillaries, called gomitoli by Fumagalli
(1942; for reference, see Daniel and Prichard, 1975), and
they form part of a first capillary bed in a portal system
of circulation.
Apart from a few vessels near the junction of the stalk
with the hypothalamus, the loops drain through long,
straight vessels of the venous type, which run down the

stalk into the anterior pituitary and empty there into a


second capillary bed. These straight efferent channels are
the long portal vessels of the hypophysial portal system,
which provide the pars distalis with by far the greater part
of its exclusively portal blood supply, serving its anterior
and lateral regions. The majority of the long portal vessels
are found on the anterior and lateral aspects of the stalk
within the superficial sheath of the pars tuberalis, but some
lie at a deeper level and others on the posterior surface
of the stalk, even where there are no epithelial cells of
the pars tuberalis. At the upper extremity of the stalk, a
few of the capillary loops drain upwards into veins in the

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Fig. 17.8a, b. A median sagittal section of the floor of the third ventricle. The following elements are shown (from left to right): OCH, optic
chiasm; ME, median eminence; IR, infundibular recess; S, stalk; PIE, postinfundibular eminence (posterior tuber) separated from the median
eminence by the sulcus infundibularis (SI); MB, mamillary body; 3eV, third ventricle. Vascular tuberohypophysial connections: (a) Anterolateral
connections. 1, capillary tufts which belong to the deep network of the primary plexus and which are supplied by the tuberal arterioles (downward-pointing arrow). These tufts have some veinules which join the tuberal veins (upward-pointing arrow); 2, portal vessels; 3, surface network
and its drainage. (b) Posterior connections. 4, superficial network lining the PIE. It continues toward the superficial network of the primary plexus
(5); 6, portal vessel; 7, drainage of the surface network by a tuberal vein; 8, deep network which is exclusively drained by tuberal veins (arrows);
9, deep network with a mixed drainage toward the hypophysis (arrow). (From Duvernoy, 1972, Fig. 23 with permission.)

tuber cinereum, but apart from this there is no outflow of


blood from the capillary bed of the stalk into the systemic
venous circulation (Daniel and Prichard, 1975).
In the lower infundibular stem, i.e. where the hypothalamo-neurohypophysial tract runs down the stalk and
bends sharply backwards to approach the infundibular
process, the vascular pattern is also characteristic (Fig.
17.8). There are many short, parallel vessels running into
the tissue from below and in front, and ending in coiled

capillary loops similar to those of the pituitary stalk. These


capillary loops can receive their blood supply from either
the inferior or the superior hypophysial arteries, as their
afferent vessels spring from an artery deep within the
gland which is continuous at one end with a branch of
the inferior or the superior hypophysial artery and at the
other with a branch of the superior hypophysial artery,
the artery of the trabecula. The efferent limbs of small
groups of these capillary loops join together to form short
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portal vessels that open into the sinusoids of the adjacent


part of the pars distalis. Apart from their smaller size,
these short portal vessels are similar to the long portal
vessels. There is no drainage from the lower infundibular
stem into systemic veins.
There are also connections between the vessels of the
portal plexus and those of the posterior tuber (Figs.
17.417.8). In the posterior tuber there is a vascular
formation whose pattern differs from that of the other
hypothalamic vessels. The meshes of the surface network
in this area are generally smaller than those of the more
rostral mantel plexus. From this network stem numerous
short capillary loops that penetrate the hypothalamus near
the infundibular nuclei. In this respect the conspicuous
neurofibrillary pathology, characterized by terminal-like
processes contacting the neurohemal vasculature of the
infundibular nucleus, is of interest (Chapter 11g). This
neurofibrillary degeneration is largely restricted to males
over the age of 60 years and seems to be located in the
terminals of neurosecretory neurons, whose chemical
nature still has to be established (Schultz et al., 1996,
1997a, b, c; see also Chapters 11 and 28.1).
(d) Infundibular process
The infundibular process or posterior pituitary has the
conventional arteryvein pattern of circulation. Its abundant network of capillaries, which are much smaller in
calibre than the sinusoids of the pars distalis, is fed by
offshoots from branches of the inferior hypophysial artery
which encircle the lobe. The drainage of this capillary
bed is through veins which empty into one of the
surrounding venous sinuses (Daniel and Prichard, 1975).
The neurovascular zone behind the tuber cinereum
extends almost to the mamillary bodies and it often
contains islands of pars tuberalis glandular cells, but this
is by no means a constant finding. The zone mainly
consists of blood vessels surrounded by connective tissue
sheets in which smooth muscle cells, collagen and reticular fibers may be recognized, and by perivascular
plexuses of nerve fibers. The contralateral connections
between the tuberal vessels and the primary portal plexus
are even more numerous in humans than in other
mammals. The descending connections, by far the more
numerous, are formed of tuberal arterioles that supply the
capillary tufts of the deep network. The very rare small
veins that form the ascending connections merge into
superficial retrochiasmatic veins (Fig. 17.8) (Duvernoy,
1972).

(e) Artery of the trabecula


A macroscopic view of the pituitary gland would suggest
that the artery of the trabecula (the loral artery), a branch
of the superior hypophysial artery that plunges into the
pars distalis from above (Fig. 17.6), carries arterial blood
to this lobe. However, dissection of injected tissues has
shown that the artery of the trabecula does not break up
into sinusoids; it merely passes through the pars distalis.
In a core of fibrous tissue, the trabecula, on its way to
supply capillary loops in the lower infundibular stem,
anastomoses with a substantial branch of the inferior
hypophysial artery that comes up to join it from below
(Fig. 17.6). Usually the artery of the trabecula gives off
one branch which runs toward the stalk near the upper
surface of the pars distalis to supply some of the capillary loops in the lower part of the stalk. The blood
circulating through the sinusoids of the pars distalis
thus seems to be solely portal venous blood. However,
in some instances a very short arterial twig, either from
the artery of the trabecula or from the dura mater
surrounding the gland, may penetrate among the immediately adjacent epithelial cells. The blood supplied
by these twigs is confined to very small areas and only
reaches the sinusoids immediately surrounding them
(Daniel and Prichard, 1975).
(f) Vascular bed of the pars distalis
The vascular bed of the pars distalis consists of a dense
network of freely anastomosing vessels, interspersed
amongst the parenchymal cells. These sinusoids, which
are larger than capillaries, receive no arterial blood, but
are fed solely by the long or the short portal vessels which
bring to them blood which has already passed through a
primary capillary bed in the infundibular stem, where the
hypothalamic releasing and inhibiting hormones are transmitted into the blood stream (Daniel and Prichard, 1975).
Indeed, magnetic resonance imaging (MRI) studies have
shown contrast material flowing from the median
eminence to the adenohypophysis in vivo in humans
(Gebarski, 1993). In contrast, in vivo collection of blood
from the pituitary stalk using transphenoidal microsurgery
again suggested the possibility of retrograde blood flow
from the pituitary to the hypothalamus. Using microsuction and hormone assays of LH, FSH, prolactin, growth
hormone, TSH and ACTH immediately after pituitary
tumor removal showed 50600 times higher levels in
pituitary stalk blood than in peripheral blood. Apart from

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retrograde blood flow from the pituitary, the authors


think that a hypothalamic secretion of these hormones
may cause these high levels. It should be noted, though,
that the aspiration technique used in that study might
have interfered with the normal direction of the
blood flow, and that aspiration took place after tumor
resection, which might also have disturbed the normal
flow.
The studies of Daniel and Prichard (1975) have shown
that the two groups of portal vessels, long and short,
each have their own territories of distribution in the
pars distalis; the long portal vessels supply the bulk of
the lobe, the short portal vessels supplying only the
region adjacent to the lower infundibular stem and
the infundibular process. This observation was originally
derived from a study of injected preparations but was
subsequently confirmed by the distribution of necrotic
and living areas found in patients subjected to pituitary
stalk section, an operation in which the long portal vessels
are severed, but the short portal vessels, together with
their afferent supply, remain intact. Having passed
through the sinusoids of the pars distalis, the blood is
collected by small venules at the periphery of the lobe
and finally empties into one of the venous sinuses that
surround the pituitary gland (Daniel and Prichard, 1975).

13

1960). The precommunicating part of the anterior cerebral


artery supplies the nucleus basalis of Meynert. It was
hypothesized that the decrease in perivascular nerve
density in this segment in Alzheimers disease may be
related to the decreased neuronal metabolic activity in
this region (Bleys and Cowen, 2001). Isolated hypothalamic infarction is an uncommon event, due to the rich
vascular supply of this region. Anteromedial arteries arise
from the anterior cerebral artery and supply the anterior
hypothalamus. Posteromedial hypothalamic perforating
arteries arise from the proximal portion of the posterior
cerebral artery at the bifurcation of the basilar artery and
supply the posterior hypothalamus. Short hypothalamic
arteries branch off from the posterior communicating
artery. In the case of fetal configuration of the posterior
bifurcation of the posterior communicating artery, which
occurs in 15% to 30% of all individuals, the blood supply
to the hypothalamus can arise solely from the carotid
system and may thus be more liable to embolic infarction
(Crompton, 1963; Rudelli and Deck, 1979; Austin and
Lessell, 1991).
(h) Optic chiasm
The arterial supply of the human optic chiasm comes
from a superior and inferior group of branches of the
circle of Willis. The superior group of vessels is derived
from the two anterior cerebral arteries and occasionally
from the anterior communicating artery above the optic
pathways. The inferior group is derived from the basilar,
the posterior communicating, the posterior cerebral and
the internal carotid arteries (Figs. 17.1, 17.9). The superior group of arteries supplies all optic nerves and tracts,
but only the lateral portions of the optic chiasm. The
decussating fibers in the central chiasm receive their arterial supply solely from the inferior group. In addition,
the inferior group supplies the optic nerves and tracts.
During pituitary tumor surgery, the inferior vessels were
often distorted, suggesting that the bitemporal hemianopsia caused by pituitary tumors can be the result of
ischemia by vascular compression rather than neural
compression (Dawson, 1958).

(g) Hypothalamus
The vascular supply of the anterior hypothalamus takes
place by means of fine arterial branches that arise from
the internal carotid artery, the anterior and posterior
communicating arteries, and the proximal portion of the
anterior cerebral artery (Table 17.1). One to three perforating arteries arise from the anterior communicating
artery and penetrate the floor of the third ventricle through
the optic tracts and anterior perforated substance (Figs.
17.1, 17.3; Crompton, 1963; De Divitiis et al., 2002).
Injection of the anterior cerebral artery has been
performed up to the point of the anterior communicating
artery, which includes the recurrent artery of Heubner
that arises just proximal to the anterior communicating
artery, courses backwards and enters the brain in the
region of the anterior perforated area. The anterior
hypothalamic nuclei, including the preoptic areas, the
paraventricular and supraoptic areas up to the region of
the infundibulum, the ventromedial and, to a lesser extent,
the dorsomedial areas, were constantly injected. The hypothalamic region thus appeared to be irrigated by a few
branches from the artery of Heubner (Ostrowski et al.,

(i) Lamina terminalis


The lamina terminalis (see Chapter 30.5b for details on
its vascularization), which covers the suprachiasmal
extension of the third ventricle, separates the lateral
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Fig. 17.9. The visual pathways and their arterial supply. It is apparent that the visual pathways pass through the circle of Willis, and the arterical
supply can be divided into a superior and an inferior group. The superior group of vessels is derived from the anterior cerebral arteries (ACA)
and spares the central chiasm. The inferior group of vessels is derived from the internal carotid artery (ICA), the posterior cerebral artery (PCA)
and the posterior communicating artery. The central chiasm containing the decussating fibers derives an arterial blood supply only from the
inferior group of vessels. (Fig. 2 from Bergland and Bronson, 1969 with permission.)

groups of arteries that descend from the anterior cerebral


arteries to the lateral portion of the chiasm. Indeed,
the lamina terminalis and underlying recess preclude
the superior group of vessels from directly contribut-

ing to the arterial supply of the central portion of


the chiasm. A surgical approach fenestrating the
lamina terminalis can be virtually bloodless (Katayama
et al., 1994; Chapter 17.2d) and is frequently

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used for lesions that occur within the anterior third


ventricle or invade or compress the walls of the chamber
(De Divitiis et al., 2002).

15

crucial role in the development of intracranial arterial


spasm that is most marked in the anterior part of the
circle of Willis is supported by a number of observations. If vasospasm develops, such an autonomic effect
may occur preferentially after the rupture of aneurysms
in locations adjacent to the hypothalamus that involve
vessels that supply the hypothalamus. There is also postmortem and postoperative evidence for such a mechanism.
The ischemic lesions may be not only ipsilateral to the
lesion, but also bilateral. Autonomic dysfunction or a
hypothalamic basis are also apparent from ECG changes
following the rupture of an aneurysm. Various pathogenetic mechanisms that cause the hypothalamic injury
and subsequently intracranial arterial spasm have been
proposed (Wilkins, 1975). There is a marked preponderance of microhemorrhages in the SON, and they are also
more severe than the microhemorrhages that occur in the
PVN. This may be due to the location of the SON close
to the pia. The highly vascularized nature of the SON
and PVN seems to make them more prone to microhemorrhages than the other nuclei of the hypothalamus.
Hypothalamic lesions generally occur together with
lesions in the cortex and basal ganglia (Crompton, 1963;
Neil-Dwyer et al., 1994).

17.2. Vascular lesions of the hypothalamus


(a) Subarachnoidal aneurysm
The hypothalamus is occasionally damaged by ruptured
subarachnoidal aneurysms of the circle of Willis (for
review, see Crompton, 1963). A number of aneurysms,
such as those arising from the bifurcation of the internal
carotid artery, may become buried in the anterior hypothalamus. Others, such as those arising from the anterior
or posterior communicating artery, may bleed directly on
the fine arterial branches that arise from the circle of
Willis and in this way supply the hypothalamus.
Crompton (1963) has reported on a consecutive series of
106 autopsies on patients dying after the rupture of berry
aneurysms, 61% of whom were found to have hypothalamic lesions. He confined his studies mainly to the
anterior part of the hypothalamus, where the majority of
lesions were found. The highest incidence of hypothalamic lesions was found in the case of aneurysms at the
anterior or posterior communicating arteries. Although
basilar artery aneurysms characteristically damage the
mamillary bodies, they may produce lesions much further
toward the front of the hypothalamus. Saccular aneurysms
may act like pituitary adenomas and cause irreversible
hypopituitarism. Such aneurysms have been described as
complications of yttrium-90 implantation for pituitary
adenomas (Horvath et al., 1997).
The hypothalamic lesions caused by ruptured
aneurysms were usually ipsilateral to the ruptured
aneurysm, or bilateral, especially with aneurysms situated
in the midline. The majority of cases involved ischemic
lesions. Microhemorrhages were not as common, and
massive hemorrhages involved the hypothalamus in only
a small number of instances. Microhemorrhages depend
to a large degree on the close proximity of the bleeding
aneurysm, whereas ischemic lesions may, in addition,
depend on vascular hypotension and arterial vasoconstriction or spasm, which may occur contralateral to the
aneurysm (Crompton, 1963). Acquired ischemic deficits
account for about 30% of the early complications of a
subarachnoidal hemorrhage (Neil-Dwyer et al., 1994).
The hypothesis that hypothalamic injury due to subarachnoidal hemorrhage or craniocerebral trauma plays a

(b) Infarction and hemorrhage


The most common lesion in the infundibulum is an infarction, taking the form of small areas of necrosis, usually
in the midline of the tuber cinereum or upper infundibular
stem. These infarcts are characterized by a pooling of
neurosecretory material around their periphery and by the
presence of adjacent axonal swellings. Occlusion of the
proximal part of the anterior cerebral artery due to occlusive arteriosclerosis may cause emotional changes,
including weakness, anxiety and poor cognitive skills and
personality disorders (Ostrowski et al., 1960; Webster et
al., 1960). Ischemic lesions may be at least part of the
basis of the neuronal damage found in the nucleus basalis
of Meynert and the reduced choline acetyltransferase
activity in the cerebral cortex observed after fatal head
injury (Murdoch et al., 2002).
Horners syndrome has been reported due to an ipsilateral posterior hypothalamic infarction that occurred in
the absence of other signs of hypothalamic dysfunction.
Symptoms of extension of the infarct into the posterior
limb of the internal capsule (i.e. contralateral faciobrachial
weakness and dysarthria) were present. Occlusion of a
hypothalamic branch of the posterior communicating
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artery was the likeliest cause of the infarction. Horners


syndrome can result from an interruption, at any point,
of the sympathetic pathway from the hypothalamus to the
orbit. Hypothalamic Horners syndromes are most often
caused by diencephalic tumors and hemorrhages, and least
often by infarction (Austin and Lessell, 1991).
In addition, a case of a highly selective anterior
hypothalamic infarction has been described as a result of
avulsion of part of the optic chiasm, together with the
anterior perforating arteries passing through it. Following
the assault, symptoms such as altered thermoregulation,
alternating diabetes insipidus and inappropriate antidiuretic hormone secretion, altered patterns of sleep and
arousal, and changing cardiac arrhythmias were found
(Rudelli and Deck, 1979). In a child in which perinatal
hypoxia was followed by hypothalamic hemorrhage, West
syndrome with gelastic seizures was found (Kito et al.,
2001; Chapter 26.2). In the pituitary stalk, linear and
petechial hemorrhages or later scarring may be seen.
Hemorrhages may also occur in the ventromedial nuclei
and corpora mamillaria (Treip, 1970b). Trauma may cause
posterior lobe hemorrhage, ischemia in the anterior
hypothalamus and destruction or avulsion of the pituitary
stalk, followed by hypopituitarism. Posttraumatic diabetes
insipidus is generally transient (Horvath et al., 1997).
Subcortical infarctions may also impact the blood
supply of the hypothalamus and interrupt the function of
the suprachiasmatic nucleus, as indicated by the greater
daytime sleepiness of these stroke patients (Bliwise et al.,
2002).
Subependymal hemorrhages around the third ventricle
are a common occurrence and may also impinge upon
the PVN. In 90% of the cases, subarachnoid hemorrhage
is accompanied by ischemic lesions of the hypothalamus:
small perivascular hemorrhages and edema of the
surrounding tissue were found in the periventricular
region, including the PVN and SON. It is hypothesized
that prolonged sympathetic activity in these patients
would cause vasoconstriction, and thus lesions in the
hypothalamus and myocard (Doshi and Neil-Dwyer,
1977). Vasopressin plasma levels have been reported to
be increased in patients with subarachnoid hemorrhage
(Mather et al., 1981), but these findings were not
confirmed by others (Franceschini et al., 2001). For
hemorrhages in the neurohypophysis, see Chapter 22.1.
Hemorrhagic lesions in the subthalamic nucleus may
cause hemiballismus, usually at the contralateral side of
the body, characterized by violent, involuntary, wild
flinging movements (Parent and Hazrati, 1995).

Multiple endocrine abnormalities have been reported


in stroke patients, namely: absence of a sleep-related
increase in growth hormone plasma levels, elevated
prolactin nocturnal release, and blunted serotonin-mediated prolactin release, low basal thyroid-stimulating
hormone levels, impaired thyrotropin-releasing hormonestimulated secretion of thyroid-stimulating hormone, and
increase in beta-endorphin cerebrospinal fluid levels.
Abnormalities of the pituitary-gonadal axis, in particular
high LH serum levels and low serum testosterone levels,
have also been reported. Furthermore, disruption of some
biological rhythms, namely of beta-endorphin and melatonin, have been described. In the past few years, attention
has also been devoted to the clinical significance of these
endocrine abnormalities, particularly with regard to the
possibility that they may worsen the extension of the
ischemic area and outcome of stroke.
In unprecedented ischemic cerebral infarction patients,
mean 24-hour plasma vasopressin levels were higher than
in control subjects, and correlated with the severity score
of the neurological deficit and with the mean size of the
lesion. The increase occurred independently of osmotic
and/or baroreceptorial mechanisms, which are known to
be the major stimuli for vasopressin secretion. Various
mechanisms may account for increased vasopressin secretion during stroke. The heightened intracranial pressure
may contort the pituitary stalk and interfere with the regulation of vasopressin release from the posterior pituitary.
Alternatively, a release of neuromodulators from the periinfarct lesion into the third ventricle and affecting the
cells within the magnocellular nuclei may be suggested.
It may also be so that in the course of cerebral ischemia
an increased serotoninergic and/or a decreased dopaminergic tone may induce an enhanced vasopressin release
from the hypothalamus (Franceschini et al., 2001).
(c) Systemic atherosclerosis
Whether or not accompanied by arterial hypertension,
systemic atherosclerosis is accompanied by degenerative
and chronic ischemic neural alterations, which are most
marked in the ventromedial nucleus. Ischemic-atrophic
lesions, sometimes with nuclear cytoplasmatic vacuolation, and neuronal hyperchromasia with or without glial
satellitosis were observed. The SON and PVN tended to
show degeneration as well as an intense accumulation of
lipofuscin in the cytoplasm. In addition, hyperplastic
astrocytes, denoting glial reaction, were found around

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small vessels, as an expression of chronic tissular anoxia.


The reactive protoplasmic astrocytes appeared more in
the subependymal paraventricular region. In all cases of
atherosclerosis, vascular alterations occurred, i.e. thickening of the intima, and hyalinosis and sclerosis of the
small vessels (Kelemen and Becus, 1977). The deep
perivascular nerves of the basal arteries of the circle of
Willis show changes with aging and Alzheimers disease.
The precommunicating part of the anterior cerebral artery
is involved in the vascular supply of the substantia innominata (Bleys et al., 1996) and suggests a relationship
between vascular changes and the decreased neuronal
activity in the nucleus basalis of Meynert (Salehi et al.,
1994, 1998).

17

(e) Radiation therapy


Radiation therapy may lead to delayed vascular complications such as obliteratur vasculopathy. Radiationinduced microscopic vascular anomalies or telangiectasia
may cause hemorrhages. In addition, intracranial fusiform
aneurysms may be formed. In chronic occlusive large
vessel disease of arteries of the circle of Willis that occurs
as a result of radiation therapy, an abnormal network
(moyamoya) may develop at the base of the brain
(Sinsawaiwong and Phanthumchinda, 1997). Moyamoya
disease may also develop following a basal meningitis
(Vrs et al., 1997), but the etiology of this vessel abnormality is unknown in most cases. The peak incidence
occurs in the first decade and there is a female predominance. In children, moyamoya disease presents most
commonly with transient ischemic attacks, and these
children may have seizures. It begins with stenosis of the
carotid fork and progresses to complete occlusion of the
middle and anterior cerebral arteries with the formation
of a vascular network of collaterals. The children may
present with decreased growth velocity, growth hormone
deficiency and hypothyroidism (Mootha et al., 1999).
Moyamoya vessels may also have a prenatally determined
origin, and some data point to a genetic basis of
moyamoya disease (Vrs et al., 1997). Rupture of the
overgrown perforating arteries that function as collaterals
may be the main cause of single or repeated cerebral
hemorrhage in moyamoya disease. The formation of a
collateral network is accompanied by aneurysms, arteriovenous malformations and ectasia or fenestration of the
cerebral arteries.

(d) Cavernous malformation


Cavernous malformation can occur at any location in the
central nervous system, including the pineal, chiasmatic
and optic nerve regions. Cavernous malformations
involving the third ventricle are rare, but several cases
have been reported. The clinical manifestations may
be visual field defects, endocrine function deficits and
hydrocephalus in those with malformation of the foramen
of Monro region, and deficits of short-term memory in
those with malformations of the lateral wall or floor of
the third ventricle. Malformations of the third ventricle,
unlike malformations in other brain regions, frequently
show rapid growth and mass effects. Cavernous malformations are known to increase in size during pregnancy
and to decrease after delivery. Rapid growth of cavernous
malformations is attributable to repeated intralesional
hemorrhages, but extra lesional hemorrhages are also not
uncommon. The treatment of this particular group of
malformations will thus have to consist of a more
aggressive approach. The risk of regrowth and extralesional hemorrhage appear to be reduced by complete
excision by means of the translamina-terminalis approach
for the suprachiasmatic region, the transventricular
or transcallosal interfornical approach for the foramen
of Monro region and the transvelum interpositum
approach for the lateral wall of the third ventricle
(Katayama et al., 1994). Later a successful zygomatic
approach using a Neuro-navigator was reported for the
treatment of a deep-seated cavernous angioma.
(Kurokawa et al., 2001). For a case of cerebrovascular
cavernous malformation in the mamillary bodies, see
Chapter 16.d.

17.3. Choroid plexus of the third ventricle


Choroid plexus tissue is found in the roof of the third
ventricle. It is made up of elements from the
leptomeninges and the ependyma. Highly vascularized
tela choroidea evaginates and acquires an epithelium to
form the choroid plexus. The choroid plexus is involved
in the production of cerebrospinal fluid (CSF), largely
due to the secretion of hypertonic saline, which is then
brought to isotonicity by diffusion of water through the
ependymal cells. The water channels aquaporin-1 and -4
are expressed in the choroid plexus, where they may play
a role in CSF formation (Venero et al., 2001). Moreover,
microvilli of the choroid plexus may be involved in readsorption. The choroid plexus is a finely regulated selective
interface for the delivery of nutrients, hormones and
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trophic factors, as well as for the transduction of peripheral signals, an enzymatic protective barrier, a clearance
site for deleterious compounds and catabolites, and an
immunologically active interface (for review, see
Strazielle et al., 2000). The capillaries of this tissue have
larger diameters (1020 m) than regular capillaries and
have been designated sinusoids. The vascular endothelium is fenestrated (McKinley and Oldfield, 1990). The
CSF-generating choroid plexus has many V1 binding sites
for vasopressin. Vasopressin decreases the CSF formation rate and elicits structural changes in the rat choroid
plexus (Johanson et al., 1999). In the choroid plexus of
the lateral ventricle of Alzheimer patients, we found an
increase in vasopressin-binding sites (Korting et al.,
1996). The functional meaning of this alteration is not
clear at present. The choroid plexus of the third ventricle
has not yet been studied.
(a) Colloid cysts
Colloid cysts of the third ventricle (Fig. 17.10) are slowgrowing, benign tumors that typically have an onset
between 20 and 55 years of age. The incidence is approximately 1:1000, which makes it the most common tumor
of the third ventricle. Occasionally colloid cysts can be
identified at autopsy, as was the case with Harvey Cushing
himself (Akins et al., 1996). Colloid cysts of the third
ventricle are sometimes more conspicuous on CT than
on MRI. There is a controversy about the origin of these
cysts. It has been suggested to be a remnant of the paraphysis, which is situated at the rostral end of the
diencephalic roof and which disappears completely prior
to birth. However, this theory was challenged by Arins
Kappers (1955). In his opinion, paraphyseal cystic tumors
developing from the choroidal fold between the foramina
of Monro in the third ventricle in the adult human brain
are, for the most part, not of paraphyseal origin but arise
from detached and degenerated embryonic diencephalic
vesicular recesses included in the choroidal fold. An endodermal nature of the cysts has also been proposed.
Another possible origin could be from the diencephalic
ependymal pouches or choroid plexus. However,
immunocytochemical and ultrastructural evidence argues
against a simple choroid plexus or ependymal origin
(Akins et al., 1996). Colloid cysts usually range from a
few millimeters to 9 cm in size. They are composed of
fibrous connective tissue wall lined by squamous,
columnar epithelial cells enclosing a homogenous gelatinous material of cellular debris and eosinophilic

substance. By a narrow pedicle or broad base, the cysts


are attached to the choroid plexus at the superior anterior roof of the third ventricle, immediately posterior to
the foramina of Monro (Gkalp et al., 1996; Hwang et
al., 1996; Fig. 17.10). The cyst wall may occasionally be
calcified (Yceer et al., 1996). The symptoms are generally attributed to acute hydrocephalus. Head positional
changes can usually alleviate the symptoms, but a case
has been described of colloid cyst rupture while disco
dancing (Akins et al., 1996). The classic symptoms
consist of intermittent paroxysmal headaches with nausea,
papilledema and vomiting. Transient diplopia, blurry
vision, dizziness, weakness and paresthesia of the extremities, gait disturbances, fever, drop attacks, loss of
consciousness, dementia, cognitive state changes and
unexpected sudden death have also been reported. The
colloid cyst may apply direct pressure on the autonomic
centers of the hypothalamus. In the absence of hydrocephalus, patients with colloid cysts may manifest
disturbances of memory, emotion and personality and
even psychosis, possibly due to compression of the
hypothalamus. Colloid cysts have been approached neurosurgically by different routes. The morbidity and mortality
rates, however, are considerable. Ventricular shunting has
been proposed, but this does not eliminate the cyst. In
addition, CT-guided stereotaxic aspiration has been used
successfully in some patients. Recurrent cysts following
previous aspiration procedures have been reported
(Lobosky et al., 1984; Nitta and Symon, 1985; Mathiesen
et al., 1993; 1997; Lewis et al., 1994; Cabbell and Ross,
1996; Filkins et al., 1996; Gkalp et al., 1996; Hwang et
al., 1996; Carson et al., 1997; Ferrera et al., 1997; Young
and Silberstein, 1997). A few cases of familial colloid
cysts of the third ventricle have been described. These
rare cases suggest that genetic factors may play a role
in the pathogenesis of these cysts. Consistent with the
idea that colloid cysts are developmental abnormalities
is the fact that they are sometimes associated with
a variety of congenital defects (Akins et al., 1996;
Vandertop, 1996).
(b) Xanthogranuloma
Xanthogranuloma of the third ventricle is considered to
be a degenerated colloid cyst (for a xanthogranulomatous
change of a craniopharyngioma, see Chapter 19.5c).
The xanthogranulamatous changes occur following
hemorrhage and macrophagic reaction. The wall shows
aggregations of pale foaming cells, hemosiderin-laden

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Fig. 17.10. Colloid cyst of the third ventricle. Sagittal T-weighted (TR 500 ms; TE 15 ms, flip angle 90) (a) and coronal T1-weighted (TR 600
ms; TE 15 ms) (b) images show that the lesion is diffusely hyperintense. (From Gkalp et al., 1996, Fig. 1 with permission.)

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macrophages, lymphoplasmatic chronic inflammatory


infiltrate, cholesterol clefts and foreign body-type giant
cells (Kudesia et al., 1996). A case has been reported of
xanthogranuloma with massive hematoma in the third
ventricle. The 35-year-old woman had a history of 1
month of progressively deteriorating consciousness. The
mass in the third ventricle that produced obstructive
hydrocephalus was successfully removed (Tomita et al.,
1996).
(c) Choroid plexus papilloma
Choroid plexus papillomas are more common in children
than in adults, and the children usually present with signs
and symptoms of increased cranial pressure due to
obstructive hydrocephalus. Macrocranium and sunset eyes
are found, while vomiting or developmental delay are
especially seen in children over 2 years of age. A shunting
procedure is frequently required. Choroid plexus papilloma is generally a histologically benign and slowly
growing tumor, although rapid growth has been described.

They often extend into the lateral ventricle through the


foramen of Monro. In a 2-year-old boy, episodic rightward anterolateral head tilt and large-amplitude positional
anteroposterior head-bobbing reminiscent of the bobblehead doo syndrome has been described, which was due
to a cystic choroid plexus papilloma that had arisen within
the left lateral ventricle but slipped into the third ventricle
through the foramen of Monro. Other clinical features
that have been described with the third ventricle papillomas include autonomic diencephalic seizures of
Penfields type, endocrine disturbances and menstrual
irregularities, obesity, precocious puberty, diabetes
insipidus, behavioral problems and psychosis (see Chapter
27.1). In one case the choroid plexus papilloma was not
attached to the choroid plexus but to the brain parenchyma
at the surface of the posterior commissure (Fortuna et al.,
1979; Jooma and Grant, 1983; Schijman et al., 1990;
Pollack et al., 1995; Shuto et al., 1995; Carson et al.,
1997; Costa et al., 1997a; Nakano et al., 1997). For third
ventricle chordoid glioma, see Chapter 19.10.

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)


The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved

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CHAPTER 18

Disorders of development and growth

syndrome (Christensen et al., 2000), with amphalocele,


diaphragmic hernia and kidney anomalies (Mazzitelli et
al., 2002).
By means of a model of four separate initiation sites
for neural tube fusion, based on observations in the mouse,
neural tube defects have been explained by failure of
fusion of one of the closures or their contiguous neuropores. According to this model, anencephaly results from
failure of closure 2 for meroacranium and closures 2 and
4 for holoacranium. Spina bifida cystica is the result of
the failure of the rostral and/or caudal closure 1 fusion.
Craniorachischisis results from failure of closures 2, 4 and
1 (Van Allen et al., 1993). Closure 3 nonfusion is rare,
presenting as a midfacial cleft extending from the upper
lip area (stomodeum) through the face (facioschisis)
and frontal bones, with resulting anencephaly (faciocranioschisis) (Van Allen et al., 1993; Urioste and Rosa,
1998). Frontal and parietal cephaloceles occur at the
sites of the junctions of cranial closures 32 and 24 (the
prosencephalic and mesencephalic neuropores). Occipital
cephaloceles result from incomplete membrane fusion of
closure 4. In humans, the most caudal neural tube was
presumed to have a 5th closure site involving L2S2.
Closure below S2 is by secondary neurulation (Van Allen
et al., 1993). Closure sites were presumed to be controlled
by separate genes expressed during embryogenesis, and
variations in rate and location of closures would make
embryos more susceptible to environmental and other
factors. Genetic variations of neural tube closure sites
occur in mice and are also evident in humans (Van Allen
et al., 1993; Zlotogora, 1995), e.g. familial neural tube
defects with Sikh heritage (proposed deficit closure 4
and rostral 1), MeckelGruber syndrome (closure 4) and
WalkerWarburg syndrome (24 neuropore, closure 4).
Environmental and teratogenic exposures frequently

18.1. Anencephaly
Optimum non nasci

(a) Failures of fusion and the factors involved


Anencephaly (Fig. 18.1) is the most severe form of neural
tube defects and is due, according to some authors, to a
failure in the closure of the rostral neuropore between 16
and 26 days after conception. Others are of the opinion
that this happens a little later, i.e. in the 4th postfertilization week (ORahilly and Mller, 1999). The incidence
of anencephaly generally ranges from 110 per 10,000
births. It is etiologically heterogeneous and has genetic
and environmental components such as maternal nutrition and exposure to teratogens. Numerous agents can
cause anencephaly in laboratory animals (De Sesso et al.,
1999; Mazzitelli et al., 2002). Anencephaly is twice more
prevalent in females than in males (Lary and Panlozzi,
2001). When genetically determined, the most obvious
form is X-linked. For prenatally detected neural tube
defects, the estimated aneuploidy rate is estimated from
2% of the isolated neural tube defects to 24% of the
multiple congenital malformation cases (Chen et al.,
2001). Genetic defects in the gene for 5,10-methylenentetrahydrofolate reductase are associated with a 3.57-fold
increased risk for neural tube defects (De Sesso et al.,
1999). One anencephalic fetus with a mosaic 45,X/146,X,
r(X)(p11.22q12) karyotype (Nowaczyk et al., 1998)
and a number of anencephalic fetuses with a ring
chromosome 13 or a deletion of chromosome 13
(Chen et al., 2001) have been reported. Anencephaly
occurs most frequently as an isolated defect, but
it has also been described in association with a partially
duplicated head (diprosopus), with the acrocallosal
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Fig. 18.1. Anencephaly.

affect specific closure sites, e.g. folate deficiency (closures 2, 4 and caudal 1) and valproic acid (closure 5 and
canalization) (Van Allen et al., 1993). Closure 3 was seen
following maternal exposure to ergot derivates (Urioste
and Rosa, 1998). However, recent careful research by precise graphic reconstructions indicates that the model of
multiple sites of fusion of the neural folds may not be
valid in humans. In human embryos, two de novo sites
of fusion of the neural folds appear in succession:  in
the rhombencephalic region and  in the procencephalic
region, adjacent to the chiasmatic plate (Fig. 18.2). Fusion
from site  proceeds bidirectionally (rostral and caudal),
whereas that from  is unidirectional (caudal only). The
fusions terminate in neuropores, of which there are 2: one
rostral and one caudal. Human neural tube defects can
thus be classified on the basis of these 3 sites of fusion
and 2 neuropores in the human embryo (ORahilly and

Mller, 2002). Anencephaly is proposed to originate as


an abnormality of mesenchymal structures, while the brain
is secondarily lost to injury in utero because of its exposed
position (Kashani et al., 2001).
(b) Brain pituitary remnants
The anencephalic child usually has no definable brain
structures rostral of the brainstem (Nakano, 1973). The
neural tissue in the more rostral areas, including the hypothalamus, is an amorphous mass of blood vessels and
primitive nerve cells (Fig. 18.3). Anencephalic fetuses
thus provide a model for pituitary development in
the absence of the hypothalamus and for revealing the
possible functions of the fetal hypothalamus in intrauterine development and birth. In anencephalics and

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Fig. 18.2. The neural tube at the middle of stage 12, showing the two regions of fusion of the neural folds. Arrows indicate the direction of fusion,
and black dots show the position of the two neuropores. The fusion of the neural folds begins first at site  and then at site . At  it spreads
in both directions, ending rostrally as the dorsal lip of the rostral neuropore, which meets the terminal lip from . The first four somites are occipital and are stippled, as is also the mesencephalon. The outlines of somites 10, 15, 20 and 25 are included. (From ORahilly and Mller, 2002,
Fig. 1 with permission.)

the pituitary in any of the seven anencephalics of 3048


weeks gestation (Visser and Swaab, 1979). Anencephalic
children do have a pars distalis of the pituitary (Nakano,
1973). In our group of anencephalics, a neurohypophysis
was present only in one case, but it did not contain
vasopressin or oxytocin (Visser and Swaab, 1979). The
normal, very high, umbilical cord levels of vasopressin
as found in controls during spontaneous labor do not
occur in anencephalics either (Oosterbaan and Swaab,
1987). However, the levels of oxytocin in amniotic fluid
and in the umbilical circulation of anencephalic children

fetuses with holoprosencephaly (cyclopsia and median


cleft), adenohypophysial tissue was found not only in the
sella turcica, but also in the open craniopharyngeal canal
and in the pharyngeal connective tissue at the external
side of the cranial base. Hormone production in the
pharyngeal pituitary was evident from immunocytochemistry (Kjaer and Fischer-Hansen, 1995; Hori et al.,
1999). On morphological grounds the pars intermedia
and neurohypophysis were reported to be absent in 75%
of the anencephalics. We did not find -melanotropin
(MSH) staining as a marker of the intermediate lobe of
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are similar in anencephalics without hydramnios and in


controls. Oxytocin is therefore probably not derived from
hypothalamic neurons but from fetal sources other than
the fetal brain (Oosterbaan and Swaab, 1987). Oxytocin
mRNA has indeed been found in human amnion, chorion
and decidua (Chibbar et al., 1993; Chapter 8e). The
adrenotropic deficiency of the pars distalis of the pituitary in anencephalic children is apparent from the fact
that the adrenal glands are invariably hypoplastic
(Nakano, 1973; Visser and Swaab, 1979; Mazzitelli et
al., 2002), while the fetal adrenal of anencephalic children can be stimulated in utero by corticotropin (ACTH)
(Honnebier et al., 1974). The low level of corticosteroids
in anencephalics also seems to be responsible for the
increased size of the thymus (Mazzitelli et al., 2002).
Fetal adrenal insufficiency goes together with low estriol
excretion by the pregnant mother (Macafee et al., 1973).
At 1718 weeks of gestation, the number and size of
ACTH cells in the pituitary of anencephalics is normal,
but after 32 weeks their number and size are reduced
(Pilavdzic et al., 1997). Bgeot et al. (1978) reported that
- and -endorphins and -lipotrophin staining were
present in the pituitary of anencephalic children, but that
the cells were smaller and less numerous than in normal
fetuses. Both growth hormone and prolactin are under
hypothalamic control during fetal development. In eight
anencephalic fetuses of 1926 weeks of gestation, blood
was sampled by cordocentesis. Both growth-hormone and
insulin-like growth factor-1 (IGF-1) levels were lower,
and prolactin levels higher, than in matched control
fetuses, indicating a disorder of hypothalamic function.
The reduction of IGF-1 is probably due to decreased
secretion of growth hormone (Arosio et al., 1995). At 32
weeks, gonadotropes are almost entirely absent in the
anencephalic pituitary (Pilavdzic et al., 1997). On the
other hand, it was found that the absence of the hypothalamus in anencephalics does not compromise the
maturation of the pituitary-thyroid function between 17
and 26 weeks of gestation (Beck-Peccoz et al., 1992) and
the morphology of lactotropes in the anencephalic pituitary is normal (Pilavdzic et al., 1997). After the age of
40 weeks, the amounts of growth hormone and
thyrotropin (TSH) in anencephalics were low, while
prolactin amounts were within the normal range (Hayek
et al., 1973).
When there is no more food for the young in the egg and
it has nothing on which to live it makes violent movements,
searches for food and breaks the membranes. In just the

same way, when the child has grown big and the mother
cannot continue to provide him with enough nourishment,
he becomes agitated, breaks through the membranes and
incontinently passes out into the external world, free from
any bounds (Hippocrates, cited from Kloosterman, 1968).

(c) Intrauterine growth and birth


Data on intrauterine growth of anencephalic children
suggest that the human fetal brain stimulates the growth
of the fetus as well as of the placenta. The intrauterine
growth rate of the anencephalic fetus is much lower than
that of the controls but shows a steady increase that
continues beyond term (Fig. 18.4; Honnebier and Swaab,
1973; Mazzitelli et al., 2002). The lowest body weights
are found in the cases of associated anencephaly. It is
interesting that, at term, the birthweight of anencephalic
boys is some 150 g higher than that of girls (Honnebier
and Swaab, 1973), showing that the presence of the fetal
hypothalamus is not required for the sex difference in
birthweight. The placenta of anencephalics also weighs
less, which suggests that the fetal brain may normally
stimulate the growth of this organ. Indeed, various pituitary hormones were found to stimulate placental growth
in a rat model for anencephaly (Swaab and Honnebier,
1974) and, surprisingly, -MSH was found to stimulate
fetal growth in rat (Swaab and Honnebier, 1974). It should
be mentioned here that the major -MSH-like substance
in the human fetal pituitary might not be -MSH itself,
but desacetyl -MSH (Tilders et al., 1981), which is
presumed to play a role in fetal development. These findings should be followed up.
The concept of the fetal brain playing a crucial role
in the start of labor originates from observations in cows
and sheep. Gestational length was increased in Guernsey
cattle with fetal pituitary aplasia (Kennedy et al., 1957)
and in cyclop fetuses, due to the poisonous plant veratrum
californicum, which caused pituitary aplasia or pituitary
dystopia (Binns et al., 1964). These observations were
followed by the classic experiments in sheep in which
fetal adrenalectomy, fetal hypophysectomy, infusion
of ACTH, and glucocorticoids showed that the fetal
hypothalamopituitary adrenal axis starts labor in this
species (Liggins et al., 1967; Drost and Holm, 1968;
Liggins and Kennedy, 1968; Liggins, 1969; Liggins,
2000). Later, a critical experiment was carried out by
McDonald and Nathanielsz (1991). They showed that
stereotactic destruction of the fetal paraventricular nucleus
in sheep was followed by prolonged pregnancy length.

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Fig. 18.3. The neural tissue left in anencephaly is an amorphous mass of bloodvessels and primitive nerve cells. (From C.U. Arins-Kappers
collection, Netherlands Institute for Brain Research.)

Observations on human anencephalics suggest that the


human fetal brain, too, is important for the timing of
the correct, at term, moment of birth. As a group,
however, anencephalics have a shorter gestational length,
since anencephalics with hydramnios are born prematurely (Fig. 18.5; Swaab et al., 1977). Mean gestation
length is normal in spontaneously born anencephalics
from pregnancies without hydramnios, in contrast to the
sheep model. However, a high percentage of prematurely
and postmaturely born anencephalic children is found,
indicating that a function of the human fetal brain in
the timing of birth (Honnebier and Swaab, 1973; Fig.
18.5). It is presumed that fetal corticotropin-releasing
hormone (CRH) from the paraventricular nucleus plays
a key role in the timing mechanism for the initiation of
human birth (see Chapter 8.5).

In addition, the course of labor is protracted in


anencephalic children. In particular the expulsion stage
and birth of the placenta take too long. This suggests that
the fetal brain releases compounds such as oxytocin that
may speed up delivery (Swaab et al., 1977; see Chapter
8.1). The fact that about 50% of the anencephalics die
during the course of labor (Honnebier and Swaab, 1973)
points to the importance of intact fetal brain systems for
dealing with the stress of birth. The extremely strong
release of fetal vasopressin that normally occurs in spontaneous labor and that is absent in anencephalics
(Oosterbaan and Swaab, 1987) may play a role, since
fetal vasopressin is involved in redistribution of the fetal
circulation to those organs that are of vital importance
(Chapter 8.1).

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Fig. 18.4. Birthweight (grams) by gestation length. The curves are the smoothed centile lines of the control group (Kloosterman, 1970). The
dots represent the birth weights of 122 anencephalic fetuses. (From Honnebier and Swaab, 1973, Fig.1 with permission.)

(d) Anencephaly, the diagnosis of death and


transplantation
An interest has arisen for the organs of anencephalics for
transplantation purposes. However, only a minority of
anencephalics may serve this purpose. Generally some
60% of the fetuses with anencephaly die before or during
birth (Honnebier and Swaab, 1973). Eighty percent of
liveborns die within 3 days. When death occurs, the
organs are usually so deteriorated that they are no longer
suitable for transplantation. However, on the parents
request, a German anencephalic newborn was reanimated
in 1987 immediately after birth and kept warm and fed
to maintain organ viability, after which the heart was
transplanted into another baby, with excellent results
(Abbatista et al., 1997).
While the organs of anencephalics can be kept viable
by means of improved intensive care techniques, it has
become increasingly difficult to determine when death
has occurred. The legislations of Western cultures unanimously accept the idea that brain death means the
irreversible loss of all those functions that identify a
person, the functions that give him a personality and

cognitive skills. Cerebral trunk deaths make these functions impossible and is thus equivalent to death. Human
life can be defined by the presence of cerebral activity
or by potential cerebral activity. In anencephalic children
cerebral trunk activity is not finalized and other cerebral
structures cannot recover in such children. In fact, brain
death occurs in anencephalics without cerebral trunk death
(Abbattista et al., 1997). In the Uniform Determination
of Death Act of the USA, two criteria for determining
death are described: irreversible cessation of circulatory
and respiratory function, and irreversible cessation of all
functions of the entire brain, including the brainstem.
Because anencephalic neonates may maintain both a
heartbeat and respiration without medical assistance, their
situation does not meet the first criterion. Moreover, they
may have an active brainstem, which means the second
criterion is not met either. Because of the definition of
brain death there is thus no practical possibility of using
anencephalic infants as organ donors under the dead
donor rule (see also Chapter 32.4). One of the possible
solutions to this problem is to change the present standard for whole brain death to make permanent loss of
consciousness the critical brain function that defines life

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Fig. 18.5. Frequency distribution of gestation length: (A) for a control group of 49,996 pregnant women; (B) for mothers of all anencephalic
fetuses (n = 147); (C) for mothers of anencephalic fetuses (n = 29) without hydramnios, omitting those who had stillborn fetuses with third-degree
maceration, fetuses given intrauterine injections or twins, and those in whom labour was induced. (From Swaab et al., 1977, Fig. 3 with permission.)

or death. These children are considered to have a lack of


consciousness from birth and an inability to ever gain
consciousness or awareness. The same arguments go
for prenatally acquired hydrocephaly. In this condition
a developmental or encephaloclastic process, often of

infectious, toxic or genetic origin, affects the major


vessels of the anterior circulation, resulting in an extensive
reduction in brain matter that is replaced with cerebrospinal fluid (McAbee et al., 2000). However, the possible
use of organs of such children raises the specter of a
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misdiagnosis, resulting in wrongful death. At present,


Germany is the only country where live-born anencephalic infants are considered to be legally dead. Another
fear is that aggressive life support for anencephalic infants
who will serve only as organ banks will erode public
confidence in transplantation (Lafreniere and McGrath,
1998).
18.2. Transsphenoidal encephalocele and empty sella
syndrome
Transsphenoidal encephaloceles are rare anomalies (Chong
and Newton, 1993; Morioka et al., 1995). They are
sporadic, with some evidence of autosomal recessive
inheritance. They are often associated with other midline
anomalies such as agenesis of the corpus callosum, cleft
palate, hypertelorism and coloboma, a v- or tongue-shaped
retinochoroidal depigmentation (Chong and Newton,
1993; Brodsky et al., 1995). Clinically, transsphenoidal
encephalocele children present with craniofacial deformities, cerebrospinal fluid (CSF) rhinorrhea, meningitis and
often panhypopituitarism (Chong and Newton, 1993;
Brodsky et al., 1995). Progressive hypothalamic-pituitary
dysfunction, diabetes insipidus and chiasmatic syndromes
result from herniation of the pituitary gland, third ventricle
and optic chiasm in a meningeal pouch that protrudes
ventrally through a large round defect in the sphenoid
bone into the nasopharynx (Chong and Newton, 1993;
Brodsky et al., 1995; Morioka et al., 1995; Fig. 18.6).
Hyperprolactinemia was found in four patients who
were considered to have had hypothalamic dysfunction
(Morioka et al., 1995). Cerebrospinal fluid rhinorrhea may
be treated surgically (Willner et al., 1994; Clyde et al.,
1995). It is presumed that the transsphenoidal encephalocele results from an early teratogenic event, occurring
between the 4th and 6th week of gestation (Brodsky et al.,
1995).
Herniation of the third ventricle/arachnoid into the
sellar fossa may be caused by surgery or radiation of
pituitary adenoma, pituitary apoplexia, bromocryptine
treatment of pituitary adenoma or postpartum pituitary
necrosis. Increased CSF pressure is presumed to be
responsible for primary empty sella syndrome. Visual
impairment is frequently associated with intrasellar herniation (Kobayashi et al., 1996). Primary empty sella
syndrome is frequently accompanied by growth hormone
deficiency and hypogonadotropic hypogonadism, but only
rarely by central hypothyroidism (Cannavo et al., 2002;

Fig. 18.6. Sagittal sections of MR image of a child with encephaloceles. (A) 0.22-T MR image (TR/TE 500/40) at 8 years of age.
Sphenoethmoidal (arrow) and transsphenoidal (arrowhead) encephaloceles are seen. A part of the transsphenoidal encephalocele protrudes
from the roof of the epipharynx (double arrows). (B) 0.5-T MR image
(TR/TE 500/30) at 11 years of age. The appearance of the basal
encephaloceles remains unchanged compared with 3 years earlier. The
stretched pituitary stalk (white arrow) extends into the encephalocele
(egg-shaped cavity with low-intensity image). A thin structure, thought
to be the pituitary gland, is seen at the posterior inferior wall of the
encephalocele (arrowhead). (C) the structure is slightly enhanced by
Gd-DTPA. (From Morioka et al., 1995, Fig. 2.)

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Chapters 18.6b, 24.1a). A combination of empty sella,


diabetes insipidus and polydipsia with Aspergers
syndrome has been published (Raja et al., 1998).

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Fisher-Hansen, 1995). Endocrine deficiencies, caused by


hypothalamic and/or pituitary dysfunction, can be the only
clinical problem in milder forms of holoprosencephaly.
Holoprosencephaly has also been found in a Klinefelter
fetus (Armbruster-Moraes et al., 1999; Michaud, 2001).
Holoprosencephaly arises during the first 4 weeks of
embryonic development due to failure of ventral forebrain
induction by axial mesendoderm. During the blastogenesis there is failure or incomplete division of the prosencephalon into cerebral hemispheres. The most severe form
of prosencephaly, cyclopia, is predicted by the requirement of the axial mesendoderm for eye separation.
Because of the importance of midline signaling in hypothalamic development, it is not surprising that the hypothalamus is either missing or lacking in structures in
holoprosencephalic brains. Multiple genetic causes have
been identified, especially in SHH, SIX3, 2IC2 and TGIF,
and chromosomal abnormalities, notably trisomies 13 and
18, have been found (Sarnat and Flores-Sarnat, 2001;
Patterson, 2002).
Aspergers syndrome has also proposed to be a mild
form of midline defect (Tantam et al., 1990). Primary and
secondary dysraphia have been reported in fetuses whose
mothers used alcohol during pregnancy (Konovalov et al.,
1997).

18.3. Congenital midline defects: optic nerve


hypoplasia and septo-optic dysplasia (De Morsiers
syndrome)
Congenital midline defects include a wide spectrum of
impaired midline clearage defects of the embryonic forebrain, including the various forms and grades of severity
of holoprosencephaly, that is seen in 80% of trisomy 13
patients (Battaglia, 2003), schizencephaly (Chapter 18.8),
septo-optic dysplasia (Chapter 18.3b) and dystopia of the
neurohypophysis (Chapter 18.4). The septum pellucidum
is generally absent (Chapter 18.8). Holoprosencephaly is
the most common brain malformation in humans, with a
prevalence rate of 1 in 250 in early embryogenesis, and
1.26 in 10,000 in a prospective birth cohort study
(Patterson, 2002). Alobar, semilobar and lobar forms
of holoprosencephaly are the different grades of severity.
In alobar holoprosencephaly, the prosencephalon fails to
cleave sagittally into cerebral hemispheres, transversely
into telencephalon and diencephalon, and horizontally
into olfactory tracts and bulbs. Minimal manifestations
discussed here include absent olfactory tracts and bulbs
(arhinencephaly), agenesis of the corpus callosum and
hypopituitarism. Feeding difficulties, neurodevelopmental
disability, visual impairment and seizures due to hypoglycemia or hyponatremia are common occurrences in
congenital midline defects (Takahashi et al., 2001). There
is always some degree of noncleavage of the hypothalamus, and the hypothalamus is one of the most severely
affected structures. As many as 67% of children with
holoprosencephaly exhibit diabetes insipidus. Other endocrinopathies involving pituitary function are less common
(Sarnat and Flores-Sarnat, 2001). Most of the patients have
multiple pituitary hormone deficiencies, and the severity
of endocrine abnormalities correlates with the degree of
hypothalamic nonseparation (Plawner et al., 2002). A few
patients with midline defects and persistent hyponatremia
due to a reset osmostat have been described, including
one with a chromosome 13 abnormality. The osmosensitive hypothalamic neurons are presumed to be dysfunctional as a result of the chromosome abnormality
and/or the anatomic midline defect (Gupta et al., 2000).
An open craniopharyngeal canal with adenohypophysial
tissue can be present in holoprosencephaly (Kjaer and

(a) Optic nerve hypoplasia


Optic nerve hypoplasia is a congenital abnormality of one
or both optic nerves associated with a diminished number
of axons. After completion of the optic nerves, insults
result in atrophy. The abnormality can be associated with
several endocrine and central nervous system disorders.
The most common is septo-optic dysplasia (see below).
Zeki et al. (1992) found that optic nerve hypoplasia can
be associated with partial or complete absence of the
septum pellucidum (52%), hydrocephaly (38%), parencephaly (24%), dilatation of the suprasella and chiasmatic
cisterns (19%), partial or complete absence of the corpus
callosum (14%), or an intracranial cyst. Incomplete forms
of septo-optic dysplasia have also been reported by others
(Furujo and Ichiba, 1998). Behavioral problems in optic
nerve hypoplasia were reported to range from attentiondeficit disorders to autistic, aggressive and violent
behavior. In literature, optic nerve atrophy has, moreover,
been associated with anencephaly, schizencephaly, cerebral atrophy, cerebral infarcts, encephalocoeles,
colpocephaly, and congenital suprasellar tumors (Zeki et
al., 1992).
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(b) Septo-optic dysplasia


Septo-optic dysplasia (De Morsiers syndrome, MIM
182230) is a developmental anomaly of midline structures
characterized by uni- or bilateral hypoplasia of the optic
nerves, tracts and chiasm, and by absence of the septum
pellucidum, that was first noted by Reeves, in 1941, and
first described by De Morsier, in 1956. In 88% of the
patients the visual system is bilaterally affected (Fig.
18.7). Children with optic nerve hypoplasia in this
syndrome are blind in 2050% of the cases, or severely
visually impaired in another 40%. A specific ocular
fundus appearance with marked small optic disc and
isolated tortuosity of the retinal veins is present. In addition to optic disc dysplasia, morning glory sign has been
found as well (Hellstrm et al., 2000). De Morsier considered the entity to be a part of median cranioencephalic
dysrhaphias, while others thought it to be a mild form
of holoprosencephaly (Ellenberger et al., 1970) or part
of a spectrum of complex midline cranio-facial malformations overlapping with optic nerve hypoplasia, the
syndrome of an absent septum pellucidum (see Chapter
18.7), and procencephaly (Hellstrm et al., 2000). Septooptic dysplasia has also been described as part of
schizencephaly, a structural disorder of cerebral cortical
development. In addition, septo-optic dysplasia may be
associated with cortical developmental malformations, the
septo-optic dysplasia-plus spectrum (Miller et al.,
2000). The scar-like lesions in the walls of the third
ventricle and the fusion of the ventricular walls are consistent with a destructive or disruptive lesion, whose nature,
however, is not clear (Roessmann et al., 1987). Viral
infections, gestational diabetes, and ingestion of large
amounts of quinidine in early pregnancy have all been
suggested as etiological factors for the sporadic form
(Acers, 1981; Costin and Murphree, 1985). In addition,
the possibility of a vascular disruption (Miller et al.,
2000), drug toxicity, and an association between fetal
alcohol effects and a complex cerebral anomaly with
features of septo-optic dysplasia and incomplete holoprosencephaly have been reported (Coulter et al., 1993;
Hellstrm et al., 2000). The insult that causes septo-optic
dysplasia occurs presumably before 10 weeks and at about
46 weeks of gestation, when the ganglion cells of the
retina are developing (Patel et al., 1975; Hellstrm et al.,
2000). The homeobox gene HESX1 is implicated in a
familial form of septo-optic dysplasia. HESX1 expression
begins in prospective forebrain tissue at the anterior
extreme of the rostral neural folds and eventually ends

Fig. 18.7. (a) Sagittal image of septo-optic dysplasia: severe hypoplasia


of the pituitary gland, the stalk and the chiasma (arrowhead). Partial
ectopy of the cerebellar tonsils in the foramen magnum (arrow). (b)
Coronal image of septo-optic dysplasia: absence of the septum pellucidum evidenced by the cross. (c) Sagittal image of posterior pituitary
ectopia (arrowhead), hypoplastic anterior pituitary, ectopia of the cerebellar tonsils (arrow) and the arachnoid cyst, posterior to the cerebellar
hemispheres (cross). (From Zucchini et al., 1995, Figs. 24 with
permission.)

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in the ventral diencephalon. However, later in development it becomes restricted to Rathkes pouch. Two
siblings with septo-optic dysplasia were homozygous for
a missense mutation within the HESX1 homeobox. In
addition, heterozygous mutations in HESX1 have been
found that are associated with milder pituitary phenotypes
(Dattani et al., 1999; 2000; Dattani and Robinson, 2000;
Thomas et al., 2001). A four-generation family with septooptic dysplasia has been reported to be associated with
Waardenburg syndrome type 1. In addition, a proband
exhibited septo-optic dysplasia; a G to C transversion was
identified in PAX3 exon 7 (Carey et al., 1998). One 25year-old patient with septo-optic dysplasia and retinitis
pigmentosa had an isolated mitochondrial complex III
deficiency and a heteroplastic mutation in the cytochrome
b gene (Schuelke et al., 2002).
Hypopituitarism is also an important component of this
syndrome (Hoyt et al., 1970), and the term septo-opticpituitary dysplasia has been in use since this study of
Hoyet et al. Hypopituitarism has been considered to be
secondary to hypothalamic damage rather than to be due
to intrinsic pituitary defects. Indeed, one child responded
to the administration of growth hormone-releasing
hormone (GHRH) with accelerated growth (Leaf et al.,
1989). On the other hand, not only a hypoplastic pituitary, but also an empty sella, with or without an ectopic
pituitary, may be found (Willnow et al., 1996). The
endocrine deficiencies may vary from isolated growthhormone deficiency to panhypopituitarism (Leaf et al.,
1989; Willnow et al., 1996). If the endocrinopathies
remain unnoticed, the children might suffer from hypoglycemia, adrenal crisis and sudden death (Hellstrm et
al., 2000). Moreover, sexual precocity, delayed puberty,
central hypogonadism, adrenal insufficiency, hypothyroidism and vasopressin-responsive diabetes insipidus
have been described (Arslanian et al., 1984; Willnow et
al., 1996; Antonini et al., 2002). In a series of 23 patients
with optic-nerve hypoplasia, hypopituitarism was found
in 15 of these patients. Stimulated prolactin levels were
higher than in controls (Costin and Murphree, 1985).
Smaller studies also showed growth hormone deficiency,
hypothyroidism, elevated prolactin, ACTH deficiency and
diabetes insipidus (Izenberg et al., 1984). One patient has
been described who grew normally despite growth
hormone and IGF-1 deficiency. IGF II or insulin levels
could not explain this finding either (Bereket et al., 1998).
Interestingly, patients have been described without CRH
or thyrotropin-releasing hormone (TRH) secretion but
with retained gonadotropin secretion. This may be

31

explained by the fact that luteinizing hormone-releasing


hormone (LHRH) neurons develop outside the hypothalamus, in the nasal placode, and migrate to the
hypothalamus after the development of the midline hypothalamic defect, i.e. after the 5th8th week of pregnancy
(see Chapter 24.2). Moreover, the abnormal hypothalamic
anatomy may alter the normal suppression of LHRH
neuron function, resulting in precocious puberty (Nanduri
and Stanhope, 1999).
The syndrome is not rare (Roessmann et al., 1987) and
is highly variable (Morishima and Aranoff, 1986). In
some series of patients with septo-optic dysplasia,
60100% of them had clinical optic nerve hypoplasia with
varying degrees of nystagmus and visual impairment.
Only 5060% lacked the septum pellucidum (Fig. 18.8;
Arslanian et al., 1984; Stanhope et al., 1984). During
pregnancy adrenal hypoplasia may result in a subnormal
maternal urinary oestriol excretion (Macafee et al., 1973).
Neurological abnormalities such as epileptic seizures,
cerebral palsy, microcephaly and mental retardation do
occur (Acers, 1981; Costin and Murphree, 1985; Antonini
et al., 2002). With the advent of brain imaging, a number
of additional cerebral hemispheric malformations have
been reported (Willnow et al., 1996). Patients with septooptic dysplasia are at risk of unexpected death at all ages,
although most deaths occur in very early childhood
(Gilbert et al., 2001).
Neuropathological study of a limited number of cases
revealed that the optic nerves were attenuated and
contained only a few myelinated fibers (Roessmann et
al., 1987). This agrees with the small optic disc that was
seen in all patients (Costin and Murphree, 1985). The
optic chiasm is also severely atrophic and the lateral
geniculate nuclei are small. In the anterior part of the
hypothalamus, the tissue may be distorted. The supraoptic
and paraventricular nuclei are sometimes absent, or the
cells may be abnormally small or few when they are identified by neurophysin staining (Fig. 18.9; Roessmann et
al., 1987). This explains the varying degrees of diabetes
insipidus and suggests that the term hypothalamic
should indeed be added to the designations (septo-opticpituitary dysplasia) mentioned above. The changes in the
hypothalamus in fact seem to be the most consistent ones.
The olfactory bulbs and tracts may also be absent (Patel
et al., 1975; Roessmann et al., 1987). The frequent perinatal problems found in this syndrome (Willnow et al.,
1996) may be related to the damaged fetal hypothalamopituitary adrenal system that is involved in the timing
mechanism of birth (Chapters 8.5, 18.1) and the fetal
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Fig. 18.8. Septo-optic dysplasia (De Morsier syndrome) in a girl of 4 years and 5 months (NHB 96-179). (A) The paraventricular nucleus (PVN)
is absent in hematoxylineosin staining (* = sulcus hypothalamicus, III = third ventricle). Bar represents 0.5 mm. (B) Only a few small PVN neurons
were present that stained for the vasopressin precursor by means of an anti-glycopeptide antibody (Boris Y-2). Bar represents 100 m.

hypothalamoneurohypophysial system that normally


stimulates the course of labor and protects the fetus
against the stress of labor (Chapter 8.1). There may be
a narrowing and a fusion of the third ventricular walls
anteriorly, with pronounced subependymal glia proliferation; the ependyma of the third ventricle may be
distorted; ependymal scars may be found and
leptomeningeal astrocytic heterotopics seen at the base of
the brain (Roessmann et al., 1987; Fig. 18.10). Aplasia
of the fornix may also be found (Willnow et al., 1996).
In two patients a hamartomatous mass was found in the
region of the cerebral trigone. The posterior pituitary may

be absent or hypoplastic. Posterior pituitary ectopia and


infundibular hypoplasia are seen as variable components
of septo-optic dysplasia (Brodsky and Glasier, 1993; see
Chapter 18.4). Enlargement of the pituitary stalk has also
been demonstrated in patients with septo-optic dysplasia
and diabetes insipidus (Zeki et al., 1992).
In collaboration with A. Dean (London, UK), we
examined a case of septo-optic dysplasia with panhypopituitarism and diabetes insipidus for which the patient
had received replacement therapy (NHB 96-179). It
concerned a girl of 4 years and 5 months who died of
bronchopneumonia. Her brain weight was 773 g, which

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Fig. 18.9. Septo-optic dysplasia (De Morsier syndrome) in a girl of 4 years and 5 months (NHB 96-179). (a) An area of necrosis in the hypothalamus
(see asterisks) lateral of the PVN. Bar represents 500 m. (b) Calcifications in the lateral part of the hypothalamus. Bar represents 100 m.

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is below the 1st percentile. Her body weight and height


were well below the 3rd centile line for age. Growth
retardation was detected from 20 weeks of gestation
onwards. Labor was induced at 41 weeks of gestation but
was diverted into an emergency Caesarian section due to
the occurrence of a maternal grand mal seizure and fetal
distress. She was born at 41 weeks with a birthweight of
2820 g. There was no evidence of antiepileptic medication
during pregnancy. The girl was found to have visual
problems and pale hypoplastic optic discs at the age of
3 months. MRI showed a hypoplastic pituitary gland with
absent or very small stalk. Neuropathology showed that
the thyroid and adrenal were about half the expected
weight and that the adrenal cortex was thin. Leptomeningeal and white-matter heterotopias and posterior
fossa crowding were found. Concerning the olfactory
pathway, the sulcus lateral to the left gyrus rectus
contained a discrete island of glioneuronal tissue that
blended with the leptomeninges and possessed a small
number of myelinated axons. The equivalent sulcus on
the right contained a small myelinated tract. The anterior
pituitary gland appeared to be normal for the most part,
but the neurohypophysis was relatively thin. The pars
intermedia was represented by a conspicuous epitheliumlined cleft. Throughout the hypothalamus there were
well-circumscribed fields of astrocytosis, with strong glial
fibrillary acidic protein (GFAP) staining. In addition, a
very strong band of GFAP positivity was present along
the lateral and third ventricle. The optic nerve, chiasm
and tracts were thin, gray and degenerated. The degenerated part of the optic nerve contained only remnants of
myelin. In the region of the optic nerve, the leptomeninga
contained GFAP-positive heterotopias. The wall of the
third ventricle was not scarred. A lesion was present in
the hypothalamus at the level of the sulcus hypothalamicus, in a position that was lateral to the normal location
of the paraventricular nuclei (PVN). The PVN and
supraoptic nuclei (SON) were, however, virtually absent
in this patient (Figs. 18.8, 18.9), but a few small PVN
neurons were stained with anti-glycopeptide along the
third ventricle above the level of the sulcus hypothalamicus and some thick-beaded fibers were found close to
the foramen of Monro. No staining was found with antiglycopeptide in the suprachiasmatic nucleus. The absence
of the SCN was also apparent from the type of arrhythmicity in a child with septo-optic dysplasia, who reacted
with normal sleepwake cyclicity to melatonin administration. In the case we studied, the hypothalamus was
strongly distorted and calcifications were present in

various areas (Fig. 18.10). However, a number of structures was distinguished, i.e. island of Calleja, diagonal
band of Broca, basal nucleus of Meynert, commissura
anterior, fornix, nucleus tuberalis lateralis and corpora
mamillaria. The arcuate nucleus could not be identified.
Anti-vasopressin (Truus, 29-01-86) or anti-oxytocin (O2-T) did not stain cells in the PVN or SON. No staining
was found in the infundibular region with anti-vasopressin, anti-oxytocin or anti-glycopeptide (Boris-Y-2).
The stalk could not be identified.
A case with both septo-optic dysplasia and Cornelia
de Lange syndrome (Chapter 32.2) has been described
(Hayashi et al., 1996) and the condition of a 16-year-old
boy with hypothalamic endocrine disorders, a hypoplastic
pituitary gland, decreased posterior pituitary lobe intensity, absence of the left eye, mental retardation and a
hypoplastic left optic nerve was also considered to be
within the spectrum of septo-optic dysplasia (Miyako et
al., 2002).
18.4. Dystopia of the neurohypophysis
(a) True ectopia
When it occurs as an isolated defect, ectopia of the neurohypophysis is considered to be due to an abnormality in
the descent of the neurohypophysis. This congenital
abnormality may be part of midline brain anomalies,
including septo-optic dysplasia (Zucchini et al., 1995).
Posterior pituitary ectopia and infundibular hypoplasia are
in fact considered to be variable components of septooptic dysplasia (Kaufman et al., 1989; Brodsky and
Glasier, 1993; see Chapter 18.3b) and may be based on
a HESX1 mutation (Mitchell et al., 2002). A developmental theory suggests that genetic, teratologic or
traumatic factors interfere with the normal development
around 6 weeks of gestation. In cases of dystopia of the
neurohypophysis, the pituitary fossa contains only adenohypophysial tissue and no endocrine abnormalities. No
instance of isolated diabetes insipidus due to dystopia of
the neurohypophysis has been reported. Dystopia of the
neurohypophysis has been described as an extremely rare
accidental finding at autopsy (Fig. 18.10). It may be
discovered by MRI as a round structure with a high-intensity signal on T1-weighted MRI images of the region of
the median eminence. In general, true dystopia of the
neurohypophysis is not associated with perinatal problems or clinical symptoms (Aydan and Ghatak, 1994).

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Fig. 18.10. (a) Inferior view of brain showing a dystopic neurohypophysis posterior to chiasma and anterior to mamillary bodies. (From Aydin
and Ghatak, 1994; Fig. 1 with permission.) (b) Dystopic neurohypophysis surrounded by a meningeal capsule. Arrowheads indicate the rim of
adenohypophyseal tissue (H&E, magnification 16). (From Aydin and Ghatak, 1994, Fig. 2 with permission.)

On MRI, dystopia of the neurohypophysis may closely


simulate tumors such as granular cell myoblastomas,
astrocytomas, neuronal hamartomas or meningiomas in
the hypothalamic area. The absence of symptoms related
to the adeno- and neurohypophysis argues in favor of true
dystopia of the neurohypophysis and the consideration of
this condition in the differential diagnosis of hypothalamic lesions may prevent unnecessary biopsies or
neurosurgical procedures (Aydan and Ghatak, 1994).

in patients with anterior pituitary abnormalities such as


pituitary dwarfism (isolated growth hormone deficiency)
or multiple pituitary hormone deficiencies, including
central diabetes insipidus, or diabetes mellitus. In addition,
periventricular heterotopias may be present (Fujisawa
et al., 1987a; Kelly et al., 1988; Maghnie et al., 1991;
Appignani et al., 1993; Mszros et al., 2000; Den Ouden
et al., 2002; Mitchell et al., 2002). In such cases the
adenohypophysis can be hypoplastic, the infundibulum
absent and the posterior lobe ectopic at the bottom of
the median eminence (Mszros et al., 2000). A 43-yearold man with eunuchoid habitus and open epilepsies
had an agenesis of the pituitary stalk, a small anterior
pituitary remnant and an ectopic neurohypophysis. He

(b) Dystopia with anterior pituitary abnormalities


Dystopia of the neurohypophysis in individuals without
clinical symptoms has to be distinguished from dystopia
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had untreated panhypopituitarism. He had always been


short for his age but continued to grow and finally reached
a length of 193 cm (Den Ouden et al., 2002). In cases of
growth hormone deficiency associated with an ectopic
posterior pituitary on MRI after gadolinium injection,
patients without a pituitary stalk present a more severe
form of the disease, with multiple anterior pituitary
hormone deficiencies (Chen et al., 1999b). Twin boys
with hypopituitarism, hypoplasia of the anterior pituitary
gland, ectopic posterior pituitary tissue and paracentric
inversions of the short arm of chromosome 1 have been
described. This syndrome is probably due to impaired
down migration of the posterior pituitary (Siegel et al.,
1995). Acquired dystopia of the neurohypophysis has
often been considered to be the result of perinatal injury
causing stalk transsection and subsequent regeneration of
the hypothalamoneurohypophysial tract fibers as a newly
formed ectopic posterior lobe at the proximal stump
(Fujisawa et al., 1987a). A large majority of the patients
with anterior pituitary abnormalities indeed have a history
of perinatal problems in the form of difficult presentation
and perinatal anoxia. However, since only 50% of the
patients with multiple pituitary deficiencies and evident
MRI damage of the sellar area have such a positive history
for adverse perinatal events (Cacciari et al., 1990), doubts
have risen about the direct association between neonatal
insult and pituitary damage. An alternative explanation
from the interruption during birth hypothesis, and a
much more likely one, is that an early prenatal congenital
disconnection defect occurs that leads to hypothalamopituitary and other brain anomalies. Because of the active
role of the fetus in the initiation and course of labor, such
congenital defects may contribute first to labor problems
and later to, e.g. growth hormone deficiency (Maghnie et
al., 1991; Argyropoulou et al., 1992; Triulzi et al., 1994;
see Chapter 18.6; for a discussion of the question whether
a difficult delivery is cause or effect, see Chapter 8.1).
18.5. The optic chiasm
The optic chiasm (4 mm thick, 12 mm wide and 8 mm
long) lies about 1 cm above the pituitary fossa). About
53% of the fibers decussate and there are about 2 million
axons for each nerve. The most frequent complaints of
patients with chiasmal compression (Fig. 19.26) from
pituitary tumors are progressive loss of central acuity and
dimming of the visual field, especially its temporal portion.
Interestingly, it has been hypothesized that that could
have been what defeated the Philistine giant Goliath, as

described in the Bible book of Samuel; the fact that he


was a slow-moving and ponderous acromegalic giant with
a pituitary tumor that caused bitemporal hemianopsia
(Berginer, 2000). For field defects in chiasmal lesions, see
Anders et al. (1999). Chiasmal compression and hypopituitarism have been found a few times in cases of
intrasellar chordomas, tumors derived from notochordal
rests (Thodou et al., 2000). Optic atrophy is a late sign of
chiasmal compression by a pituitary tumor. T2-weighted
reversed MR images depicting the optic pathway are
useful in selecting the appropriate surgical approach
(Eda et al., 2002). Chiasmal apoplexy or hemorrhage into
the optic chiasm is generally caused by intrachiasmal
cavernous or arteriovenous vascular malformation, but has
also been found due to a pituitary macroadenoma hemorrhaging into the optic chiasm (Pakzaban et al., 2000).
(a) Misrouting in albinism
Retinofugal axons are misrouted in the optic chiasm so
that some of the axons from the temporal retina those
that stay on their own side in normal brains cross in
albinos. The abnormality is present in any animal and
human individual that lacks pigment in the retinal pigment
epithelium, no matter what genetic mechanisms are
responsible for the lack of pigment. Abnormalities in
the lateral geniculate nucleus of a human albino have
been described (Guillery et al., 1975). The abnormal
decussation of temporal retinogeniculostriate projections
associated with albinism is reflected in the potential distribution of the visual evoked potentials (VEP). Following
monocular stimulation, misrouted optic projections
produce VEP asymmetry across the occipital left and right
hemispheres in 100% of the albinos and not in normal
controls (Apkarian et al., 1983). Several reports have
suggested that some patients with PraderWilli syndrome
(see Chapter 23.1) also demonstrate the presence of
misrouted optic pathway projections (Creel et al., 1986,
1987). In PraderWilli syndrome, hypopigmentation of
hair, skin and eye have indeed been described and
proposed to be of neural crest origin. However, Apkarian
et al. (1989) did not find the characteristic contralateral
hemispheric asymmetry of VEPs as seen in albinism. On
the other hand, their VEP profiles were found to be atypical and difficult to interpret. Moreover, an 8-month-old
boy has been described with Angelmans syndrome, with
crossed asymmetry in monocular flash VEP scalp distribution, previously considered to be pathognomonic of
albinism. He had skin and hair hypopigmentation, but

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Fig. 18.11. Achiasmatic child (111.12). Coronal axial MRI slices demonstrate an abnormality of the chiasmal region. T1-weighted MRI coronal
sections with 4-mm-image slice thickness failed to show a normal chiasmal plate but rather two separate tracts adjoining the inferior region of
the third ventricle. Midsagittal sections also failed to identify a chiasmal structure or normal supraoptic recesses. Beginning anteriorly: (A) Coronal
T1-weighted section shows normal intracranial optic nerves (arrows) lying beneath the frontal lobes and above the pituitary gland; (B) as the
coronal sections advance 4 mm posterior to the preceding section, a downward-bulging third ventricle is visualized along with adjacent optic
structures on the left and right. However, no chiasmal structure is imaged. (From Apkarian et al., 1993, Fig. 3 with permission.)

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normal ocular pigment and normal maculae. Cytogenetic


studies demonstrated a microdeletion of the maternal
chromosome 15q11-13 (Thompson et al., 1999).
(b) Non-decussating retinal-fugal fiber syndrome
In two unrelated children, a visual pathway malformation was found in which nasal retinal-cortical projections
were unable to decussate due to an inborn absence of the
optic chiasm (Fig. 18.11). These fibers erroneously route
ipsilaterally to visual projection targets. Both children had
reduced distance visual acuity for their age, alternating
esotropia, torticellis, head tremor and ocular motor instability in the form of early-onset nystagmus. When tested
for VEPs, using full field monocular stimulation, instead
of showing contralateral asymmetry as found in albinism,
the VEP profiles of both children revealed misrouted ipsilateral asymmetry (Apkarian et al., 1994).
(c) Other optic chiasm pathology
For arterial supply of the optic chiasm, see Chapter 17.1h.
A case of avulsion of the optic chiasm is described in
Chapter 17.2b. In a case of primary bilateral anophthalmia, the supraoptic nucleus was described as lying flat,
parallel to the meningeal surface and in one mass, but
otherwise normal (Recordon and Griffiths, 1938). A rare,
lethal X-linked syndrome with microcephaly, dysmorphic
features and normal eyes is accompanied by bilateral optic
pathway aplasia. Necrosis of the optic pathways, hypothalamus and brainstem following irradiation of a pituitary
tumor has been described. Gliomas in the optic pathway,
which tend to occur in young children, may cause vision
loss and optic atrophy. For a chiasmatic glioma, see Fig.
19.10. Optic pathway gliomas may be associated with
neurofibromatosis type I as described in Chapter 19.4b.
Chiasmatic and chiasmatic/hypothalamic gliomas are different entitities. For the chiasmatic/hypothalamic tumors,
there was more morbidity and no prolongation of time to
progression when radical resections were compared with
more limited resections. A less radical resection and radiotherapy for preventing a subsequent progression is, therefore, recommended (Steinbock et al., 2002). The most
common site for optic pathway gliomas with neurofibromatosis is the orbital nerve, followed by the optic chiasm,
while the most common localization of involvement for
the optic pathway gliomas without neurofibromatosis is
the optic chiasm (Kornreich et al., 2001).

Neurofibramatosis type 1 is an autosomal dominant


genetic disorder, but about half of the cases are spontaneous mutations. Patients with this disorder run an
increased risk of developing both benign and malignant
tumors. Gliomas, astrocytomas and ependymomas have
frequently been reported. A patient with a neurofibromatosis type 1 had a mass in the hypothalamus and
anterior optic pathway that disappeared over a 9-month
period, suggesting dysplastic changes rather than a
neoplasm (Zuccoli et al., 2000). Gangliomas and
ganglioneuromas of the optic chiasm have also been
described (Shuangshoti et al., 2000). Neurohypophysial
germinomas may not only cause diabetes insipidus and
anterior pituitary dysfunction but also compression of the
optic chiasm (Saeki et al., 2000; Iwaki, 2001).
In septo-optic dysplasia the optic nerves and optic
chiasm are affected (see Chapter 18.3). The optic chiasm
is often affected in neurosarcoidosis (Westlake et al.,
1995; Chapter 21.1; Fig. 21.1), in multiple sclerosis
(Chapter 21.2; Fig. 21.5) and Wolframs syndrome
(Chapter 22.7). In addition, Langerhans cell histiocytosis
(Chapter 21.3) may affect the optic pathway. The histiocytes are characterized by CD1a- and S-100-positive
cells, and ultrastructurally by the presence of membranous cytoplasmic structures of 200400 nm in width and
shaped like tennis rackets, which are known as Birbeck
granulas. In Wolframs syndrome (Dean et al., unpubl.
observations) the optic nerves and optic chiasm are atrophied. Although rare, visual loss may result from primary
central nervous system lymphoma in AIDS (Lee et al.,
2001b). According to some studies, there is optic nerve
degeneration in Alzheimers disease (Hinton et al., 1986;
Chapter 4.3).
Slight demyelization of the optic tracts and chiasm has
been reported in LaurenceMoon/BardetBiedl syndrome
(Chapter 23.3) and in acute intermittent porphyria
(Perlroth et al., 1966; Chapter 28.3).
18.6. The growth hormone axis in development and
aging
Growth hormone synthesis and release are regulated by a
number of hypothalamic factors that are delivered to the
pituitary gland by the pituitary portal system. GHRH forms
out of 4044 amino acids (Schally et al., 2001) and stimulates growth hormone production, while somatostatin
(Chapter 8.7b) inhibits its secretion. The endogenous
growth hormone pulses are most likely due to episodic
release of GHRH and not influenced by somatostatin

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(Dimaraki et al., 2001). Growth hormone-releasing


peptide (GHRP), Ghrelin, is an endogenous ligand for the
growth hormone secretagogue receptor (Tolle et al., 2003)
and stimulates GHRH release (Wren et al., 2002). This
growth-hormone secretagogue of 28 amino acids is also
an orexigenic peptide, acting through activation of
the neuropeptide-Y (NPY) pathway (Kojima et al.,
2001; Chapter 23c) and induces a release of CRH and
vasopressin (Wren et al., 2002). Ghrelin secretion is
sexually dimorphic with women in the late follicular
phase having higher levels than men and is suppressed
by somatostatin (Barkan et al., 2003). In addition to the
growth hormone-releasing and -inhibiting factors, growth
hormone secretion is controlled by autofeedback connections (Farhy et al., 2001). In their turn, GHRH and
somatostatin synthesis and release are modulated by NPY,
pro-opiomelanocortin, galanin, thyroid hormones, gonadal
hormones and adrenal corticosteroids. In addition, growth
hormone secretion is regulated by acetylcholine that
topically inhibits somatostatin in the hypothalamus. In
obesity a chronic state of hypersecretion of somatostatin
results in inhibition of growth hormone release. Also
the noradrenergic system is involved in growth hormone
regulation. GHRH is a member of a gene family that also
includes genes for vasoactive intestinal polypeptide (VIP;
Chapter 4a), pituitary adenylcyclase-activating polypeptide (PACAP), secretin, gastric inhibitory peptide (GIP)
and glucagon. The gene consists of 6 exons. Exon 2-4
encodes a GHRH precursor that is cleaved into GHRH and
a carboxy-terminal peptide. GHRH is widely expressed
in the nervous system, but the most prominent activity
is located in the median eminence and infundibular
nucleus. GHRH neurons are activated in this nucleus
during prolonged illness (Goldstone et al., 2003). GHRH
affects growth hormone production, thus stimulating the
proliferation of the pituitary somatotrophs by enhancing
growth hormone synthesis at the transcriptional level.
Growth hormone secretion is also stimulated. In plasma,
GHRH is rapidly inactivated by a dipeptidylaminopeptidase to GHRH3-44 with a half life of approximately
7 min (Cordido et al., 1989; Bluet-Pajot et al., 1995; 1998;
Baumann and Maheshwari, 1999; Ghigo et al., 2000;
Veldhuis et al., 2001).
Immediately postnatally, GHRH causes a growth hormone hyperresponsiveness which in all likelihood is due
to a reduced pituitary sensitivity to somatostatin. After a
period of stable plasma levels, growth hormone responses
to GHRH decline after the third to fourth decade in men
and after the menopause in women (Mller et al., 1993).

39

Sexual dimorphism is present in the regulatory mechanisms involved in growth hormone and IGF secretion
(Jaffe et al., 1998). Newborns secrete high levels of
growth hormone, but low levels of IGF-I. Estradiol stimulates the IGF-I production in puberty (Ghigo et al.,
2000). The brain is also a target for growth hormone.
Growth hormone receptor mRNA is expressed in the
human brain and growth hormone participates in laboratory animals in the modulation of feeding behavior, sleep
and breathing control, and learning and memory. Growth
hormone mRNA has so far not been found in human
brain samples (Castro et al., 2000).
Eutopic and ectopic GHRH hypersecretion by certain
tumors may be associated with pituitary growth hormone
cell hyperplasia or adenoma and growth hormone hypersecretion. Hamartomas (Chapter 19.3) or gliomas
(Chapter 19.4) may secrete high levels of GHRH.
Hypersecretion of GHRH occurs in fewer than 1% of the
cases of acromegaly. In the large majority of these cases,
patients have carcinoid tumors in the bronchus, gastrointestinal tract or pancreas, which secrete high levels of
GHRH (Schally et al., 2001).
(a) Noonan syndrome
In 1963 Noonan and Ehmke first described several children with a typical facial appearance, i.e. hypertelorism,
down-slanting palpebral fistures, ptosis and low-set
posteriorly rotated ears. The incidence of Noonan
syndrome is suggested to be between 1 in 1000 and 1 in
2000. Apparently, there are familial and sporadic cases
of this syndrome (Collins and Turner, 1973). Growth
reduction is the same for height and weight, while
head circumference has a normal distribution. There are
additional characteristic features in Noonan syndrome.
Polyhydramnios complicates 33% of the affected pregnancies and there is a high incidence of cardiac anomalies.
Major milestone delay is a common feature, puberty is
often delayed, and there is hypotonia and hyperextensibility in the younger child. Significant feeding difficulties
are present in 76% of the children. However, developmental outcome in the older child does not seem to confirm
earlier reports of frequent mental retardation. Speech delay
may be related to loss of hearing in Noonan syndrome. In
fact, abnormal hearing is present in 40% and abnormal
vision in 94% of the children with Noonan syndrome
(Sharland et al., 1992). Growth hormone secretion, which
has been reported to be characterized in Noonan syndrome
by low-amplitude and few spontaneous bursts, is held
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responsible for the short stature and low growth velocity.


The levels of plasma IGF-I, the main mediator of growth
hormone actions, would be low or low normal, but these
data are controversial (Spiliotis et al., 1984; Ahmed et al.,
1991; Tanaka et al., 1992). The evidence for a defect in
the growth hormone/IGF-I axis in Noonans syndrome
has led to growth hormone therapy (Ahmed et al.,
1991; Thomas and Stanhope, 1993). The average age
at diagnosis of Noonan syndrome is 9 years (Sharland
et al., 1992). The differential diagnosis includes Turners
syndrome, various other chromosomal abnormalities (see
below), teratogens such as alcohol and primidone.
We have seen the hypothalamus of a 6-year-old girl
with Noonans syndrome (A253/94) referred to us by Dr.
A. Dean (London, UK). She died following a liver graft
given because of a liver failure that was probably due
to a reaction to repeated exposure to halothane. The
hypothalamus revealed normal microscopic anatomy.
Following long-microwave treatment of the sections,
GHRH-containing neurons became visible in apparently
normal amounts in the arcuate nucleus (Fig. 18.12).
Quantification was not performed.
(b) Multiple pituitary deficiencies, isolated growth
hormone deficiency
Patients with multiple pituitary deficiencies, including
growth hormone deficiencies, generally have an MRI
pathology that indicates suprasellar damage that usually
also appears from neuroendocrine tests (Cacciari et al.,
1990; Den Ouden et al., 2002). The occurrence of acquired
severe growth hormone deficiency is extremely common
in adult patients bearing non-functional tumor masses in
the hypothalamo-pituitary area and increases following
neurosurgery or radiation (Corneli et al., 2003; Chapter
25.3). Also in isolated growth hormone-deficient children,
the anterior lobe of the pituitary may be hypoplastic, the
infundibulum absent and the posterior pituitary ectopic at
the bottom of the median eminence (Mszros et al.,
2000). In addition, pediatric patients with mitochondrial
myopathy, encephalopathy, lactic acidosis and stroke-like
episodes were diagnosed with growth-hormone deficiency,
most probably based upon a defect in the GHRH neurons
(Matsuzaki et al., 2002). Children with organic causes for
growth hormone deficiency, i.e. congenital malformation,
tumor, radiation, chemotherapy or infiltrating disorders,
have elevated responses of the hypothalamo-pituitary
adrenal axis, possibly by disruption of central control
pathways (Finkelstein et al., 2001; Chapter 25.3).

Interruption of the pituitary stalk by a perinatal insult


and regeneration of the posterior pituitary from the proximal stump have been presumed to be the cause of growth
hormone defects in children (see Chapter 18.4; Zucchini
et al., 1995; Yoo, 1998). However, the absence of perinatal insults and the presence of other brain anomalies,
such as microcephaly, facial or sella abnormalities,
ectopic or absent neurohypophysis, periventricular heterotopias, thin or absent pituitary stalk, anterior visual
pathway anomalies such as optic nerve hypoplasia, and
a HESX1 mutation suggest the presence of a congenital
developmental defect in some patients (Maghnie et al.,
1991; Argyropoulou et al., 1992; Triulzi et al., 1994;
Mszros et al., 2000; Mitchell et al., 2002). An undescended pituitary stalk would be part of such defects.
There are patients in this group whose somatotrophs function but whose hypothalamic GHRH release is impaired.
In patients with an invisible or thin pituitary stalk on MRI
and prenatal or perinatal onset of hypothalamic pituitarism, growth hormone deficiency and ACTH deficiency
gradually develop during the first decades of life
(Miyamoto et al., 2001). Growth hormone deficiency is
also found in septo-optic dysplasia (Chapter 18.3).
Prolonged labor and breech delivery have been documented in only 5060% of the children with growth
hormone deficiencies, and one may question, therefore,
the idea that disturbed labor is the cause of growth
hormone deficiencies. An alternative explanation for
the combination of labor problems and pituitary stalk
abnormalities is that early prenatal congenital hypothalamic-pituitary abnormalities could contribute to labor
problems because of the participatory role of the fetus in
the induction and course of labor. Breech delivery and
prolonged labor may thus be part of a complex clinical
picture, including congenital brain anomalies (Maghnie
et al., 1991; Argyropoulou et al., 1992; Zucchini et al.,
1995; Chapter 8.1). Abnormal embryonic development,
e.g. due to alcohol abuse during pregnancy, could serve
as an explanation. It is presumed that growth hormone is
the pituitary hormone most likely to be affected by lesions
in the hypothalamic region, since it has only a limited
reserve capacity for GHRH (Hellstrm et al., 1998). It is
of interest in this respect that isolated growth hormone
deficiency may go together with pituitary stalk interruption and ectopic neurohypophysis (Vanelli et al., 1997).
In the case of growth hormone deficiency associated
with a posterior pituitary hyperintense MRI signal,
patients without a pituitary stalk on MRI after gadolinium
injection present a more severe form of the disease in

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Fig. 18.12. The immunoreactivity of growth hormone-releasing hormone with antibody 747 in the arcuate nucleus of Noonans syndrome, Wolframs
syndrome and control cases. (a) A Noonans syndrome case stained with antibody 747; no. A253/94. (b) The same case as (a), shown at lower
magnification. (c) A 6-year-old control; no. 87-305. (d) The same case as (c), shown at lower magnification. Note that there is no clear difference
between the Noonans syndrome and control cases. Bar = 50 m. (Preparation by A. Salehi.)

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childhood, when associated with multiple anterior pituitary hormone deficiency (Chen et al., 1999b). The idea
that growth hormone deficiency is often a result of hypothalamic rather than pituitary dysfunction is supported by
the observation that synthetic GHRH analogues can
promote accelerated linear growth in such cases (Thorner
et al., 1985; Zucchini et al., 1995).
Drastic effects of growth hormone deficiency on intelligence have not been found (Meyer-Bahlburg et al.,
1978) and children with growth hormone deficiency
referred for growth hormone therapy are generally of
normal intelligence. However, they do have more learning
problems and are also at risk for behavioral problems.
Characteristically such children are shy, withdrawn
and socially isolated and have problems with mood and
attention. Anxiety, depression, somatic complaints and
attention deficits have been identified. The frequency of
these symptoms declines over a period of 3 years, beginning shortly after the start of the growth hormone
replacement therapy, which suggests that growth hormone
therapy might have central effects as well (Stabler et al.,
1996; Nyberg, 2000). Growth hormone also acts directly
on the brain, since growth hormone receptors are present
in the brain (Nyberg, 2000). Indeed, growth hormone
therapy early in development leads to a rapid catch-up
of cranial growth, whereas in isolated growth hormone
deficiency head circumference is reduced (Laron et al.,
1979). Moreover, hypopituitary women had significantly
lower scores in 4 out of 7 neuropsychological tests,
although they had received suitable replacement therapy
for TSH and ACTH insufficiency. This group of patients
had a higher incidence of mental disorders and increased
symptoms of mental distress. Although the cause of
impairment was most probably multifactorial, growth
hormone deficiency probably contributed to the results
(Blow et al., 2002). It thus seems that the central effects
of growth hormone should get more attention in the future.
Multiple pituitary deficiencies go together more
frequently with empty sella (34%) than isolated growth
hormone deficiency (less than 10%), in which few abnormalities of the sellar region are found. Empty sella is
generally considered to be of congenital origin, possibly
a malformation due to an incomplete or deficient sellar
diaphragm (Cacciari et al., 1990, 1994). However, empty
sella is commonly seen in patients with benign intracranial hypertension and may also be the sequel to
pituitary apoplexy. About 50% of the adult patients with
primary empty sella have antipituitary antibodies that
indicate previous autoimmune hypophysitis (Anderson

et al., 1999). Primary empty sella syndrome is frequently


accompanied by growth hormone deficiency and hypogonadotropic hypogonadism, but not by central
hypothyroidism (Cannavo et al., 2002). In addition, empty
sella accompanied by growth hormone deficiency is
observed in Gitelmans syndrome (Bettinelli et al., 1999).
Growth hormone deficiency in combination with empty
sella syndrome has also been described in BardetBiedl
syndrome (Chapter 23.3). Long-term survivors of childhood malignancies who received cranial and craniospinal
radiation may result in decreased final height. Substitution
of growth hormone after diagnosis of growth hormone
deficiency should be considered for these patients at a
young age (Mller et al., 1998a; Chapter 25.3). Partial
empty sellar syndrome with an atrophied pituitary gland
is seen in primary neuroendocrinopathies and in patients
with elevations in intracranial pressure and has once been
reported in a top body builder with a long history of
exogenous abuse of growth hormone, testosterone and
thyroid hormone. Whether this was due to negative
hormone feedback or frequent elevation of intracranial
pressure by weight lifting is not known (Dickerman and
Jaikumar, 2001).
Moyamoya disease is a rare vascular disease that results
in narrowing of the blood vessels of the circle of Willis
and the formation of a network of collateral vessels at the
base of the brain for compensatory perfusion (see Chapter
17.2). Moyamoya disease may be accompanied by growth
hormone deficiency and hypothyroidism (Mootha et al.,
1999).
In the acute phase of a severe head injury, an augmented
tone of both GHRH and somatostatin may be present. The
increased IGF-1 levels suggest that these alterations could
be advantageous for rapid recovery (De Marinis et al.,
1999). Growth hormone deficiency is also a very frequent
occurrence after neurosurgery for hypothalamus-pituitary
masses.
In narcolepsy patients, 50% of the growth hormone
secretion takes place in daytime, whereas controls secrete
only 25% during the day. Hypocretin deficiency (Chapter
28.4) is thus accompanied by a disruption of circadian
GHRH release (Overeem et al., 2003).
(c) Genetic forms of GHRH deficiency
An autosomal recessive form of hypothalamic GHRH
deficiency has been described. This is a genetically heterogeneous group of disorders that are generally inherited

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as an autosomal recessive trait. Autopsy of a 78-year-old


dwarf with this syndrome revealed a normal pituitary and
hypothalamus (Rimoin and Schechter, 1973). However,
no immunocytochemistry or quantification of hypothalamic nuclei was performed. In addition, two siblings
have been described with partial trisomy 1 (q31.1-q32.1)
due to a familial insertion. Short stature was found with
growth hormone deficiency and an ectopic pituitary
growth velocity responded well to treatment with growth
hormone. Intelligence was normal (Schorry et al., 1998).
Humans with GHRH resistance due to an inactivating
mutation in the GHRH-receptor gene have been described
that resemble in many aspects the little mouse model
that has a single base change (A G) in the gene for
the GHRH receptor. The human families became known
by the occurrence of a Karachi newspaper article on The
dwarfs of Sindh. The mode of transmission is autosomalrecessive with a high degree of penetrance. Several
families with mutations of the GHRH receptor have
now been described. The clinical picture of homozygous
individuals with the inactivating GHRH-receptor mutation largely resembles that of severe, isolated growth
hormone deficiency. The affected individuals have normal
proportions and look like miniature versions of normal
people. Although intelligence seems to be normal,
the skull is considerably smaller (some 4 SD below the
normal mean) than what has been described in classic
growth hormone deficiency, where head circumferences
are near normal to about 2 SD below normal. This is
in agreement with the microcephalus described in the
little mouse. The endocrine profile corresponds to that
of isolated growth hormone deficiency (Baumann and
Maheshwari, 1999).
In hereditary Gitelman disease, growth hormone
deficiency is associated with a partial vasopressin
deficiency, empty sella and a renal tubular disorder. It is
caused by mutations in the gene encoding the thiazidesensitive sodium chloride transporter (TSC; SLC12A3) of
the distal convoluted tubes (Bettinelli et al., 1999). In
addition, a possible familial syndrome of retinitis pigmentosa, growth hormone deficiency and acromegalic skeletal
dysplasia has been described (Hedera and Gorski, 2001).
In Downs syndrome the neuronal control of GHRH
secretion is impaired, while the pituitary growth hormone
pool is fully preserved. It is thought that the precociously
impaired tuberoinfundibular cholinergic pathways may
lead to somatostatinergic hyperactivity and low growthhormone responsiveness to GHRH (Beccaria et al., 1998;
Chapter 26.5).

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(d) Adult growth hormone deficiency


After cessation of longitudinal growth, growth hormone
continues to serve an important role in the regulation of
body metabolism to optimize body composition and function. In all species examined, peripheral growth hormone
levels decline with age (Bartke, 1998), probably reflecting age-related neurotransmitter control leading to GHRH
hypoactivity (Ghigo et al., 2000). Adults, especially those
with a history of hypothalamic or pituitary disease, or
those that underwent growth hormone treatment in childhood, may be deficient for growth hormone, which causes
adiposity, reduced lean body mass and reduced physical
fitness. Although some patients may be asymptomatic,
others have specific complaints of fatigue, low energy
levels, and impairment of memory and concentration.
Patients with growth hormone deficiency can be diagnosed by a provocative test such as an insulin-tolerance
test (Newman and Kleinberg, 1998). It has been suggested
that the age-related changes in growth hormone secretion
in humans may be due to an increased somatostatin tone.
Endocrine studies are, however, also compatible with the
view that the GHRH neurons may be involved in declining growth hormone secretion during aging (Russell-Aulet
et al., 1999). The contribution of GHRH to the maintenance of growth hormone secretion appears to be
sexually dimorphic and more important in men than in
women (Orrego et al., 2001). The concept that the
somatopause is primarily hypothalamically driven is supported by the observation that long-acting derivatives of
the hypothalamic peptide GHRH given subcutaneously to
healthy 70-year-old men increase growth hormone and
IGF-I levels to those encountered in 35-year-olds
(Lamberts et al., 1997b). Changes in GHRH neurons
during aging have so far not been studied in the human
hypothalamus.
In many adults who were growth hormone-deficient
as children, a high incidence of social phobia and depression has been found. Growth hormone-deficient adults
put on growth hormone therapy report improvements
in their psychological well-being and health, mental
alertness, motivation and working capacity, indicating
the presence of central effects of growth hormone in
adulthood. This possibility is reinforced by the observation that adult patients with either multiple pituitary
hormone deficiencies or isolated growth hormone deficiencies may show subnormal memory performance
that may be reversible with growth hormone treatment.
Growth hormone receptors are indeed present in the brain
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(Deijen et al., 1996; Nyberg, 2000). Growth hormone


may prevent the auto-cannibalistic effects of acute
diseases on muscle mass. Lamberts et al. (1997) have,
moreover, shown that, in a randomized placebo-controlled
trial of 6 weeks, growth hormone administration in
elderly individuals with an acute hip fracture causes a
statistically significant earlier return to independent
living after the fracture. Growth hormone replacement in
elderly people may also have positive effects on body
composition, exercise tolerance and lipids. Multicenter,
double-blind placebo-controlled long-term follow-up
studies are needed to study the long-term central effects
and side-effects of such a therapy (Whitehead et al., 1992;
Bartke, 1998; Newman and Kleinberg, 1998; Barkan
et al., 2000). Probably only a subgroup of elderly people
may benefit from growth hormone substitution (Marcus,
1996). Guidelines for the diagnosis and treatment of adults
with growth hormone deficiency have been formulated
(Invited report of a workshop, 1998). In a report of the
Australian multicenter trial of growth hormone treatment
in growth hormone-deficient adults, excessive IGF-1
levels were found, together with modest decreases in total
and low-density lipoprotein cholesterol, substantial reductions in fat mass and modest improvements in perceived
quality of life (Cuneo et al., 1998). Long-term follow-up
studies are needed even more now that overexpression of
growth hormone above the physiological range in transgenic mice and in patients with acromegaly is known to
be associated with reduced life expectancy. In contrast,
Ames dwarf mice with hereditary growth hormone,
prolactin and thyrotropin deficiency live much longer than
normal animals from the same strain (Bartke, 1998).
Acute critical illness or injury initially results in an
elevation of circulating levels of growth hormone. The
number of growth hormone bursts is increased, and
the peak growth hormone levels as well as interpulse
concentrations are high (Van den Berghe, 1999).
The catabolic state of prolonged critical illness is considered to be a natural defense mechanism in case of serious insults, providing the metabolic substrates and host
defense required for survival and for the delay of anabolism.
This condition of protein wasting is not prevented or
reversed by food. The endocrine response to prolonged illness consists of an inactivation of anabolic pathways, i.e. a
decreased activity of the thyrotropic axis as found in nonthyroidal illness (Chapter 8.6c), reduced pulsatile secretion
of ACTH, TSH, luteinizing hormone (LH) and prolactin,
and a low activity of the somatotropic axis, as indicated by
reduced pulsatile growth hormone levels and IGF-1 levels.

The pathogenesis apparently has a hypothalamic component, since both axes are readily activated by coinfusion of
TRH and growth hormone secretagogues (Van den Berghe
et al., 1998). In fact, infusion of growth hormone secretagogues appears to be a novel endocrine strategy to reverse
the catabolic state of critical illness (Van den Berghe et al.,
1997a, Van den Berghe, 2000).
18.7. Hydrocephalus
(a) Hydrocephalus and the subcommissural organ
The subcommissural organ lies below the rostral part of
the posterior commissure and develops in the second
month of intrauterine life, concurrently with the pineal
gland, to reach its maximum development during fetal
life. It regresses around the time of puberty. In the adult
only isolated relics remain. This organ is highly permeable but does not have fenestrated capillaries. Therefore,
it formally fails to qualify as a circumventricular organ.
There is some evidence that it may be involved in the
hypertension produced by aldosterone acting on the brain.
The subcommissural organ also contains an appreciable
number of prolactin receptors that may be involved in
the regulation of water metabolism. Moreover, the subcommissural organ is a secretory organ and the site of
origin of Reissners fiber, a mucopolysaccharide strand
that passes down the center of the brainstem and spinal
cord to the filum terminale (Ganong, 2000). In human
fetuses of 180230 mm crown-to-heel length, a subcommissural organ is found that has glandular properties.
The posterior lobe of the pineal organ is built up from
this specialized ependyma. A Reissners fiber, however,
has not been formed at that moment (Olsson, 1961). Two
main components of the subcommissural organ are
distinguished: the ependymal part, forming the secretory
cells, and the hypendema, which consists of glia, vascular
and parenchymal-like cells. In experimental animals
spontaneously showing hydrocephalus, and in induced
postnatal hydrocephalus, complete absence or a progressive reduction of the subcommissural organ has been
found. In two hydrocephalic brains from spontaneous
abortions of 20 and 21 gestational weeks that showed a
significant dilation of the lateral and third ventricles, the
subcommissural organ was also severely altered. The
rostrocaudal length was only 50% of its normal value,
and the global volumes were much smaller. The pseudostratified ependymal cells, normally high, were arranged

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Fig. 18.13. Frontal views of the subcommissural organ (SCO) and subjacent ependyma. A, B: SCO of the normal case 3H. D, E: SCO of the
hydrocephalic case 1H. C, F: border between SCO and subjacent ependyma of the fetal brain (C, normal; F, hydrocephalus; PC, posterior
commissure). Bars: A, D 60 m; B, C, E, F 35 m. (From Castaeyra-Perdomo et al., 1994; Fig. 2 with permission.)

in a narrow layer (Fig.18.13; Castaeyra-Perdomo et al.,


1994). These alterations might be interpreted as a consequence of hydrocephalus (Weller and Schulman, 1972),
since atrophy of the ependymal lining as well as of the

paraventricular nuclei has been reported in cases of


slightly increased pressure of the cerebrospinal fluid
(Bauer, 1959). Castaeyra-Perdomo et al. (1994), on the
other hand, interpret the presence of a possibly functional
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but considerably reduced subcommissural organ in one of


their subjects as a precocious involution of the organ, possibly causing pathological changes in the regulation of
fetal cerebrospinal fluid, and ultimately leading to hydrocephalus. At present, cause and effect of the dysplastic
subcommissural organ changes in the fetus with hydrocephalus are not clear.
(b) Hypothalamic symptoms of hydrocephalus
In some 38% of hydrocephaly cases, optic nerve hypoplasia
is involved (Zeki et al., 1992; Chapter 18.3). A 4-year-old
child with optic chiasm glioma, nonobstructive hydrocephalus, optic nerve hypoplasia and hypernatremia
without polyuria or polydipsia, possibly due to hypothalamic osmoreceptor dysfunction, has been described.
She had postventriculoperitoneal shunting ascites that
improved with chemotherapy. The high protein content
was presumed to alter CSF adsorption (Shuper et al.,
1997). Permanent visual loss is a well-established major
sequela of idiopathic intracranial hypertension. One case
has been reported of a woman who had visual loss, an
empty sella turcica and polycystic ovary syndrome (Au
Eong et al., 1997). Hydrocephaly of the child may go
together with low estriol excretion by the pregnant mother
(Macafee et al., 1973), illustrating the importance of an
intact fetal hypothalamicpituitaryadrenal axis for the
production of this maternal hormone. Increased CSF levels
of vasopressin have also been recorded in hydrocephalus
(Srensen et al., 1985; Srensen, 1986).
In children, akinetic mutism has been described as an
extremely rare complication of obstructive hydrocephalus,
possibly due to damage of the ascending dopaminergic
projections that run periventricularly. The gradually
increasing size of the third ventricle will probably damage
the median forebrain bundles that contain the dopaminergic projections coming from the brainstem (Lin et al.,
1997). Indeed, parkinsonism has been found to be associated with akinetic mutism in a case of obstructive
hydrocephalus that was treated with a shunt. Other
patients with akinetic mutism after surgical removal of a
tumor from the anterior hypothalamus, or patients with
obstructive hydrocephalus, responded to dopamine
receptor agonists, but not to presynaptic dopamine
mimetics, supporting the idea that the symptoms were
due to a loss of dopaminergic input (Ross and Stewart,
1981; Anderson, 1992).
Hydrocephalus may also be accompanied by behavioral
disorders: a 9-year-old child has been described with a

psychosis due to a third ventricular choroid plexus papilloma and mild to moderate hydrocephalus (Carson et al.,
1997; see Chapter 17.3).
High serum levels of growth hormone, IGF-I and
diabetes mellitus have been reported in a case of obstructive hydrocephalus caused by a diverticulum of the third
ventricle. IGF-I is a mediator of growth hormone. The
endocrine abnormalities improved after the placement of
a ventriculoperitoneal shunt. The diverticulum of the third
ventricle might have compressed the aquaduct through
the dorsal and ventral aspects of the mesencephalon. It
is not clear whether the increased growth hormone levels
were due to hypersecretion of GHRH or hyposecretion
of somatostatin from the hypothalamus (Okada et al.,
1998).
Autonomic dysfunction is often associated with hydrocephalus (Thorley et al., 2001) and the cardiovascular
failure that may suddenly lead to unexpected death may
be due to pressure on the hypothalamus and other brain
structures (Rickert et al., 2001).
(c) Causes of hydrocephalus
Chronic hydrocephalus in later life may result from
aquaduct stenosis. Compression of the surrounding
parenchyma may result in dysfunction of the hypothalamopituitary axes, leading to precocious puberty,
amenorrhea, hyperinsulinemia, impaired growth hormone
responses, abnormalities of temperature control, obesity,
diabetes insipidus, abnormalities of autonomic regulation,
visual symptoms, and disorders of temperature and other
biological rhythms. The hypothalamus may ultimately be
transformed into a thin membrane with a loss of nuclear
architecture and gliosis (Page et al., 1973; Suzuki et al.,
1990; Horvath et al., 1997). A cyst of the septum pellucidum is rarely so large that it leads to hydrocephalus,
but a number of such cases have been described (Sarwar,
1989; Silbert et al., 1993; Lancon et al., 1996; Chapter
18.8). However, a colloid cyst of the third ventricle may
more frequently cause hydrocephalus (Chapter 17.3a;
Hwang et al., 1996). Hydrocephaly, in addition, may be
caused by cavernous malformations of the third ventricle
when these are situated in the region of the foramen of
Monro (Katayama et al., 1994; Chapter 17.2a).
Diencephalic syndrome may go together with hydrocephalus (Chapter 19.4) and craniopharyngiomas of early
childhood can produce hydrocephalus and symptoms of
increased intracranial pressure (Costin, 1979; Chapter
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(Todd et al., 2000; Chapter 19.10). In addition, hydrocephaly is a symptom of Biemond syndrome type
II and related disorders (Verloes et al., 1998; Chapter
23.3b).
Endoscopic third ventriculostomy has become a wellestablished procedure for the treatment of various forms
of noncommunicating hydrocephalus. Although it is
generally considered to be an easy and safe procedure, a
case in which the patient suffered a fatal subarachnoidal
hemorrhage has been reported in the literature. In order
to avoid vascular injury, perforation of the floor of the
third ventricle should be performed in the midline,
halfway between the infundibular recess and the mamillary bodies, just behind the dorsum sellae. If it is done
this way, diabetes insipidus, oculomotor palsy and
vascular injury are claimed to be unlikely to occur
(Chapter 17.1i).

47

months. Moreover, the cavum septum pellucidum is seen


in 1220% of the adult autopsies but in much lower
frequencies in neuroimaging studies (i.e. some 2.2%).
This discrepancy is probably due to the CSF that is
drained from the ventricles at autopsies and the limited
resolution of imaging techniques (Bruyn, 1977; Sarwar,
1989). In addition, the prevalence of the cavum septum
pellucidum, determined by patient seclection since
Pauling et al. (1998) found that the incidence was 1.1%
in healthy children vs. 6.9% as the outcome of a clinical
pediatric sample. This possibility is supported by the work
of Nopoulos (1990). A cyst of the septum pellucidum is
arbitrarily defined as a space with a diameter of more
than 10 mm. Symptomatic cysts are rare (Sarwar, 1989),
but an expanding cyst of the septum pellucidum may
cause obstruction of the interventricular foramina and
produce headaches, papilledema, emesis and loss of
consciousness. Behavioral, autonomic, sensorimotor,
neuro-ophthalmic symptoms and hydrocephalus may
occur (Lancon et al., 1996).
The cavum Vergae (Verga, 1851) is the posterior extension of the cavum septum pellucidum and develops in
the 5th month of pregnancy. It is connected to the cavum
septum pellucidum by an aquaduct (Fig. 18.14).
Embryologically they are a single cavity. The cavum
Vergae does not extend further than the recessus suprapinealis of the third ventricle and according to autopsy
studies it is present in 100% of the fetuses but only in
30% of the full-term neonates. Anteriorly its boundaries
are the anterior limbs of the fornix, superiorly the
boundary is the body of the corpus callosum, posteriorly
it is the splenium and inferiorly the psalterium and
hippocampal commissure (Bruyn, 1977; Sarwar, 1989).
A cavum Vergae alone does not identify individuals at
risk for cognitive delays, in contrast to a cavum septum
pellucidum that may serve as a significant marker of
neurodevelopmental abnormalities (Bodensteiner et al.,
1998). A cyst of the cavum Vergae causing definite symptoms is a rare occurrence (Leslie, 1940).
Although there is a great deal of controversial literature about this subject it seems that there is no statistically
significant relationship between the prevalence of a cavum
septum pellucidum and cavum Vergae, either on their
own or concurrently, and neurological or psychiatric
deficits (Bruyn, 1977; Sarwar, 1989; Schaefer et al., 1994;
Kwon et al., 1998). Nevertheless, a wide cavum septum
pellucidum in which the leaves of the cavum are separated by more than 1 cm is frequently associated with
abnormalities of neurological function. Variations in the

18.8. Septum pellucidum abnormalities


The septum pellucidum, called septum telencephali by
Stephan and Andy (1962), is a thin translucent plate of
two laminae and extends from the anterior part of the
corpus callosum to the superior surface of the fornix, and
from the organum vasculosum lamina terminalis to the
splenium of the corpus callosum. The septum pellucidum
is continuous with the septum verum (Chapter 7.3). The
septum pellucidum is only present in higher primates. It
forms at 67 weeks of gestation (Groenveld et al., 1994)
and contains glia cells, fibers, some scattered neurons and
veins that connect with the choroid plexus. It is lined
with ependyma on the ventricular side. The septum pellucidum is an important relay station between the
hippocampus and hypothalamus (Bruyn, 1977; Sarwar,
1989), but a functional deficit in their ability to navigate
was not found in children without a septum pellucidum
(Groenveld et al., 1994).
The cavum septum pellucidum, first described by the
Leyden professor Francois Dubois de la Bo or Silvius
in 1671 (Bruyn, 1977), is a space between the mesial
blades of the septum pellucidum (Fig. 18.14). The cavum
septum pellucidum is thus not part of the ventricular
system and should not be considered as the fifth
ventricle. The one-cell-thick lining of the cavum is not
epidymal. It is bordered superiorly by the corpus callosum
and anterior commissure and its floor is formed by the
fornix. It is macroscopically present as a 1-mm-wide
space in 100% of the fetuses, in 85% of the subjects at
1 month postnatally, 45% at 2 months and 15% at 36
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Fig. 18.14. ac. Schematic representation of the cerebral ventricular


system. (a) Lateral view; hatched area represents the cavum septi pellucidi (1), the aquaductus septi (2) and the cavum Vergae (3). (b, c)
Anteroposterior view, showing cavum septi pellucidi (b) and both cava
(c) (dotted areas). (From Bruyn, 1977, Fig. 8, p. 303.)

septum pellucidum might represent anomalous development of midline structures and might therefore be one of
the markers associated with clinical abnormalities such
as mental retardation (Schaefer et al., 1994). Indeed, a
number of cases of neurological and psychiatric disorders have been described that are associated with the
presence of a cavum septum pellucidum. An increased
prevalence of cavum septum pellucidum may be related
to boxing injuries, described as dementia pugilistica or
punch-drunk syndrome. A cavum septum pellucidum is
present in 18% of boxers and in 5% of the general population. The main width of the cavum is 5.2 mm, compared
with only 3% of the control subjects, and it is not
uncommon for the fornix to become totally severed
(Corsellis et al., 1973; Casson et al., 1984; Silbert et al.,
1993). Although there is no question that there is a
positive association between professional boxing and the
presence of a cavum septum pellucidum, it has been
hypothesized that this abnormality may be one of the
alterations in the limbic system, resulting in a behavior

that makes pugalism a more attractive career choice in


this subgroup of people (Bodensteiner and Schaefer,
1997). This possibility can be studied by prospectively
scanning those who want a license to fight professionally. Patients with large cysts of the septum pellucidum
and cavum Vergae have been reported who suffered from
persistent or intermittent obstructive hydrocephalus, intermittent headache and postural loss of consciousness. The
symptoms are directly related to pressure effects from the
cavum septum pellucidum, since stereotactic puncture of
the cyst or shunting produces a sustained remission from
further headaches (Silbert et al., 1993). Cases with
akinetic mutism have been reported that are related with
pathology in the septal area or hypothalamus. Akinetic
mutism resulting from obstructive hydrocephalus, e.g.
following shunt failure, is thought to be due to damage
to the periventricular area, where ascending dopaminergic
projections pass. Two of such cases (9 years and 13 years
of age) were reported to have a prominent cavum septum
pellucidum (Lin et al., 1997). It is, however, not clear
what the exact role is of the observed wide cavum septum
pellucidum in the pathogenesis of akinetic mutism in these
children. Midline cerebral malformations, e.g. cavum
Vergae and cavum septum pellucidum, are also more
frequently found in schizophrenia (Scott et al., 1993;
Kwon et al., 1998; Nopoulos et al., 1998; Rajarethinam
et al., 2001). The enlargement of a cavum septum pellucidum may even be more severe in patients with childhood
schizophrenia. Moreover, patients with a complete nonfusion of the septal leaflets were observed in this category,
lending further support to the probability of a developmental disorder as arising of this disease (Nopoulos et
al., 1998; Chapter 27.1). The presence of a cavum septum
pellucidum in schizophrenia may be associated with a
poor prognosis (Fukuzako and Kodama, 1998). Cavum
septum pellucidum not only has increased prevalence in
schizophrenia and neurodevelopmental disorders, but also
perhaps in other psychotic disorders (Kirkpatrick et al.,
1997; Kwon et al., 1998). Indeed, after a comprehensive
review, Bruyn (1977) concluded that one-third to onehalf of the patients with cavum septum pellucidum had
seizures and 15% often suffered from psychosis, dementia
and/or personality changes. This conclusion has been
supported by the study of Kwon et al. (1998), who
observed an increased prevalence of cavum septum pellucidum, not only in schizophrenia patients but also in
patients with affective disorder or schizotypical personality disorder. The combination of cavum septum
pellucidum and schizophrenia has been associated with

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part of a spectrum of complex midline craniofacial malformations. Moreover, a case of septo-optic dysplasia in
Cornelia de Lange syndrome has been described (Hayashi
et al., 1996; Chapter 32.2). Overlap occurs between septooptic dysplasia, optic nerve hypoplasia and the syndrome
of an absent septum pellucidum with proencephaly. The
septum pellucidum is also absent in holoprocephaly, in
Aperts syndrome (acrocephalosyndactyly), sometimes
following neonatal leptomeningitis, or neonatal brain
trauma, and can be present in Chiari type II malformations (Bruyn, 1977; Sarwar, 1989; Groenveld et al., 1994).
Tumors that originate from the septum pellucidum are
extremely rare, but gliomas, astrocytomas and oligodendrogliomas from the corpus callosum may extend into
the septum pellucidum. Midline lipomas, sometimes calcified, are usually developmental malformations of the
corpus callosum, but a lipoma confined to the septum
pellucidum has been described (Sarwar, 1989). Tumors
in the septal region may be associated with aggression
(Albert et al., 1993). Slowly growing tumors of the anterior midline structures affecting the septum pellucidum
and adjacent structures such as the fornix may in addition cause emotional instability and memory problems,
while, in fast-growing tumors, increasing stupor is seen
(Zeman and King, 1959).

hemizygous deletion of 22q11 chromosome (Catch 22


syndrome), and to partial trisomy of chromosome 5
(Vataja and Elomaa, 1998). In mental retardation or developmental delay, the frequency of septum pellucidum is
increased, but a cavum Vergae has been observed with
the same frequency as in normal and retarded populations (Bodensteiner et al., 1998). A rare case of an abscess
that formed in the cavum septum pellucidum after the
elimination of a bacterial meningitis by antibiotics has
been reported. The abscess disappeared during continuation of the antibiotics (Kihara and Miyata, 2002).
The absence of the septum pellucidum almost always
signifies substantial neurological disease, since it is hardly
ever an isolated finding. However, isolated absence of
the septum pellucidum does exist (Supprian et al., 1999),
and the rare absence of the septum pellucidum alone does
not predict significant intellectual, neurological or behavioral dysfunction (Groenveld et al., 1994). A few patients
present with schizophrenic psychosis (Supprian et al.,
1999). Agenesis of the septum pellucidum can be part of
a developmental brain disorder such as schizencephaly
(Denis et al., 2000) as part of a continuum of the spectrum of proencephaly or the absence can be acquired in
case of a long-standing, substantial hydrocephalus. In the
developmental category, septo-optic dysplasia should be
mentioned (see Chapter 18.3), which is considered to be

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)


The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved

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CHAPTER 19

Tumors

19.1. Symptoms due to hypothalamic tumors

(67%), hypothalamic hamartomas (100%) and subarachnoid cysts or arachnoidocele (100%). With the exception
of one patient with pineal germinoma, all lesions were
localized in the suprasellar area. The data suggested that
in glial cell tumors (Chapter 19.4), hamartomas (Chapter
19.3), gangliogliomas of the tuber (Chapter 19.3c) and
subarachnoid cysts an unknown factor, probably secreted
by the tumors, accelerates luteinizing hormone-releasing
hormone (LHRH) maturation (Rivarola et al., 2001). A
cranial MRI is thus indicated for children with central
precocious puberty (Ng et al., 2003). Tumors of the
tuberal and preoptic region of the hypothalamus are often
found in hypogonadism (Bauer, 1954). This is the case,
e.g. for craniopharyngioma (Chapter 19.5a), infundibuloma (Chapter 19.4c), pineal region tumors (Chapter
19.7), peritheloid sarcomas and angiomas. Other symptoms of hypothalamic tumors are hyperphagia and obesity
(Fig. 19.13), subcutaneous fat depletion (Connors and
Sheikholislam, 1977), fits of rage (Albert et al., 1993;
Chapter 26.3 for ventromedial hypothalamus syndrome),
amnesia, and attacks of laughter or crying (Bauer, 1954;
Haugh and Markesbery, 1983; Kahane et al., 1994;
Chapters 19.2, 19.3, 19.5). Cachexia (diencephalic
syndrome; Chapter 19.4a) and markedly elevated leptin
plasma levels, with increasing body mass index (Bmi),
are found in patients with hypothalamopituitary damage,
which suggests unrestrained leptin secretion. Leptin insensitivity is presumed in these patients (Patel et al., 2002).
In a patient with a probable hypothalamic germ cell
tumor, hypoadrenalism, hypogonadism, diabetes insipidus
and hypercalcenia have been found (Hotta et al., 1998).
Cushing described patients with hypothalamic tumors
associated with a duodenal ulcer and proposed the
existence of a parasympathetic center in the hypothalamus, which would send fiber tracts to the vagal center

Primary tumors and metastasis may be the causes of


nonspecific symptoms such as headaches, nausea,
vomiting, papilledema or seizures, or of more specific
hypothalamic symptoms, depending on the size of the
tumor and its location. But also in nonspecific symptoms
the hypothalamus may be involved. For instance, plasma
and cerebrospinal fluid (CSF) levels of vasopressin are
increased in brain tumors with brain edema (Tenedieva
et al., 1994), and intracranial tumors may accompany
increased levels of CSF vasopressin (Srensen et al.,
1985; Srensen, 1986; Tenedieva et al., 1994).
(a) Endocrine and autonomic disturbances
Bauer (1954) reviewed 60 cases with various hypothalamic lesions that were collected from the literature and
that consisted largely of different kinds of hypothalamic
tumors, which are dealt with in Chapters 19.119.9. This
group of tumors contained low-grade optic gliomas as
found in pediatric patients with neurofibromatosis type I
(Robben et al., 1995; Chapter 19.4b), an astrocytic hamartoma (Chapter 19.3a), an infundibuloma (Chapter 19.4c),
astrocytoma (Chapter 19.4b), ependymoma or germinoma
(see Chapter 19.2).
Bauer (1954) listed a number of tumors, such as
hamartomas, that affect the posterior region of the hypothalamus, in particular the corpora mamillaria, and that
may cause precocious puberty (Chapters 19.3, 24.1).
Ganglioglioma were found to produce precocious puberty
in babies, three times more often in boys than in girls
(Sheehan and Kovacs, 1982; Chapter 19.4c). In a more
recent study, precocious puberty was found to be associated with glial cell tumors (19%), germ cell tumors
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(Carmel, 1985; Dolenc, 1999; Buijs and Kalsbeek, 2001;


Chapter 30). Autonomic seizures, paroxism of hypertension, tachycardia and sweating have been found in the
diencephalic syndrome (Chapter 19.4a; Connors and
Sheikholislam, 1977). When tumors cause ventricular
obstruction with a rise in intracranial pressure and/or
hydrocephalus, a loss of circadian temperature fluctuations may be found (Page et al., 1973), due to a disorder
of the circadian system (Chapter 4).
Other hypothalamic symptoms found in cases
with tumors are retarded growth, diabetes insipidus,
amenorrhea, panhypopituitarism, dysthermia, bulimia,
hydrocephalus (Coffey, 1989; see also Chapters
19.219.5, 19.7), prolonged fever and hyponatremia

(Spiegel et al., 2002; Chapters 22.6, 30.2). Tumors in the


region of the optic pathway or infundibulum may cause
optic atrophy, visual deficits (see Chapters 19.219.5)
or visual hallucinations (Baruk, 1936; Haugh and
Markesbery, 1983). Hypothalamic hamartomas (Chapter
19.3) may cause gelastic seizures, but this may also occur
after tumors (Chapter 26.2). Following a hypothalamic
glioma, a patients sexual orientation changed from
heterosexual to pedophile with impotence (Miller et al.,
1986; Fig. 19.1; Chapter 24.5e).
Hypothalamic lesions due to craniopharyngioma or
pilocytic astrocytoma may be accompanied by decreased
nocturnal melatonin levels and increased daytime sleepiness (Mller et al., 2002a).

Fig. 19.1. An infiltrating hypothalamic glioma in a patient with a change in sexual orientation from heterosexuality to pedophilia. (From Miller
et al., 1986, Fig. 3 with permission.)

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astrocytoma (Sorensen et al., 1995). Akinetic mutism was


observed following surgical removal of an epidermoid
cyst from the anterior hypothalamus that had probably
destroyed the median forebrain bundles that contain the
dopaminergic projections (Ross and Stewart, 1981;
Chapter 18.8). A similar condition has been described in
the literature in a case of chronic encephalitis that led to
destruction of the posterior hypothalamic nuclei and the
mamillary bodies. On the basis of akinetic mutism due
to an epidermoid cyst of the third ventricle (Cairns et al.,
1941), it was hypothesized nearly 40 years ago that
consciousness depends on the synthesis of impressions
from the outside world with those from inside the body,
and that hypothalamicthalamic connections, such as the
bundle of Vicq dAzyr and the connection between the
posterior hypothalamic nucleus and the medial nucleus
of the thalamus, would play a crucial role in this process.
From the data that are available now it seems that
lesioning of the dopaminergic projections from the brainstem is responsible for the symptoms of akinetic mutism
(Chapter 18.8). Removal of a hypothalamic tumor resulted
in an overwhelming urge to sleep during daytime. This
was hypothesized to be due to destruction of the suprachiasmatic nucleus (Chapter 4) or to an incomplete lesion
of the hypocretin/orexin system (Arii et al., 2001; Chapter
14, 28.4). Tumors, especially of the posterior part of the

(b) Cognitive and behavioral disorders


Psychiatric symptoms due to the tumors localized in the
hypothalamus included psychiatric disturbances, diagnosed, for example, as schizophrenia, psychoneurosis and
manic excitement (Malamud, 1967; Chapter 27.1; Fig.
19.2). Another example is a 9-year-old boy with a choroid
plexus papilloma of the third ventricle (Chapter 17.3c)
who developed a psychosis (Carson et al., 1997; Chapter
19.5a). A patient with craniopharyngioma (Chapter 19.5)
or prolactinoma may present with a significant behavioral
disturbance accompanied by deteriorated work performance, intermittent explosive disorder, hypersexual
behavior, confusional syndromes and hallucinations
(Carroll and Neal, 1997).
Patients with tumors of the region of the third ventricle
may exhibit the symptoms of Korsakoffs syndrome:
some impoverishment of intellect, changes of personality
(usually euphoria or apathy), disorientation, confabulation and memory impairment. The memory defects
concern both imprinting and retrieval (Williams and
Pennybacker, 1954). Tumors causing bilateral destruction
of the fornix may cause memory problems (Chapter 16),
but there are exceptions (Woolsey and Nelson, 1975).
Periods of transient global amnesia have been reported
after spontaneous hemorrhage in a hypothalamic pilocytic

Fig. 19.2. Left, periventricular location of tumor in floor, walls, and roof (including fornix) of third ventricle. Right, Histologic appearance of a
glioblastoma multiforme with characteristic pleomorphism, giant cells and focal necrosis (hematoxylin Van Gieson; slightly reduced from  75).
The clinical diagnosis was schizophrenic reaction and epilepsia of unknown origin. (From Malamud, 1967, Fig. 4 with permission.)

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hypothalamus, may cause somnolence or altered levels


of consciousness (Davison and Demuth, 1946; Coffey,
1989). Coma with hyperthermia is a prominent symptom
after acute injury of the hypothalamus, seen, e.g. after
removal of craniopharyngial tumors from the floor of the
third ventricle (Cairns, 1952).
Near total destruction of the anterior and middle part
of the hypothalamus and a partial preservation of the more
caudal part following total removal of a craniopharyngioma in a child has been described. The child survived
for a period of 6 years. The following symptoms were
found: diabetes insipidus due to destruction of the
supraoptic and paraventricular nucleus (SON and PVN;
see Chapter 22.2), chronic hypernatremia, which persisted
in spite of vasopressin substitution, absence of thirst
(characteristic of a lesion of the anterior hypothalamus;
Chapter 22.2), hyperphagia (based upon lesion of the
PVN and ventromedial nucleus (VMN)); (Chapters 23.1,
26.3), hypothyroidism and hypoadrenalism due to a
lesion of the PVN; Chapters 8.5, 8.6), impairment of
temperature regulation (damage of, e.g. the laterocaudal
hypothalamus, preoptic area and PVN; Chapter 3030.2),
abnormality of sleep pattern and reversal of diurnalnocturnal sleep rhythms, probably due to a lesion of
the suprachiasmatic nucleus (SCN) and posterior
hypothalamus; Chapter 4), episodic savage behavior
(lesion of the VMN; Chapter 26.3, 26.9) and diabetes
mellitus due to hyperphagia (Killeffer and Stern, 1970;
Chapter 26.3).
Hypothalamic syndromes may also be caused by a large
number of different pathological processes that arise in
the pituitary or the parasellar region, e.g. due to pituitary masses that undergo silent infarction, cysts, pituitary
adenomas, acute or chronic infection with abscess formation, metastasis or aneurysms (Melmed, 1995).
The syndrome of idiopathic hypothalamic dysfunction
of childhood may accompany permanently dilated pupils,
obesity, central hypoventilation, hypersomnia, hyperphagia, personality changes, abnormal temperature
regulation, decreased sensitivity to pain, adipsic hypernatremia, hyperprolactinemia, seizures amd precocious
puberty (North et al., 1994; Sirvent et al., 2003; Chapter
32.1). It is thought to be a nonmetastatic paraneoplastic
syndrome, secondary to a neuronal crest tumor, e.g. to
a ganglioneuroma or ganglioneuroblastoma. There can
be extensive lymphocytic/histocytic infiltrates in the
hypothalamus and other brain areas, associated with
some neuronal loss and reactive gliosis. The neoplasm
may produce antineuronal antibodies, such as anti-Hu

(Ouvrier et al., 1995), as has also been observed in limbic


encephalitis (Alamowitch et al., 1997; Chapter 32.1).
Paraneoplastic encephalitis is characterized by personality changes, irritability, depression, seizures, memory
loss and sometimes dementia, due to antineuronal antibodies. Patients with anti-Ta (also called anto-Ma2)
antibodies are young men with testicular tumors. They
frequently show hypothalamic involvement through
symptoms such as diabetes insipidus, loss of libido,
hypothyroidism, hypersomnia, hyperthermia and panhypopituitarism, and a poor neurological outcome. Sometimes
the outcome is favorably influenced by treatment of the
tumor (Gultekin et al., 2000).
19.2. Germinoma and teratoma
One-third of all brain tumors in the pineal region (see
Chapter 19.7) consist of parenchymal tumors (pineocytomas, pineoblastomas), one-third of glia tumors
(astrocytomas, ganglion gliomas) and one-third of germ
cell tumors, of which less than one-third are germinomas
(Styne, 1993; Fig. 19.19). Germinomas and teratomas are
tumors of germ cell origin and make up 0.49.4% of all
childhood brain tumors. Germinomas are the least differentiated of the germ cell group, whereas teratomas
differentiate along all three germ cell layers (Fig. 19.3;
Chong and Newton, 1993). Germ cell tumors may contain
one cell type (pure) or more than one cell type
(mixed) (Schut et al., 1996). Twenty to thirty-five
percent of the germinomas are present in the sellar and
suprasellar region.The age of the patients is limited to
the first three decades. Germinomas were previously
known as pinealomas, ectopic pinealomas, atypical
teratomas or dysgerminomas (Coffey, 1989; Fujisawa
et al., 1991; Styne, 1993; see Chapter 19.7). They tend
to be located in the midline area, such as in the pineal
region (Chapter 19.7), and in the suprasellar and third
ventricular regions. Germinomas of the hypothalamoneurohypophysial axis seem to originate from the
neurohypophysis (Saeki et al., 2000). A 5-year-old girl
that presented with diabetes insipidus and a loss of the
hyperintense MRI signal of the neurohypophysis was
found to have an immature hypothalamic teratoma 7
months later (Lee et al., 1996). A 16-year-old boy had
polyuriapolydipsia and diplopia. MRI was suggestive of
an optic nerve glioma, but the high human chorionic
gonadotropin (HCG) levels led to the right diagnosis, i.e.
germinoma (Carella et al., 1999). Neurohypophysial
germinomas may cause not only diabetes insipidus and

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Fig. 19.3. Suprasellar teratoma. A. Parasagittal MR scan shows an area of hyperintensity in the interpeduncular cistern, representing the fatty
component of the tumor. B. Midsagittal section shows the more solid portion of the tumor with irregular areas of hyperintensity and isointensity.
C. Midsagittal postcontrast-enhanced MRI scan shows enhancement of the solid portion of the tumor. (From Chong and Newton, 1993, Fig. 27
with permission.)

et al., 1997). The initial endocrine symptoms are generally diabetes insipidus or pituitary insufficiency, but also
hyperprolactinemia, hydrocephalus, visual field defects
and optic atrophy (Coffey, 1989; Fujisawa et al., 1991;
Rutka et al., 1992; Chong and Newton, 1993; Nishio et
al., 1993a; Mootha et al., 1997; Saeki et al., 2000; Iwaki,
2001). In addition, polydipsia and adipsia have been
reported (Zazgornik et al., 1974). In a woman with a
hypothalamic germinoma, profound anterograde amnesia
and hyperphagia were reported (Coffey, 1989).
Interestingly, the fine structure of the suprasellar germinoma which can be revealed by transphenoidal biopsy
when the lesion progresses or if tumor markers (see
below) are positive (Mootha et al., 1997) is identical
to that of the classic testicular seminoma, consisting of
primordial germ cells with large pleomorphic nuclei with
prominent bar-like nucleoli and vacuolated cytoplasm
containing alkaline phosphatase (Schut et al., 1996), infiltrated with lymphocytes.
In men, germinomas may cause precocious puberty
because they may secrete chorionic gonadotropins
(HCG), which stimulate the secretion of testosterone.
Some germinomas such as endothelial sinus tumors

multiple anterior pituitary deficiencies, but also compression of the optic chiasm and of the hypothalamus (Saeki
et al., 2000). What we know of the pineal germinomas
also applies to those of the suprasellar region (Schut
et al., 1996); they have even been seen synchronously in
a few patients (Ellenbogen and Moores, 1997; Saeki
et al., 1999; Fig. 19.4), suggesting a common origin.
Germinomas are malignant but also highly radiosensitive,
which makes early diagnosis of vital importance
(Fujisawa et al., 1991; Mootha et al., 1997; Leger et
al., 1999). Endoscopic management of a pineal and
suprasellar germinoma has been reported (Ellenbogen
and Moores, 1997). A combination of radiotherapy and
chemotherapy is advocated in order to improve the
outcome. However, pituitary dysfunctions often persist
after treatment (Saeki et al., 2000).
In contrast to craniopharyngiomas, germinomas tend
to be homogeneous and rarely have cystic components.
The first abnormal, contrast-enhanced MRI finding is
generally isolated pituitary stalk thickening (Mootha et
al., 1997; Czernichow et al., 2000). The normally hyperdense MRI signal of the posterior pituitary is often absent
(Rutka et al., 1992; Chong and Newton, 1993; Mootha
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Fig. 19.4. Pineal and suprasellar germinoma. Precontrast (A) and postcontrast-enhanced (B) midsagittal MR imaging scans. A suprasellar-enhancing
mass has caused distortion of the anterior third ventricle. Note also the downward displacement of the supratentorial portion of the aqueduct and
the anterior displacement of the posterior third ventricle caused by the pineal-region mass (arrows). (From Chong and Newton, 1993, Fig. 26 with
permission.)

secrete -fetoprotein or placental alkaline phosphatase,


which may also be used as tumor markers (Styne, 1993;
Mootha et al., 1997; Carella et al., 1999; Rivarola et al.,
2001; Fig. 19.18). Increased serum levels of lactate-dehydrogenase have been proposed as another marker for a
germinoma (Carella et al., 1999). HCG is strongly
elevated in chorion carcinomas (Schut et al., 1996). With
the exception of the benign teratoma, all intracranial germ
cell tumors are malignant, capable of CSF dissemination
and of forming systemic metastases. Tumors in the
suprasellar region may be metastatic when it concerns
germinomas involving the pineal gland. Pineal region
germinomas (Fig. 19.4) are more common in males, while
there is a distinct predilection for females to harbor these
tumors in the suprasellar region. Subependymal spread
along the lining of the third ventricle is a common feature
(Rutka et al., 1992; Chong and Newton, 1993; Iwaki,
2001). In a 25-year-old man, a neurohypophysial tumor
that presented with visual disturbance and hyperprolactinemia appeared to be a rare mixture of a germinoma
and prolactinoma (Sugiyama et al., 1999). One case of a
suprasellar germinoma in a patient with Cornelia de Lange

syndrome has been reported, suggesting a causal relationship between teratogenesis and oncogenesis (Sugita
et al., 1986).
Teratomas may be mature (benign) or immature (malignant). Teratomas differentiate along all three germ cell
layers. Fat and calcifications are often present in teratomas
(Chong and Newton, 1993; Fig. 19.3). In one case of
primary bilateral anophthalmia, a teratoma of 5  2 mm
size containing cysts, glandular structures, intestinal
epithelium, fibrous tissues with nerve cells and fibers and
cartilage, was found in the region of the mamillary body
(Recordon and Griffiths, 1938). Yolk sac or endodermal
sinus tumor, choriocarcinoma and embryonal cell tumor
represent the less-common nongerminoma germ cell
tumors. The endodermal sinus tumor is also found in
the ovaries, testes, cervix and vagina of children. A
few of such tumors have been identified in the pineal
gland region (Chapter 19.7). The tumor has a typical
honeycomb pattern and is believed to be derived from
antecedents of the yolk sac (yolk sac carcinoma).
It is a highly vascular tumor capable of producing fetoprotein, while the HCG levels are usually negative.

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the tissue. They do contain neurons large and small


that are similar to those of the tuber and adjacent
structures (Driggs and Spatz, 1939; Clarren et al.,
1980; Albright and Lee, 1992; Fig. 19.8). Cystic changes
have occasionally been observed in huge hypothalamic
hamartomas due to intratumoral hemorrhage and liquefactive necrosis (Prasad et al., 2000). Hamartomas were
shown to contain neuron-specific enolase, synaptophysin
and neurofilaments, and some of them have corticotropinreleasing hormone (CRH), LHRH, metenkephalin
(Valdueza et al., 1994a) or growth hormone-releasing
hormone (GHRH) (Scheithauer et al., 1983)-containing
neurons. Generally, hamartomas are associated with an
MRI that is isointense, relative to gray matter. However,
a 1.5-year-old patient with a pedunculated hypothalamic
hamartoma was described whose T1-weighted MRI
images were hyperintense and thus suggestive of adipose
tissue. Microscopically an admixture of neuroectodermal
elements, namely glial cells, neurons and nerve bundles,
was found, along with mesenchymal elements in the form
of fibroadipose tissue (Sharma et al., 1998).

It metastasizes early to various regions of the brain,


including the hypothalamus (Yen, 1993; Schut et al.,
1996) and it has been proposed that these germ cell tumors
are derived from errant germ cells origin-ating in the yolk
sac endoderm (Chong and Newton, 1993).

19.3. Hamartoma
(a) Hypothalamic hamartoma
Hypothalamic neuronal hamartomas are rare malformations that may arise from the mamillary bodies or the
tuber cinereum and that occur at the ventral aspect of
the posterior hypothalamus (Chong and Newton, 1993;
Figs. 19.5, 19.6). In rare cases they may have a prechiasmatic location (Valdueza et al., 1994a). They
may be pedunculated or sessile, i.e. with a broad and
unconstricted interface with the hypothalamus (Albright
and Lee, 1992; Valdueza et al., 1994a; Arita et al., 1999;
Fig. 19.7). Arita et al. (1999) distinguished a parahypothalamic (= pedunculated) and an intrahypothalamic
(= sessile) type. Hamartomas are made up of mature but
disorganized neural tissue that shares similarities with
the tissue observed in the normal hypothalamus and are
therefore considered to be malformations rather than
neoplasms. They usually do not grow and do not invade

Symptoms of hamartomas
Gelastic seizures, characterized by attacks of laughter,
have been noted in 48% of the hamartomas. In addition,
attacks of crying have been described (see Chapter 26.2).
The epileptic syndrome is characterized by gelastic

Fig. 19.5. Hamartoma of the tuber cinereum. Midsagittal (A) and coronal (B) T1-weighted MR scans. A pedunculated mass (arrows) is noted in
the region of the tuber cinereum. The lesion is isointense to the adjacent brain. (From Chong and Newton, 1993, Fig. 24 with permission.)

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Fig. 19.6. Asymptomatic hypothalamic hamartoma (NHB 84186; 29 years of age) in the median eminence/pituitary stalk region stained for its
strong vasopressin innervation. The tumor was less densely innervated by oxytocin fibers and did not stain for luteinizing hormone-releasing
hormone. Bar = 1 mm.

seizures beginning in early childhood, often in the


neonatal period. One child was diagnosed at 3 months of
age with spells characterized by hyperpnea, followed by
cooing respirations, and giggling and smiling at 1520
min intervals. Single photon-emission computed tomography (SPECT) demonstrated dramatic ictal uptake in the
area of the 2.8-cm-diameter tumor, with normalization
during the interictal phase (DiFazio et al., 2000). Usually
there is a later development of focal seizures and a pattern
of symptomatic generalized epilepsy with tonic, atonic
and other seizure types in association with low spikeand-wave discharge and cognitive deterioration (Berkovic
et al., 1997). In a patient with refractory localizationrelated epilepsy associated with a hypothalamic
hamartoma, it was found that the frontal and temporal
cortex contributed to slowing of the heart rate, while the
lesion per se in the hypothalamus was not involved in
that phenomenon (Kahane et al., 1999). SPECT showed

ictal hyperperfusion in the hamartomas, the hypothalamic


regions and thalamus only. Depth electrodes implanted
in the hamartoma demonstrated focal seizures and electrical stimulation reproduced the typical gelastic events.
Stereotactic radio frequency lesioning of the hamartoma
resulted in seizure remission. These observations indicate
that the gelastic seizures originate from the hypothalamic
hamartoma and adjacent structures (Berkovic et al., 1997;
Kuzniecky et al., 1997; Freeman et al., 2003). However,
the interictal spike-wave does not arise from the hamartoma itself since it did not disappear following hamartoma
resection (Freeman et al., 2003). Tasch et al. (1998) could
not find any neuronal damage in the temporal lobes of
patients with hypothalamic hamartomas and gelastic
epilepsy using proton magnetic resonance spectroscopy
imaging, which is further evidence that gelastic seizures
do not originate in the temporal lobe but in the hamartomas themselves.

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A study of interictal spike electroencephalographic


(EEG) source analysis in hypothalamic hamartoma
epilepsy also demonstrated that the source of the spike
activity was located in the neighborhood of the
hamartoma and not in the cortex (Leal et al., 2002). In
addition, visual disturbances, precocious puberty (in 74%
or more of the cases; Styne, 1997; Rivarola et al., 2001),
acromegaly, diabetes insipidus or other endocrinopathies
have been reported. A child has been described with
precocious puberty due to a hypothalamic hamartoma on
the basis of neurofibromatosis type 1 (Biswas et al., 2000).
Children with gelastic seizures and hypothalamic hamartoma display a great number of psychiatric disorders,
including oppositional defiant disorders (83%), attentiondeficit-hyperactivity disorder (75%), conduct disorder
(33%) speech retardation and learning impairment (33%),
and anxiety and mood disorders (17%). In 3058%,
significant rates of aggression were noted (Weissenberger
et al., 2001). The behavioral and cognitive defects
illustrate the role of the hypothalamus in these processes.
Hamartomas may be associated with seizure disorders
that become drug-resistant (Munari et al., 1995).
Moreover, there may be behavioral disorders; the children are restless, violent, emotionally unstable, antisocial
and intellectually impaired. All children with gelastic
seizures and hypothalamic hamartoma display cognitive
deficits ranging from mild to severe (Frattali et al., 2001).
The mental decline is often progressive. The behavioral
disorders are probably mediated by disruption of the
connections between the mamillary bodies and other brain
structures.
Hamartomas are clinically evidenced in infants ranging
between 1 and 7 years of age and may range from 2 to
30 mm in size. The manifestation in a neonate has
also been described (Guibaud et al., 1995). The clinical
symptoms of hamartomas depend on their size and local-

ization (Valdueza et al., 1994a; Fig. 19.7 and Table 19.1).


Precocious puberty usually occurs in small, autonomous
LHRH-producing pedunculated hamartomas (types 1a and
1b, according to Valdueza et al., 1994a, Fig. 19.10;
Debeneix et al., 2001; Table 19.I), or the parahypothalamic type, according to Arita et al., 1999; Nishio et al.,
2001). Precocious puberty may be accompanied by rapid
statural growth, persisted breast swelling and pigmented
areolae as a sign of the exposure to high levels of oestrogens (Arisaka et al., 2001). Precocious puberty in a case
of hypothalamic hamartoma has also been described in
association with agenesis of the corpus callosum
(Alikchanov et al., 1998). For a differential diagnosis of
sexual precocity, see Albright and Lee (1992) and Chapter
24.1. Gelastic epilepsy and associated seizures are
observed only in large, sessile type IIa and IIb hamartomas (Fig. 19.7), characterized by a broad attachment to
the mamillary bodies (Valdueza et al., 1994a; Debeneix
et al., 2001). A displacement of the floor of the third
ventricle and/or an intrahypothalamic location (type IIb;
Fig. 19.7) may cause behavioral abnormalities (Valdueza
et al., 1994a). Hyperphagia, obesity, rage and dementia
have been described in a 20-year-old woman who had
a hamartoma that destroyed the ventromedial hypothalamus. She experienced hallucinations, had hypofunction
of the adrenals, gonads, thyroid, diabetes insipidus
and diabetes mellitus, and unexplained fever, probably
also due to the fact that autonomic regulatory functions were affected (Reeves and Plum, 1969; see VMN
syndrome, Chapter 26.3.). However, hamartomas are not
always accompanied by symptoms. The lesion can also
be found incidentally on postmortem examination
(Mahachoklertwattana et al., 1993; Kahane et al., 1994;
Valdueza et al., 1994a; Munari et al., 1995). We observed
a strong vasopressin innervation and some oxytocin innervations, but no LHRH or CRH in a hamartoma that was

TABLE 19.1.
Classification of hypothalamic hamartoma.
Type

1a

1b

11a

11b

Size
Attachment
Origin
Hypothalamic displacement
Common features

Smallmedium
Pedunculated
Tub cin
No
PP (or asymptomatic)

Smallmedium
Pedunculated
Mam bod
No
PP (or asymptomatic)

Mediumlarge
Sessile
Tub cin/mam bod
Slight
Gel, gen

Mediumlarge
Sessile
Tub cin/mam bod
Marked
Gel, gen, beh

Tub cin, tuber cinereum; Mam bod, mamillary body(ies); Gel, gelastic epilepsy; Gen, generalized and/or other epileptic types; Beh, behavioral
disorder; PP, precocious puberty. (From Valdueza et al., 1994a.)

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Fig. 19.7. Schematic drawing of different types of hypothalamic hamartomas on sagittal images. (From Valdueza et al., 1994a, Fig. 8 with
permission.)

found by accident at autopsy and that was situated in the


stalk/median eminence region (Fig. 19.6).
Pathogenesis. There are a number of theories on the
pathogenesis of endocrinopathies in relation to hamartomas:
ii(i) Neurons within a hamartoma would stimulate
hypothalamic neuroendocrine systems by direct
connections;
i(ii) The tumor might have a mechanical effect on the
hypothalamus. As an example, a case has been
reported of a 1.9-year-old girl with precocious
puberty and gelastic seizures due to a hypothalamic
hamartoma that was situated dorsally of the SCN.
She had melatonin levels that were low for her
chronological age but appropriate for the pubertal
status, suggesting a causal relationship between
lowered melatonin levels and puberty, due to
interruption of the connections between the SCN
and the pineal gland (Commentz and Helmke,
1995). However, the alternative, i.e. that decreased

melatonin levels are found following induction of


puberty by whatever mechanism and without interruption of the connections between the SCN and
pineal, seems at least as probable (Chapter 4.5d).
(iii) Neurons of the hamartoma would actively secrete
a hormone that activates the pituitary (Wolman
and Balmforth, 1963; Scheithauer et al., 1983;
Mahachoklertwattana et al., 1993). Judge et al.
(1977) demonstrated that a hamartoma in a
19-month-old boy with precocious puberty showed
all the characteristics of an independent neuroendocrine unit, supporting the latter of the three
hypotheses. It contained neurons that resembled
those of the hypothalamus, containing 100 nm of
neurosecretory granules and blood vessels, with
fenestrated endothelium and double basement
membranes, characteristics of vessels of the median
eminence that would permit release of neurosecretory products into the blood- stream. Each vessel
was almost totally surrounded by axons. In addition,
immunocytochemically the neurons appeared to
contain LHRH. The negative feedback between
gonads and brain was intact but partially resistant to
steroid suppression. These observations indicate that
the hamartoma may have caused precocious puberty
by autonomous production and release of LHRH.
Also the demonstration of neurosecretory cells and
their fibers that end on the portal vessels in a
girl with precocious puberty and a hypothalamic
hamartoma (Wolman and Balmforth, 1963) supports
this concept. In a review on long-term data
concerning 10 children with an LHRH-producing
hamartoma and their effective treatment with LHRH
agonists (see below), Mahachoklertwattana et al.
(1993) conclude also that the congenital malformation functions as an ectopic LHRH pulse generator.
Scheithauer et al. (1983) described a patient
who had a hypothalamic neuronal hamartoma that
had been present for 31 years and was associated
with hypopituitarism, a growth-hormone-producing
pituitary adenoma and acromegaly. Microscopically
the hamartoma was composed of ill-defined aggregates of small and large neurons and neuritic
processes. The neurons contained an abundance of
75- to 125-nm electron-lucent granules. GHRH
(somatoliberin) was demonstrated in these neurons.
The pituitary contained a predominantly growth
hormone-containing adenoma that was presumed to
be secondary to the neuronal abnormality, and a

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minute nodule of prolactin adenoma. So this case,


too, supported the third possible pathogenetic mechanism, i.e. hormone secretion by the neurons in the
hamartoma.
(iv) Hypothalamic hamartomas may induce precocious
puberty by the production of trophic factors that are
able to activate the normal LHRH network in the
patients hypothalamus. One of such factors is transforming growth factor-, which facilitates the gliato-neuron signaling process controlling the onset of
female puberty in rodents and nonhuman primates.
This factor (and not LHRH) has been found in girls
with hamartomas that induced precocious puberty
(Jung et al., 1999; Rivarola et al., 2001; Jung and
Ojeda, 2002).

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However, some patients did report episodes of emotional


lability (Feuillan et al., 2000).
A number of papers advise against surgery as the initial
management of precocious puberty in case of hypothalamic hamartomas, because of the delicate site where the
tumor is located, and advised LHRH agonists (Stewart et
al., 1998). Surgical resection may, however, be an alternative treatment to LHRH only in the rare instance of
mass enlargement or compression of adjacent tissues that
is causing progressive neurological deficits or hydrocephalus (see also Albright and Lee, 1992; Valdueza
et al., 1994a), or when the seizures are refractory to
antiepileptic medication. Successful, complete or nearly
complete resection of hypothalamic hamartomas has been
achieved by a subtemporal approach (Nguyen et al.,
2003), the transcallosal approach (Rosenfeld et al., 2001;
Freeman et al., 2003) and by the lamina terminalis
approach (Kramer et al., 2001; Chapter 30.5). Resection
of hypothalamic hamartomas can alleviate both the
seizures and the behavioral and cognitive abnormalities,
but complications are frequent (Palmini et al., 2002).
However, examinations of a small series of children with
precocious puberty who underwent microsurgical treatment, suggested that this treatment was a good decision
(Luo et al., 2002). A case has been presented with gelastic
seizures associated with a hypothalamic hamartoma.
Partial resection failed to reduce the seizures, but subsequent stereotactic radiofrequency ablation resulted in
progressive improvement (Parrent, 1999). The new development of noninvasive focal radiation performed with a
gamma knife was successful in a number of patients with
intractable epilepsy, abnormal behavior and precocious
puberty due to an inaccessible hypothalamic hamartoma.
MRI performed 12 months later demonstrated complete
disappearance of the lesion (Arita et al., 1998; Regis
et al., 2000; Dunayer et al., 2002), but no change in the
size of the lesion was observed in other cases (Unger
et al., 2000, 2002). Gamma knife surgery may be especially useful for small sessile lesions, failed partial
resections and patients not appropriate for open surgery
(Nguyen et al., 2003). In patients with refractory epilepsy
secondary to hypothalamic hamartomas, seizures were
also controlled by intermittent stimulation of the left vagal
nerve (Murphy et al., 2000).
Related disorders. Hypothalamic hamartomas may also
be found as part of the orofacialdigital syndrome (MIM
165590; Fujiwara et al., 1999), which is a heterogeneous
syndrome and includes at least 11 types. They include
hypothalamic hamartomas, developmental delay, multiple

Therapy. The response to antiepileptic drug therapy has


invariably been disappointing (Wakai et al., 2002). It
should be noted that hamartomas are developmental
abnormalities that may well be found with other widespread abnormalities in the brain, which may provide a
structural basis for the poor response of seizures to
removal of the hamartomas or the presence of other apparently focal epileptogenic zones (Sisodya et al., 1997). An
example is a boy who had gelastic epilepsy, hypothalamic hamartoma, precocious puberty and agenesis of the
corpus callosum. The child had a dramatically impaired
mental function and a split brain pattern of the interictal EEG, indicating a developmental anomaly of the
commissural structures of the brain (Alikchanov et al.,
1998).
Mahachoklertwattana et al. (1993) treated nine patients
with an LHRH agonist. The basis of this therapy is that
interruption of the obligatory pulsatile release of LHRH
downregulates the release of follicle-stimulating hormone
(FSH) and LH. The response to this therapy was excellent. Later also young children, for example a 1-year-old
girl and an 8-year-old boy with precocious puberty, were
successfully treated with a super long-acting LHRH analogues that indeed induced regression of the hypothalamic
hamartoma (Nishio et al., 2001). Long-term follow-up
studies of children treated with LHRH analogues have
started only relatively recently (Feuillan et al., 1999). One
year after stopping the LHRH therapy, the LHRH-stimulated LH and FSH and testosterone returned to the normal
range. By 4 years after therapy, all patients had pubic hair.
The dimensions of the patients hamartomas did not
change with therapy, and no new neurological symptoms
or signs after discontinuation of therapy occurred.
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gingival granula, hamartomatous nodules on the tongue,


low-set ears, micrognathia and polysyndactyly of the
hands and feet. Orofacialdigital syndrome type VI
(Vradi syndrome) is an autosomal recessive trait of
orofacial anomalies, cerebellar dysgenesis and polysyndactyly. Cerebellar hypoplasia and variants of the
Dandy-Walker complex are the most common CNS
malformations reported in patients with this syndrome. A
boy with Vradi syndrome had hypothalamic hamartoma
and precocious puberty (Stephan et al., 1994). In addition, a boy was reported with hypothalamic hamartoma
and precocious puberty associated with agenesis of the
corpus callosum, Dandy-Walker complex and heterotopic
gray matter (Gulati et al., 2002).
(b) Hamartomatous nodules
In a thorough study of 239 consecutive autopsies, Sherwin
et al. (1962) found small hamartomatous nodules of the
posterior hypothalamus in 21% of the patients, suggesting
that such lesions are far from rare. Endocrinological
abnormalities and systematic neoplastic processes were
significantly associated with the presence of such malformations. An intimate relationship between the nodules and
perforating vessels existed. The nodules were located adjacent to or 1 mm lateral to the mamillary body, and 1 mm
rostral to the corresponding cerebral peduncle. In all cases
a branch of the posterior communicating artery penetrated
the center of the nodule. By carefully following the path
of this artery, the nodule was often found surrounding its
site of entry into the brain (Fig. 19.8). Microscopically,
the nodules were composed of an outer layer of compact
glial tissue and a central, loose glial tissue containing nerve
cells. These harmatomatous nodules should be distinguished from the true hamartomous nodules that arise
almost invariably from the central portion of the tuber
cinereum caudal from the pituitary stalk.
(c) Intrasellar gangliocytoma
A tumor related to a hamartoma is an intrasellar neuronal
choristoma or intrasellar gangliocytoma with neurons
of hypothalamic type, often within growth hormonecontaining pituitary adenomas resulting generally in
acromegaly and sometimes in Cushings syndrome,
galactorrhea and amenorrhea. Sometimes these are
endocrinologically nonfunctioning masses (Scheithauer et
al., 1983; Asa et al., 1984; Morikawa et al., 1997; Geddes
et al., 2000; Chapter 19.10). In a pituitary corticotroph

adenoma, neurons that stained for corticotropin (ACTH)


were described (Vidal et al., 2002). The term choristoma is preferable to the term hamartoma when
abnormal neoplastic cells are displaced from the normal
anatomical site (Rhodes et al., 1982). However, the term
choristoma is confusing, since it is also used for the
unrelated pituicyte-derived granular cells of the neurohypophysis (Chapters 19.4c, 22.1; Figs. 19.14, 21.1).
Rhodes et al. (1982) call these pituitary tumors ganglionneuromas. In addition, the terms gangliomas and
gangliocytoma are used for this group of tumors
(Morikawa et al., 1997). A case report mentioned the
presence of a gangliocytoma masquerading as a
prolactinoma with suprasellar and temporal lobe extension. The 36-year-old man presented with bitemporal
hemianopsia and a high serum prolactin concentration.
Later the tumor appeared to consist of dysplastic neurons
that were strongly immunoreactive for the neuronal
markers synaptophysin and neurofilament, and for
prolactin. This appeared to be a prolactin-secreting
gangliocytoma (McCowen et al., 1999). Such tumors in
acromegalic patients are closely associated with pituitary
adenomas and are often growth hormone and prolactin
positive (Geddes et al., 2000). It seems as if ganglion
cells have differentiated within the adenoma. For the
pathogenesis of this type of tumor, the alternative, i.e.
that it is primarily a tumor of neurons producing a GHRH
inducing secondary adenomas and acromegaly has also
been considered by some authors and discounted by others
(Geddes et al., 2000). It has also been suggested that a
progenitor cell might give rise to both adenohypophysial
cells and neurons producing, e.g. GHRH (Asa et al.,
1984). The tumors contain ganglion cells, fascicles of
unmyelinated neuronal processes, collagen and some glial
cells. If they contain neoplastic astrocytes they are termed
gangliogliomas. Rhodes et al. (1982) described a
ganglion-neuroma with epithelial cysts, the cells of which
resembled ependymal cells of the floor of the third
ventricle. Some of these cells were glial fibrillary acidic
protein (GFAP)-positive. It is supposed to be a tumor of
embryonic rests from the ventral neural ridge, displaced
early in development (Asa et al., 1980; Rhodes et al.,
1982; Morikawa et al., 1997). A ganglioglioma of the
tuber is a congenital tumor that at first glance appears to
be microscopically similar to an ordinary glioma, but it
produces a specific clinical picture: it is characterized by
precocious puberty in babies. In addition to astrocytes, it
contains nerve cells, sometimes scattered diffusely and
sometimes arranged in groups. It is three times as common

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Fig. 19.8. Hamartomatous nodules. A. In the right posterolateral tuber cinereum a conical nodule is shown (arrow). A small artery, arising from
the midpoint of the posterior communicating artery, enters its base. Two veins emerge from the nodule. BF. Representative serial sections are
demonstrated through the same nodule, beginning with the mamillary body level and extending to the extreme lateral tuberal area. In B, the band
of tissue between the vessels with a reversed 7 shape is the subpial white matter of the nodule. In C, D, and E the perforating artery appears
to have pulled down a wedge of tissue from the hypothalamic floor. In F the protuberant nodule exhibits ganglion cells, nerve fibers, and
whorled subpial fibers on the right. (From Sherwin et al., 1962, Fig. 13 with permission.)

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in men as in women. The patients usually die before the


age of 8 (Sheehan and Kovacs, 1982). Cases without
endocrinopathies may represent incomplete expression of
the hypothalamic neuronal choristoma-pituitary adenoma
complex (Scheithauser et al., 1983). For gangliocytoma
of the neurohypophysis, see Chapter 19.10.
(d) Hamartoblastomas (PallisterHall syndrome)
PallisterHall syndrome is a developmental disorder
consisting of hypothalamic hamartoma, pituitary dysfunction, polydactyly and visceral malformations. This
syndrome was first reported in infants. It consists of
hamartoblastomas of the hypothalamus with primitive,
undifferentiated neurons. For this reason the term hypothalamic hamartoblastoma was assigned initially to these
tumors. However, when children with this condition
survive, the neurons look more or less mature and are
admixed with astrocytes and minimal white matter, and
they are now thought to be hamartomas (Sills et al., 1993;
Kuo et al., 1999). On MR images the classic hypothalamic hamartoma/hamartomablastoma is noncalcified and
nonenhancing, homogeneously isointense to gray matter
(Kuo et al., 1999). A multilobulated mass arising from
the base of the brain that was shown to be a subhypothalamic heterotopia on the basis of a hamartoblastoma
has been described by Splitt et al. (1994). This patient
also had short or absent olfactory tracts.
The disorder is inherited as an autosomal dominant
trait with incomplete penetration, variable expressivity or
gonadal or somatic mosaicism (Biesecker et al., 1994;
Penman Splitt et al., 1994) and has been mapped to chromosome 7p13, colocalizing the PNS locus and the GL13
gene encoding a zinc finger transcription factor (Kang et
al., 1997). An unbalanced chromosomal translocation
between 7p and 3q has been reported in one patient
(Squires et al., 1995). Most cases are sporadic, but one
familial case has been reported (Sills et al., 1993; Kuo
et al., 1999). Hamartoblastomas arise probably in the 5th
week of pregnancy and seem to be part of a complex
pleiotrophic congenital syndrome that includes absence
of the pituitary, craniofacial abnormalities, cleft palate,
malformations of the epiglottis or larynx, congenital heart
defects, hypopituitarism, short-limb dwarfism with postaxial polydactyly, anorectal atresia, renal anomalies and
abnormal lung lobulation and hypogenitalism. For
syndromes that overlap with PallisterHall syndrome, see
Sills et al. (1993) and Kuo et al. (1999).

Endocrine evaluation showed hypopituitarism, i.e. low


serum cortisol, T4, growth hormone and insulin-like
growth factor (IGF-1) (Feuillan et al., 2001). One case
was treated with growth hormone until final height
was reached (Galasso et al., 2001). It was suggested
that hypothalamic deficiency would contribute to hypopituitarism in this syndrome. In addition, short olfactory
tracts suggest a relation with the arrhinencephaly defects.
The neurohypophysis is sometimes absent. The condition
was thought to be fatal in the neonatal period, but has
also been described in a patient older than 12 years
(Clarren et al., 1980; Chong and Newton, 1993; Sills et
al., 1993; Squires et al., 1995). The main cause of death
in the first cases to be described was acute adrenal insufficiency associated with panhypopituitarism (Kuo et al.,
1999).
19.4. Glioma
The majority of the gliomas affecting the hypothalamus
are diffusely infiltrative fibrillary or pilocytic (hair cell)
astrocytomas. Depending on their location, hypothalamic
gliomas may manifest themselves in the form of, e.g.
eating disorders, disturbances of temperature regulation,
precocious puberty, somnolence, rage, visual impairment
or hydrocephalus (Dolenc, 1999; Rivarola et al., 2001).
Pilocytic astrocytoma causing hypothalamic lesions may
be associated with decreased nocturnal melatonin levels
and increased daytime sleepiness (Mller et al., 2002a).
A rare case of a hypothalamic low-grade astrocytoma
causing gelastic seizures has been reported (Coppola et
al., 2002; Chapter 26.2). Most pilocytic astrocytomas arise
within the visual system. Optic pathway gliomas tend to
occur in young children and comprise 5% of the pediatric intracranial tumors (Janss et al., 1995). They may
(1) be confined to the optic nerve and cause opthalmological symptoms, including visual hallucinations (Haugh
and Markesbery, 1983) or (2) involve the optic chiasm
and hypothalamus and cause neuroendocrine symptoms
and symptoms of raised intracranial pressure. Chiasmatic/
hypothalamic tumors and tumors involving the chiasm
should only be distinguished because they are different
entities with a different prognosis and different treatments
(Steinbock et al., 2002). In addition, they may give rise
to diencephalic syndrome (Russells syndrome), spasmus
nutans or moyamoya disease. Very rarely does a hypothalamic glioma bleed within the subarachnoid space,
into the cerebrum or into the ventricles (Devi et al.,
2001). The diencephalic syndrome is seen in infants with

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children (Kornreich et al., 2001). They may give rise to


diencephalic syndrome of emaciation in infancy and
childhood, which was originally described by Russell in
1951. It is typified by severe weight loss, despite normal
linear growth, optic atrophy and signs of hypothalamic
dysfunction. In 90% of cases, it is due to a hypothalamooptic glioma (Pelc, 1972; Figs. 19.919.13), such as a
fibrillary or pilocytic astrocytoma, craniopharyngioma or
germ cell tumor. Pure optic gliomas are rare. Of the
32 cases of the diencephalic syndrome in which the
cellular type of the tumor was established, 25 had an
astrocytoma, 4 a polar spongioblastoma (now called
juvenile pilocytic astrocytoma), 1 an oligodendroglioma,
1 an astro-oligodendroglioma and 1 an ependymoma (Pelc,
1972). Burr et al. (1976) found a germinoma in one case.
The presence of Rosenthal fibers or intracytoplasmatic
masses of electron-dense material is characteristic (Styne,
1993). Possible embryological elements were present in
tumors of five other patients. It has become apparent that
in some 9% of the cases, nondiencephalic tumors appeared

posterior chiasmatic-hypothalamic tumors and is the only


neoplastic disorder of the central nervous system associated with infantile failure to thrive. Spasmus nutans is
characterized by head bobbing, head tilt and monocular
nystagmus in infants and is caused by gliomas that
are confined to the optic nerve. Moyamoya disease is
an occlusive disorder of the large cerebral arteries of
the circle of Willis, causing an abnormal capillary
network of moyamoya vessels to develop at the base of
the brain. It may occur as a consequence of irradiation
of optic pathway gliomas and may lead to massive cerebral hemorrhage (Chapters 17.2e, 25.3; Oka et al., 1981;
Chamberlain, 1995; Sinsawaiwong and Phanthumchinda,
1997).
(a) Diencephalic syndrome: hypothalamo-optic
glioma/optic pathway glioma
This low grade astrocytoma accounts for 5% of all brain
tumors and for 1015% of supratentorial tumors in

Fig. 19.9. A. Diencephalic syndrome. Note the severe emaciation of the whole body and the characteristic pseudohydrocephalic appearance. B.
MRI of the brain. T1-weighted sagittal images (repetition time/echo time: 570/15) after gadolinium enhancement demonstrate the presence of a
large tumor involving the hypothalamic region, distorting the chiasm and brainstem, and extending into the third ventricle. Neuropathologically,
the tumor proved to be a hypothalamic astrocytoma with pilomyxoid features. (From Zafeiriou et al., 2001, Figs. A, B, with permission.)

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Fig. 19.10. Chiasmatic glioma. Sagittal (A) and parasagittal and coronal (B) MR scans. The tumor has enlarged the left side of the chiasm and
the left optic nerve (arrows). (From Chong and Newton, 1993, Fig. 25 with permission.)

to be present with similar clinical features (Burr et al.,


1976). The majority of pilocytic astrocytomas are nonaggressive and have a low proliferation index. However, a
subpopulation has a propensity for aggressive behavior.
Diffuse astrocytomas show a high proliferation index
(Cummings et al., 2000). Although most optic gliomas
are histologically low-grade astrocytomas, they tend to
infiltrate along the optic pathways. In 70% of cases with
hypothalamic glioma, involvement of the optic nerves or
the whole optic pathway is also present. Some chiasmatic
tumors remain quiescent for several years, others grow
slowly (Pelc, 1972; Rutka et al., 1992; Perilongo et al.,
1997). However, the whole spectrum from pilocytic (WHO
grade I) to glioblastoma (WHO grade IV) may be present
(Cummings et al., 2000). Gliomas of the optic nerve
include highly infiltrative tumors that behave in a malignant manner (anaplastic astrocytomas, WHO grade III;
glioblastomas, WHO grade IV) (Cummings et al., 2000).
The age of onset ranges from the newborn period to
4 years, with the peak incidence between 2 and 7 months
of age (Pelc, 1972). In 63% of cases, death occurs before
the 2nd year (Pelc, 1972).

Although extremely rare, diencephalic syndrome of


emaciation can occur in an adult harboring a tumor, e.g.
a craniopharyngioma, in the anterior hypothalamus
(Miyoshi et al., 2003). The main clinical features of the
diencephalic syndrome include a failure to thrive, extreme
cachexia with normal height, hyperkinesis, alert appearance, vomiting, surprisingly happy affect or euphoria,
pallor without anemia, hypothermia, excessive sweating,
nystagmus and decreased visual acuity. Nystagmic eye
jerking is found in 70% of the cases (Pelc, 1972).
Precocious puberty has also been described (Robben et al.,
1995) and is probably related to tumor location (CollettSolberg et al., 1997). In addition, disturbances of temperature regulation or appetite, autonomic seizures, paroxisms
of hypertension, tachycardia, diabetes insipidus or a
syndrome of inappropriate vasopressin secretion are found
(Chong and Newton, 1993; Connors and Sheikholislam,
1977; Chapter 22.6). Despite a normal caloric intake, these
children lose weight, according to some authors possibly
due to their disproportionately high energy output (Braun
et al., 1959; Greenes and Woods, 1996). Other factors in
emaciation may be the anterior pituitary defect (Russell,

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Fig. 19.11. Inferior surface of brain. The large multiloculated cystic tumor can be seen anterior to the brain stem in the region of the
hypothalamus. (From Braun et al., 1959, Fig. 2 with permission.)

gigantism with growth hormone excess (Manski et al.,


1994). A 4-year-old child with optic chiasm glioma had
nonobstructive hydrocephalus. He had a ventriculoperitoneal shunt following which marked ascites developed.
The ascitic fluid was rich in protein, most probably
explaining the hydrocephalus he had previously. The
CSF protein level and the amount of ascites fluid were
influenced by chemotherapy. Very unusual hypernatremia
develops in those cases, presumably by osmoreceptor
dysfunction (Shuper et al., 1997).
Surgery, chemotherapy and radiation therapy have
been advocated as therapies for chiasmatic-hypothalamic
gliomas (Nishio et al., 1993b; Konovalov et al., 1994;
Valdueza et al., 1994b; Chamberlain, 1995; Janss et al.,

1951), elevated growth hormone levels or other endocrine


defects (Greenes and Woods, 1996), or subcutaneous fat
depletion due to autonomic alterations (Connors and
Sheikholislam, 1977). Hydrocephalus is sometimes also
present, as are large hands, feet and genitalia. Tumor cells
and/or increased concentration of CSF protein is present
in most patients. Dissemination via the CSF has also been
reported. There may be an inappropriate, even paradoxical,
plasma growth hormone response to hyperglycemia and
hypoglycemia, and lack of diurnal variation in plasma
cortisol (Burr et al., 1976; Costin, 1979Greenes and
Woods, 1996). In a 16-month-old boy, an extensive
optic pathway glioma probably infiltrating into somatostatinergic pathways was observed, accompanied by
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Fig. 19.12. Midsagittal section of brain. The cyst is seen to invaginate the wall of the third ventricle. The cyst is ovoid and contains a
gelatinous, slightly granular matter. (From Braun et al., 1959, Fig. 3 with permission.)

1995; Greenes and Woods, 1996Silva et al., 2000; Kageji


et al., 2003; Khafaga et al., 2003). Decisions about the
institution of chemotherapy depend on many factors, such
as the age of the patient, whether the child has a neurofibromatose type of tumor (see below), tumor grade and
tumor size, tumor location, and the potential sequelae of
radiotherapy and chemotherapy (Packer, 2000). A high
response rate to cisplatin/etoposide was found in childhood low-grade glioma (Massimino et al., 2002).
According to some authors, postoperative radiation
therapy is effective and can prevent loss of vision
(Grabenbauer et al., 2000). Others start more conservatively with CSF shunting, treating a rapidly expanding
tumor with mass surgery and giving chemotherapy. Only

when chemotherapy is found to be ineffective do they


advise radiation therapy (Alshail et al., 1997). Treatment
of the diencephalic syndrome with carboplatin and
vincristine regimen results in demonstrable weight gain,
may cause tissue shrinkage and in some cases significantly delays the need for other therapies. Dolenc
(1999) points to the recently radically changed treatment
which has made atraumatic microsurgical resection
the method of choice for hypothalamic gliomas. Gammaknife radiosurgery is effective in low-grade astrocytomas. Complete cure was observed in some cases (Kida
et al., 2000). Spontaneous involutions of pilocytic
astrocytoma has been reported in some children
(Balkhoyor and Bernstein, 2000). It should be noted

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Fig. 19.13. Magnetic resonance images: (a) Coronal brain section showing the normal human hypothalamus at the level of the optic chiasm; and
(b) line drawing of the principal structures. (c) Sagittal section through normal pituitary gland and hypothalamus; and (d) line drawing of the principal structures. (e) Coronal section demonstrating suprasellar mass lesion (glioma) with invasion of the mediobasal hypothalamus and distortion
of the third ventricle, leading to obesity, and (f) line drawing of the principal structures. (g) Sagittal image showing upward expansion of glioma
into medial hypothalamus; and (h) line drawing of the principal structures. (From Pinkney et al., 2002 Fig. 1 with permission.)

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that major causes of endocrine abnormalities in hypothalamic chiasmatic gliomas were field irradiation and
tumor surgery (Collett-Solberg et al., 1997).
(b) Gliomas of the optic pathways
Associated with neurofibromatosis, gliomas of the optic
pathway are considered to be separate entities and account
for 1070% of this group of tumors (Kornreich et al.,
2001). The diencephalic syndrome, diffuse EEG changes,
delayed development and seizures are also found in
patients with neurofibromatosis type I (Venes et al., 1984;
Chong and Newton, 1993; Robben et al., 1995; Cummings
et al., 2000). This is an autosomal, dominant disorder with
a prevalence of 1 in 3000 to 4000 and is caused by a
mutant gene on the long arm of chromosome 17 (q11.2)
(Styne, 1997). Approximately half of the cases are
spontaneous mutations (Zuccoli et al., 2000). The neurofibromatose gene encodes a tumor-suppressor factor
which interacts with the ras oncogene p21 (Gottschalk
et al., 1999). The data provided on the association between
glioma of the optic pathway are variable. Ten to seventy
percent of the patients with visual-pathway gliomas have
neurofibromatosis and 515% of patients with neurofibromatosis have a tumor of the optic pathway (Styne,
1993; Valdueza et al., 1999b; Janss et al., 1995). Optic
pathway glioma is the most common brain tumor
associated with Von Recklinghausens disease. In patients
with neurofibromatosis, the most common site of
involvement is the orbital nerve; the tumor is smaller,
the original shape of the optic pathway is preserved and
optic components are uncommon (Kornreich et al., 2001).
Neurofibromatous type I patients may follow a more
aggressive course of the disease (Valdueza et al., 1994b).
One of these cases with emaciation, marked increase in
serum growth hormone levels, and anaplastic astrocytoma
of the optic chiasmahypothalamic region has been
described in an adult (Tanabe et al., 1994). In a 5-yearold boy with neurofibromatosis type I, a chiasmatic glioma
caused a rapid visual acuity loss, which improved significantly after radiation (Adams et al., 1997). However,
generally there is only minimal tumor enlargement, while
in most cases the optic glioma patients without neurofibromatose show a clear propensity (Kornreich et al.,
2002). Hydrocephalus as complication (Gottschalk et al.,
1999) is extremely rare in neurofibromatosis cases
(Kornreich et al., 2001). Endocrine dysfunction occurs
less often in neurofibromatosis patients who are treated
conservatively (Collett-Solberg et al., 1997). Differential

diagnosis includes germinoma, craniopharyngioma,


meningeoma, lymphoma, histiocytosis and inflammatory
conditions. Traditionally the treatment has included
radiation, surgical resection and, in some special cases,
chemotherapy (Gottschalk et al., 1999). The observation
of postoperative regression of a biopsy-proven opticochiasmatic glioma strengthens the argument for conservative therapy in young children with neurofibromatosis
(Venes et al., 1984). In some patients, mainly children,
with neurofibromatosis I as revealed on serial MRI, spontaneous partial or even total remission of the neoplasm in
the hypothalamic region was found, implying also that a
cautious approach to therapeutic management should be
taken in asymptomatic cases (Gottschalk et al., 1999;
Zuccoli et al., 2000).
(c) Other gliomas
Intrinsic astrocytomas of the posterior pituitary (pituicytomas) or stalk (infundibulomas) are rare (Scothorne,
1955). Infundibuloma (or astrocytoma of the third
ventricle or glioma of the tuber) occur mainly in childhood or adolescence and often cause death at that stage,
although there are long survivors. Histologically it is a
fibrillary astrocytoma. In children the capillaries tend to
be arranged in plexuses remarkably reminiscent of the
gomitoli in the upper part of the pituitary stalk (Chapter
17.1c), suggesting that the tumor is derived from the
neurohypophysial tissue of the infundibulum (Sheehan
and Kovacs, 1982). In contrast to the granular cell tumors,
the cells contain no pigment (Massie, 1979). Only a few
pilocytic pituitary astrocytomas or pituicytomas have been
described. MRI shows extension of the tumor into the
stalk. There may be panhypopituitarism as an early manifestation, whereas diabetes insipidus may be absent,
probably by vasopressin release above the level of the
tumor (Nishizawa et al., 1997). The astrocytic nature of
such a tumor can be confirmed by the presence of GFAP
staining. Such tumors closely resemble pilocytic astrocytomas in other parts of the central nervous system
(Schothorne, 1955). A 40-year-old man has been
described with such a tumor, visual failure and hyperprolactinemia (Rossi et al., 1987). Another case of a
pituicytoma presented in a 26-year-old woman with dizziness and visual obscuration. MRI revealed a pituitary
mass with suprasellar extension. Immunocytochemistry
was positive for GFAP, S-100 and vimentin. This pituicytoma was not a pilocytic variant (Hurley et al., 1994).
One case of a pituicytoma causing hypopituitarism and

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Fig. 19.14. Granular cell tumor. NHB 98-010, female, 75 years of age. Hematoxylineosin. Bar = 2 mm.

visual impairments or headache (Jenevein, 1964; Symon


et al., 1971; Massie, 1979; Horvath et al., 1997; see also
Chapter 22.1).
Gliomatosis cerebri is an uncommon tumoral pathology,
but its incidence may be grossly underestimated. It is a
neuroepithelial neoplasm of unknown origin. Less than
200 cases have been reported in the literature. The tumoral
proliferation consists of astrocytes, oligodendrocytes or
both, with different degrees of maturation. When infiltrating myelinated tracts, the cells often form parallel rows
among nerve fibers. In these cases myelin sheaths may be
destroyed, but axons survive. Immunocytochemistry may
or may not show GFAP expression. Areas of high mitotic
activity and microvascular proliferation may be observed,
but there is no necrosis. The hypothalamus may be affected,
in some cases resulting in a hypothalamic syndrome.
However, the most frequent clinical manifestations are
mental deterioration and personality changes. In addition,
signs of increased cranial pressure, including empty sella,
have been reported (Peretti-Viton et al., 2002).

visual disturbances was not only positive for GFAP,


vimentin and epithelial membrane antigen, but had aggregates of intermediate filaments in a concentric pathway
(fibrous body) and secretory granules. It might also have
arisen from the stromal folliculostellate cells of the adenohypophysis (Cenacchi et al., 2001).
A special form of gliomas are the granular cell tumors
or choristomas that are composed of large cells with
granular, lightly eosinophilic, cytoplasm. They are
thought to derive from pituicytes, i.e. modified astrocytes
in the neurohypophysis. Occasional tumor cells may
contain brown pigment similar to that found in pituicytes.
The granules in this pigment stain with Sudan black,
characterizing it as a lipopigment. Minute nodules of granular cells are commonly found in the posterior pituitary
and stalk. They occur in some 5% of the pituitaries, are
called tumorlets, granular cell myoblastoma or choristoma, and are generally asymptomatic (Fig. 19.14, 22.1;
Horvath et al., 1997). Symptomatic granular cell tumors
are rare and may be associated with diabetes insipidus,
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For third ventricle chordoid glioma (Pomper et al.,


2001), see Chapter 17.3; and, for septum pellucidum
tumors, see Chapter 18.8. The subependymal giant cell
astrocytoma in tuberous sclerosis is described in Chapter
19.8.
19.5. Craniopharyngioma, Rathkes cleft cysts and
xanthogranuloma
(a) Craniopharyngioma
A low-grade developmental neoplasm, craniopharyngioma is thought to be derived from Rathkes pouch, the
pituitary anlage and can arise anywhere along the
craniopharyngeal canal. This canal is usually obliterated
during the 12th week of gestation. Rathkes pouch occurs
in embryos of 812 mm (2nd6th week) and is obliterated

between 6 and 8 weeks (Rottenberg et al., 1994). Rare


cases have indeed been described with a persistent craniopharyngeal canal and an intimate relationship that showed
up on MRI between the canal and the infrasellar part
of a craniopharyngioma (Chen, 2001), or with a nasopharyngeal extension of a normally functioning pituitary
gland extending into the nasopharynx (Ekinci et al., 2002).
It is the commonest intracranial tumor of nonglial origin
and accounts for 713% of all intracranial tumors under
14 years of age. The peak age is at 7 years (Costin, 1979),
but there is also a second, smaller peak in the sixth decade
(Harwood-Nash, 1994; Miller, 1994). A craniopharyngioma arising de novo in middle age has also been
reported (Arginteanu et al., 1997). A subset of craniopharyngiomas consists of monoclonal tumors arising from
activation of oncogenes located at specific chromosomal
loci.

Fig. 19.15. Craniopharyngioma in infundibulum. An incidental autopsy finding. NHB 96.077, male, 63 years of age. Hemotoxylineosin. Bar =
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but frequently extends into the third ventricle (Tada et


al., 1992) and stretches the optic chiasm (Fig. 19.16).
Craniopharyngiomas of the third ventricle occur twice
more often in men than in women (Tada et al., 1992).
Craniopharyngioma is best visualized by MRI (HarwoodNash, 1994; Hald et al., 1995; Fig. 19.16), while white
calcifications are best visualized by computed tomography
(CT) (Hald et al., 1995). On T1-weighed MRI images,
not only peritumoral edema but also edema spreading
along the optic tracts can be observed. Patients with large
pituitary adenomas or with tuberculous sellae meningiomas have such edema along the visual pathway. Edema
along the optic tract is thus a useful MRI finding with
which to distinguish craniopharyngiomas from other
common parasellar tumors (Nagahata et al., 1998).
Neuroradiologically, a third ventricle craniopharyngioma
may mimic a choroid plexus papilloma (Tada et al.,
1992). Tumors present in early childhood frequently
produce hydrocephalus (Chapter 18.7) and symptoms
of intracranial pressure (see Chapter 19.1; headache,
vomiting, memory loss, seizures, hemiparesis or abnormal
behavior), which may obscure the multiple endocrine
abnormalities (for review, see Costin, 1979).
Craniopharyngioma are present in two distinctive histological patterns: one resembling tooth-forming tissues,
i.e. the adamantinomatous craniopharyngiomas, and the

Craniopharyngiomas grow slowly, are usually well


encapsulated, and may be solid and contain calcium or
may be cystic (Costin, 1979). Pediatric craniopharyngiomas were found to be cystic in 99% and to contain
calcifications in 93% (Zhang et al., 2002). The cysts
contain machinery oil fluid consisting of cholesterol,
keratin, proteinaceous fluid, hemorrhage and necrotic
debris (Chong and Newton, 1993). Cystic craniopharyngiomas contain moderate to high immunoreactivity
for vascular endothelial growth/permeability factor, in
contrast to the more solid form of this tumor (Vaquero
et al., 1999). Craniopharyngioma are considered to arise
from squamous cell nests, thought to be vestigial remnants
of Rathkes pouch and frequently found in the
hypophysial stalk. Both the epithelial portions of craniopharyngiomas and the squamous cell nests in the pars
tuberalis of the pituitary stalk express keratin (Asa et al.,
1981; Fig. 19.15). Craniopharyngiomas do not express
cytokeratins 8 and 20 (Xin et al., 2002). Malignant transformation of craniopharyngioma is rare. It was proposed
that leukemia inhibitory factor (LIF), which is expressed
in the epithelial cells of adamantinomatous craniopharyngiomas, may play a role in the development and
progression of craniopharyngiomas (Tran et al., 1999).
In the majority of cases, the craniopharyngioma does
not remain confined to the sella, causing hypopituitarism,

Fig. 19.16. Suprasellar craniopharyngioma. Precontrast (A) and postcontrast (B) sagittal T1-weighted images. A heterogeneous mass is noted in
the suprasellar region, causing marked distortion of the anterior third ventricle. The anterior portion appears to be cystic, with rim-like enhancement after contrast administration. The posterior portion of the tumor, showing low signal intensity on T1-weighted images and heterogeneous
enhancement on the post-contrast-enhanced scans, represents the solid portion of the tumor containing calcifications. A pineal cyst is noted
incidentally. (From Chong and Newton, 1993, Fig. 18 with permission.)

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less common squamous papillary craniopharyngiomas.


These two types of craniopharyngiomas can be distinguished radiologically. The adamantinomatous type has
typically large, nonenhancing hyperintense cysts on
T1-weighed images, while the squamous-papillary type
appears as a hypointense cyst on noncontrast T1-weighed
image. The adamantinomatous type simulates adamantogenic tumors. This type of craniopharyngioma may
originate from migrated dental progenitor cells which are
presumed to accompany the upward extension of Rathkes
cleft in an early embryonal stage (Oka et al., 1997).
A few adamantinomatous craniopharyngeomas were
found to contain melanin pigment, which attests to the
similarities with odontogenic tumors of the jaw (Harris
et al., 1999). Transitional or mixed examples of the
two types of craniopharyngioma also occur. Previous
suggestions that the squamous papillary type is found
only in adults, never calcifies, does not invade the
brain and is associated with a better outcome (no recurrences, better clinical status) are only partially correct
(Miller, 1994; Crotty et al., 1995). The cases studied
by Davies et al. (1997) were evenly divided between
the adamantinomatous and the papillary types. Although
the benign tumor with an aggressive course is believed
to develop from the epithelial cell remnants of the
hypophysial-pharyngeal duct or Rathkes pouch, it is
difficult to account for squamous papillary tumors
on the basis of this hypothesis, since they do not resemble tumors of the tooth-forming epithelium. Also,
Rathkes pouch remnants do not usually have a stratified epithelium (Miller, 1994). Estrogen and progesterone
receptors have been demonstrated in both types of
craniopharyngiomas, raising the possibility that
these tumors can be influenced by steroids (Thaper et al.,
1994).
Craniopharyngiomas of the third ventricle may originate in ectopic epithelial nests of the infundibulum (Fig.
19.15), or a more distant site of an epithelial nest in the
brain around the third ventricle (Tada et al., 1992). They
are wholly within the third ventricle and can be distinguished from suprasellar lesions by the presence of an
intact floor of the third ventricle. Headache and visual
disturbances are the most common presenting features,
while, unlike the suprasellar craniopharyngiomas, endocrine disturbances are not a common finding. Subtotal
removal followed by radiotherapy has been proposed as
the treatment of choice (Davies et al., 1997), but in
children younger than 5 years it may be reasonable to
follow subtotal resection and to delay radiation until

recurrence, in order to diminish neurocognitive sequelae


(Khataga et al., 1998).
The signs and symptoms of a craniopharyngioma are
characteristically: headache, nausea and vomiting (BinAbbas et al., 2001; Rutka et al., 1992), growth failure,
increased intracranial pressure, and visual loss. However,
the clinical features depend on the size of the tumor and
its location, as well as the age of the patient (Costin,
1979). Presenting endocrine complaints are infrequent but
hypothalamic symptoms may include diabetes insipidus,
inappropriate antidiuretic hormone secretion, hyperprolactinemia, deficiencies of LH, FSH, ACTH, TSH, cortisol
or panhypopituitarism (Miller, 1994; Sklar, 1994; Paja et
al., 1995; Gonzales-Portillo et al., 1998; Bin-Abbas et al.,
2001), including hypogonadism (Bauer, 1954). Which of
these symptoms are due to hypothalamic lesions, to pressure on the hypothalamic pituitary vessels or on the
pituitary itself remains debatable, since many of the
lesions extend into the third ventricle (Crotty et al., 1995).
Growth hormone deficiency is generally present in children with craniopharyngioma. The growth rate of these
children may, however, stay normal, since craniopharyngeomas induce an increase in insulin secretion that keeps
IGF-1 normal (Pinto et al., 2000). In addition, patients
with a craniopharyngiomas often suffer from severe
obesity. Significantly, higher leptin levels were found in
patients with a suprasellar craniopharyngioma. It has been
suggested that these patients develop obesity because their
hypothalamic structures become insensitive to leptin,
resulting in a disturbed feedback from the hypothalamus
to adipose tissue. Severe hypoglycemia and reduction
of insulin requirement have been found in a girl with
insulin-dependent diabetes mellitus as a first sign of a
craniopharyngioma (Lebl et al., 1999). Increased daytime
sleepiness and decreased night-time melatonin levels
have been found in craniopharyngiomas, probably
due to hypothalamic lesions (Mller et al., 2002a).
Craniopharyngiomas may also cause psychiatric symptoms, e.g. hypersexual behavior, confusional syndromes,
hallucinations, or marked deterioration in occupational
performance (Carroll and Neal, 1997). Two cases of
patients have been published who meet the DSM-III-R
criteria for intermittent explosive disorder. Episodes
of rage develop before and/or after surgery for removal
of the craniopharyngioma. MRI revealed hypothalamichypophysial involvement. It was suggested that
hypothalamic lesions played a major role in the development of aggressive behavior in both cases (Tonkonogy
and Geller, 1992). Moreover, Killefer and Stern (1970)

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reported a case in which episodic savage behavior and


rage spells developed several weeks after total removal
of a craniopharyngioma. Malamud (1967) presented three
cases with craniopharyngiomas, respectively diagnosed as
schizophrenia, manic excitement and psychoneurosis. A
rare case of an adult with a craniopharyngioma presenting
with a diencephalic syndrome of emaciation was reported
(Miyoshi et al., 2003).
Total surgical tumor removal while avoiding hazardous
intraoperative manipulation provides favorable early
results and a low risk of recurrence of the craniopharyngioma (Fahlbusch et al., 1999; Duff et al., 2000).
The frontobasal interhemispheric approach, even made
through a small craniotomy window, is a valid choice for
the removal of craniopharyngiomas extending outside the
sellarsuprasellar region. Tumors can be removed via
this approach with preservation of the pituitary stalk,
hypothalamic structures and perforating vessels (Shirane
et al., 2002). The trans-lamina terminalis hypothalami
approach seems to be a valid choice for the removal of
purely intraventricular craniopharyngeomas (Maira et al.,
2000). Subtotal resection is associated with increased
risk of tumor recurrence and is usually followed by
radiotherapy. Long-term disease control is excellent after
subtotal resection and postoperative radiotherapy,
while a high risk of recurrence is found in the subtotal
resection without radiation. In that case, approximately
one-third of the patients exhibited morbid obesity (Duff
et al., 2000; Eisenstat, 2001). Following radiotherapy
the periods of tumor shrinkage are often long (mean
29 months). Temporary enlargement of the solid component usually occurs during radiotherapy and does not
represent tumor progression. Sometimes cystic enlargement also occurs comparatively early after radiotherapy,
and enlarged cysts often shrink spontaneously. After
shrinkage, small solid or cystic nodules enhanced with
contrast medium often remain. MRI allows assessment
of the extent of hypothalamic damage after surgery for
craniopharyngioma and thereby prediction of the patients
most at risk for severe postoperative weight gain (De Vile
et al., 1996). Multiple pituitary hormonal deficiencies
are quite frequent following radical surgery (Bin-Abbas
et al., 2001). It is worth preserving the pituitary stalk
and gland at surgery because of the definite chance that
intact anterior pituitary functions may be maintained.
Postoperative diabetes insipidus must be accepted as a
common complication of complete removal of a craniopharyngioma (Honegger et al., 1999), but judicious use
of desmopressin (DDAVP) and stress doses of gluco-

75

corticoids are advised to guide the patient through the


postoperative period (Eisenstatt, 2001). In addition,
gamma-knife radiosurgery, external beam irradiation,
fractionated stereotactic radiotherapy and intracavitary
irradiation give encouraging results (Eisenstatt, 2001;
Isaac et al., 2001; Barajas et al., 2002; Schulz-Ertner et
al., 2002; lfarsson et al., 2002; Varlotto et al., 2002).
A phase II study showed that interferon--2a is active
against some childhood craniopharyngiomas and may
provide an alternative treatment strategy (Jakacki et al.,
2000).
A small number of craniopharyngiomas with ciliated
epithelia has been described. In these tumors, craniopharyngiomatous tissue and Rathkes cleft epithelium are
intermingled, which seems to imply an intimate relationship between these two lesions (Oka et al., 1997).
(b) Rathkes cleft cysts
Cysts known as Rathkes cleft cycsts are relatively
common incidental microscopic findings, i.e. in some
1233% of the normal pituitaries at autopsy (Matsudo et
al., 2001), and are found during life, with increasing
frequency, by CT or MRI scans (Ward et al., 2001).
Occasionally the cysts become larger and symptomatic
by compression of surrounding structures, i.e. the hypothalamus, pituitary and visual pathways (Concha et al.,
1975; Eisenberg et al., 1976). Most of them occur in
the zona intermedia of the pituitary and may derive
from remnants of Rathkes pouch, thus sharing a similar
origin with craniopharyngioma (Ward et al., 2001).
Concomittant pituitary adenoma and Rathkes cleft cysts
are found. The frequency of the combination is some 4%
of the pituitary adenomas and 11% of the Rathkes cleft
cysts (Sumida et al., 2001). Patients may develop symptoms such as headache, hyperprolactinemia, galactorrhea,
decreased libido, impotence, visual field deficits, diabetes
insipidus, inappropriate secretion of vasopressin, amenorrhea or hypopituitarism such as adrenal insufficiency if
the cyst is large enough to push against adjacent structures. Repeated aseptic meningitis and spontaneous
resolution of Ratkes cleft cyst are also noted (Matsuno
et al., 2001; Ward et al., 2001).
The cyst wall is composed of a single layer of
columnar, cuboidal or squamous epithelium, which
may be ciliated and contain goblet cells. The cyst
may contain mucoid yellow and grumous material,
serous or CSF-like contents, or cellular debris (Chong
and Newton, 1993; Eguchi et al., 1994; Iwai et al.,
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2000; Ward et al., 2001). In addition, a case with amyloid


deposition (Concha et al., 1975) and one with ossification (Nakasu et al., 1999) has been described. These cysts
are usually confined to the sella (in older literature the
disorder is termed intrasellar craniopharyngioma) and
usually do not calcify (Harwood-Nash, 1994). The cysts
are seldom located entirely in the suprasellar region,
which then often leads to the mistaken diagnosis
of a craniopharyngioma (Rottenberg et al., 1994).
Histologically one may distinguish Rathkes cleft cysts
from craniopharyngiomas, e.g. in biopsies, by staining for
cytokeratins. Rathkes cleft cysts and pars intermedia of
the pituitary express cytokeratins 8 and 20, whereas craniopharyngiomas do not express these cytokeratins (Xin
et al., 2002). Moreover, Rathkes cleft cysts do not grow
they lack calcification and machine oil-like fluid content
which distinguishes them from craniopharyngiomas
(Chong and Newton, 1993). The unique MRI finding of
Rathkes cleft cysts high intensity on T1-weighted
images and low signal intensity on T2-weighted images
seems to depend on the protein and not on
the cholesterol concentration (Hayashi et al., 1999).
Symptoms of Rathkes cleft cysts may include generalized pituitary hypofunction, hyperprolactinemia, multiple
endocrinopathies, headaches and visual disturbances
(Rutka et al., 1992; Horvath et al., 1997). A few cases
have been described with symptomatic pituitary hemorrhage into a Rathkes cleft cyst with sudden, severe
retro-orbital headache, nausea and visual loss (Nishioka
et al., 1999). A case has been described of a Rathkes
cleft cyst, surrounded by areas of noncaseous granulomatous tissue with scattered multinucleated giant cells of
foreign body type, similar to a sarcoid lesion. Two years
later the patient reported a sudden visual impairment due
to sarcoidosis of the optic nerve. Remission of neurological symptoms followed corticosteroid therapy. The
diagnosis sarcoidosis was firmly confirmed when the
patient underwent surgery for new lesions on the acoustic
and facial nerves. The pituitary lesions were probably due
to secondary granulomatous infiltration of the pituitary
gland, where a small congenital asymptomatic Rathkes
cyst was already present (Cannav et al., 1997). Rathkes
cleft cyst was also found in a mosaic Klinefelter
46,XY/47,XXY patient with hypothalamic panhypopituitarism, partial diabetes insipidus and other endocrine
disorders (Gotoh et al., 2002).
Overexpression of LIF in mice that are transgenic for
LIF was found to lead to invagination of the anterior wall
of Rathkes pouch and the formation of cysts lined by

LIF-immunoreactive epithelial cells. Strong LIF immunoreactivity was also found in human Rathkes cleft cysts
(Tran et al., 1999), suggesting failed differentiation of
Rathkes epithelium to hormone-secreting cells (Akita et
al.,1997). Treatment consists of excision of the lesion,
and the transnasal transphenoidal approach has been
advocated (Ward et al., 2001).
(c) Xanthogranuloma
Xanthogranulomas (cholesterol granulomas) are considered to be a xanthogranulomatous change of craniopharyngioma (for a xanthogranulomatous degeneration
of a colloid cyst, see Chapter 17.3b). They consist of
cholesterol clefts, macrophages, chronic inflammatory
infiltrates, necrotic debris and hemosiderin deposits. They
lack the additional features of adenomatous craniopharyngiomas and some 35% contain squamous or
ciliated cuboidal cells. They preferentially occur in
adolescents and young adults (mean age 27 years), have
a predominant intrasellar localization, smaller tumor size,
more severe endocrinological deficits, longer preoperative history, lower frequency of calcification and visual
disturbances, better resectability and a more favorable
outcome than craniopharyngiomas. They are therefore
proposed to be clinically and pathologically distinct from
the classic adenomatous craniopharyngiomas (Paulus
et al., 1999).
19.6. Dermoid and epidermoid tumors
Dermoid and epidermoid cysts may compress the hypothalamus and pituitary and cause hypopituitarism, diabetes
insipidus or cranial nerve deficits. Both of these tumors
are benign and slow growing. They tend to wriggle around
adjacent neural structures, depending on the spaces they
occupy. The cyst walls of these tumors contain stratified
squamous epithelium and an outer layer of connective
tissue. Dermoid tumors occur in children but also in
adults. They are most commonly located in the fourth
ventricle or the vermis and are less commonly seen in
juxtasellar position. The cyst walls of these tumors contain
dermal appendages, hair follicles, sebaceous glands and
sweat glands, and stratified squamous epithelium. The
yellow contents of the cyst consist of a waxy material
containing desquamated keratin products, hair and cholesterol crystals. Epidermoid tumors occur in the fourth to
fifth decades of life. They are found in the basal cisterns,

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often in a lateral location, and produce remarkably few


pressure effects. The cyst walls of these tumors contain
a simple stratified squamous epithelium resting on an
acute layer of connective tissue. No skin appendages such
as sweat glands or hair follicles are found. The cyst
contains a waxy material with desquamated keratin products and cholesterol crystals. The cholesterol in the lumen
shines through, giving a silvery appearance, so that they
are sometimes called pearly tumors (Sheehan and
Kovacs, 1982; Chong and Newton, 1993). In the case of
an epidermoid (Rathkes pouch) cyst of the third ventricle,
a state of akinetic or trance-like mutism has been
described in the older literature. A 14-year-old girl slept
more hours than normal, but was easily aroused. Her eyes
followed moving objects but there were no other voluntary movements. She was quite mute or answered in
whispered monosyllables. She suffered loss of emotional
expression and painful stimuli caused reflex withdrawal.
Repeated commands were carried out occasionally, albeit
feebly, slowly and incompletely. She had to be fed, but
swallowed readily. There was total incontinence. This
syndrome was treated three times by aspiration of the
cyst. Each time there was a rapid, almost immediately
disappearance of the symptoms. Ten minutes after
the cyst was emptied, the child sat up in bed and said
Where am I?, as if waking from a sleep. The state of
akinetic mutism was not due to a general rise of intracranial pressure. Most functions that were affected are
considered to be cortical functions, i.e. voluntary movement, including speech, spontaneous activity of all
kinds, emotional expression, perception and memory. The
state of akinetic mutism was therefore interpreted as
an interruption of pathways between hypothalamus and
thalamus alongside the third ventricle by local pressure,
leading to an interruption of the hypothalamic input to
the cortex. The two connections speculated to be involved
are the bundle of Vicq dAzyr and the connection between
the posterior hypothalamic nucleus (Chapter 13.3), which
is considered to be a controlling center for the sympathetic system and the medial nucleus of the thalamus.
The latter fibers run along the third ventricle (Cairns
et al., 1941).

77

(pineocytoma and pineoblastoma), (iii) glial neoplasms,


and (iv) cysts (Fetell and Stein, 1986; Fig. 19.18;
Smirniotopoulos et al., 1992). Most pineal region masses
are malignant germ cell tumors that occur in young male
patients. The most common one is a germinoma (Fig.
19.17). Malignant, aggressive tumors (germinomas,
pinealoblastomas, immature teratoma and lymphoma)
invade the pineal parenchyma, generally leading to a
complete abolishment of melatonin secretion. On the other
hand, less aggressive benign tumors (pineocytomas, pilocytic astrocytomas and meningeoma) generally allow
normal secretion and circadian rhythm of melatonin
(Grimoldi et al., 1998). A child with a germ cell tumor
involving the pineal region markedly suppressing melatonin secretion suffered from severe insomnia. Exogenous
melatonin restored sleep continuity, thus providing
evidence for the essential role of melatonin in normal
sleep (Etzioni et al., 1996; see Chapter 4.5). The differential diagnosis of pineal region masses is extensive and
includes tumors, vascular lesions and even a case of histiocytosis (Gizewski and Forsting, 2001).
(a) Germ cell tumors
Primordial germ cells develop from embryonic cells of
the yolk sac wall, near the allantois. Between 5 and 8
weeks of gestation, they move into the genital ridges.
Misguided germ cells that move into the hypothalamicpineal region are supposed to give rise to extragonadal
germ cell tumors. Germ cell tumors occur primarily in
children and young adults in midline structures throughout
the body, including the pineal and suprasellar region
(Smirniotopoulos et al., 1992; Fig. 19.19). For suprasellar
and sellar localization, see Chapter 19.2. Pineal region
germ cell tumors occur almost exclusively in male
patients, while suprasellar germ cell tumors do not have
a sex preference.
Germ cell tumors are classified according to Teilums
scheme (Fig. 19.18; Fetell and Stein, 1986). In Fig. 19.18
the presence of the tumor markers HCG and -fetoprotein
are also indicated. Such markers can also be used to
monitor therapeutic interventions (Massie et al., 1993;
Tarng and Huang, 1995). CSF levels of these markers
may be more sensitive and precede elevations in serum.
Germinomas are generally negative for -fetoprotein,
while HCG is usually absent or only slightly elevated. HCG is markedly elevated and -fetoprotein is
usually normal with choriocarcinomas (Schut et al.,
1996). Germinomas do not have a pineal origin and thus

19.7. Pineal region tumors


According to the pathological classification of Russell
and Rubinstein, the following types of tumors have to be
distinguished in the pineal region: (i) teratomas (including
all germ cell-derived tumors); (ii) pineal cell tumors
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Fig. 19.17. Intrachiasmal craniopharyngioma. Sagittal (A) and coronal (B) T1-weighted MR scans. The tumor has a slightly heterogeneous
appearance and has caused marked expansion of the chiasm (arrows). (From Chong and Newton, 1993, Fig. 20 with permission.)

Fig. 19.18. Teilums proposed scheme of differentiation of germ cell tumors. HCG = human chorionic gonadotropin, AFP = -fetoprotein.
(Modified by Fetell and Stein, 1986, Fig. 4.)

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generally do not produce melatonin. Only a few rare


cases of germinomas have been described that produce
melatonin. The melatonin-synthetizing enzymes N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) were present in this case, while the
high blood levels of melatonin became undetectable
postoperatively (Grimoldi et al., 1998).
A germinoma is the most typical pineal region mass. It
was formerly called atypical teratoma and is histologically identical to ovarian dysgerminoma and testicular
seminoma. Male patients are 217 times more affected
than female patients. The peak age of presentation is in
the second decade. A germinoma is a malignant tumor
composed of large, multipotential, primitive germ cells
and infiltrating lymphocytes, epithelioid cells (probably
derived from macrophages) and macrophages. Often the
lymphocytes penetrate deeply into the cytoplasm, even
into the nucleus of the tumor cell. The infiltrating cells
may be directly cytotoxic to the tumor cells (Wei et al.,
1992; Grimoldi et al., 1998). Histologically germinomas
of the pineal region are identical to those in the suprasellar region (Chapter 19.2; Schut et al., 1996). A germinoma
may invade the adjacent brain structure and also spread
through the CSF (Fig. 19.19) in 3237% of cases (Schut
et al., 1996). Pure germinomas are associated with low or
undetectable HCG levels in serum and CSF (Sklar, 2002).
A primitive germ cell that may lead to a malignancy
is called an embryonal carcinoma. It may give rise to a
differentiated teratoma that is a benign and slow-growing
tumor but may also be locally invasive or metastasize.
Teratoma also have a male prevalence of a factor 2.8.
Teratoma are neoplasms that recapitulate normal organogenesis, usually producing tissues representing a mixture
of two or more of the embryonic layers of ecto-, mesoand endoderm. It might produce tissue that mimics the
skin and has to be differentiated from a dermoid cyst
(Chapter 19.6) by the presence of components of diverse
tissues. They contain lipid areas and may have calcifications (Fig. 19.20). Usually -fetoprotein and HCG are
elevated or slightly above normal (Schut et al., 1996).
Some embryonal carcinomas contain elements of teratoma
and are termed teratocarcinomas. An embryonal carcinoma cell is believed to be a precursor malignancy that
can also differentiate into a tumor of extraembryonic
tissue. These tumors give both elevated -fetoprotein and
HCG levels (Schut et al., 1996). If the resulting tumor
contains trophoblastic tissue it is called a choriocarcinoma (which usually produces markedly elevated HCG
levels) (Schut et al., 1996), if it contains yolk sac elements

Fig. 19.19. Germinoma with seeding. (a) Sagittal T1-weighted MR


image of a 22-year-old man demonstrates two lesions (dots) that are
homogeneous and are equal in signal intensity to that of gray matter.
There is a dominant mass in the pineal region and a second, smaller
mass in the suprasellar cistern. (b) Coronal T1-weighted MR image of
the same patient after administration of gadopentetate dimeglumine
demonstrates abnormal enhancement of the enlarged pituitary
infundibulum, which represents seeding from the pineal germinoma. (c)
Sagittal gross specimen obtained at autopsy of a different patient also
demonstrates two prominent masses. The original germinoma is the
large mass in the pineal region. The second mass, in the suprasellar
cistern, represents CSF dissemination. Together, these two masses
compress and distort the brain stem. The pineal mass extends well
below the tentorium and encroaches on the roof of the fourth ventricle.
It also spreads anteriorly, to the foramen of Monro, through the cistern
of the velum interpositum (*). (From Smirniotopoulos et al., 1992, Fig.
4 with permission.)

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Fig. 19.20. Teratoma. (a) CT scan of a 4-year-old boy demonstrates a heterogeneous mass in the pineal region extending anteriorly into the cistern
of the velum interpositum. The mass contains several large chunks of calcification and a darker, cystic-appearing area (arrowhead). Heterogeneity
like this, especially when there is lipid material and calcification, is a hallmark of a mature teratoma. (b) After contrast material is administered,
there is relatively homogeneous enhancement of the noncalcified solid portions of the tumor. The cystic region does not appear enhanced. (c) T1weighted MR image of the same patient demonstrates a mildly heterogeneous mass largely isointense relative to gray matter. However, there are
focal areas of T1-weighted shortening (arrowhead) from lipid material (e.g. sebaceous). The cystic region (*) has higher signal intensity than that
of CSF because of proteinaceous material. (d) Sagittal T1-weighted MR image of an 8-year-old boy demonstrates a grossly heterogeneous mass
with large amounts of hyperintense lipid material. It extends anteriorly toward the cistern of the velum interpositum and posterior third ventricle.
Note the cystic region (*). The signal intensity void of the internal cerebral veins (arrowhead) is superior to the mass, but, in addition, there is a
thin rim of hypointensity encircling the mass, suggesting a tumor capsule. (Courtesy of L. Baker, MD, University of California, San Francisco).
(e) Sagittal gross specimen of a mature pineal teratoma from a different patient shows a grossly heterogeneous mass that is well encapsulated
(arrowhead). The varied contents of this partially cystic mass include a superior portion with a cheesy consistency for sebaceous material. In
the sagittal plane, it is clear that much of this mass is below the tentorium. (From the L. Rubinstein collection, AFIP.) (From Smirniotopoulos,
1992, Fig. 5 with permission.)

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Fig. 19.21. Yolk sac tumor in a 9-year-old boy. (a) Axial CT scan obtained without the use of contrast material demonstrates a round, relatively
homogeneous, low attenuation mass, engulfing the calcifications within the central pineal gland. Germinomas are usually high-attenuation masses;
thus, other diagnoses should be considered. However, the appearance is neither specific for nor suggestive of yolk sac tumor. There is an incidental dural osteoma (arrow). (b) Axial CT scan obtained after contrast material is administered shows homogeneous enhancement, which is also
non-specific. (c) Axial T2-weighted MR image demonstrates nonspecific homogeneous hyperintensity (higher than the signal intensity of gray
matter) of the mass. (d) Sagittal MR image obtained without the use of contrast material demonstrates minimal heterogeneity in the mass, which
is slightly hypointense relative to gray matter. (e) Sagittal MR image obtained after administration of gadopentetate dimeglumine shows prominent
but slightly heterogeneous enhancement. (Smirniotopoulos, 1992, Fig. 9 with permission.)

it is called an endodermal sinus tumor or yolk sac tumor


(which usually produces high levels of -fetoprotein
(Schut et al., 1996) (Fig. 19.21). Both are highly malignant
(Fetell and Stein, 1986; Smirniotopoulos et al., 1992).

Adjuvant therapy consisting of preoperative chemotherapy with cisplatin and ectoposide and concomitant
radiotherapy, followed by radical surgical removal of the
tumor, is proposed as a highly effective treatment of
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Fig. 19.22. Pineocytoma. (a) Plain CT scan shows a large and relatively homogeneous mass in the pineal region, with peripheral displacement of
pineal calcification (arrows). The mass has extended anteriorly along the velum interpositum. This is the exploded pineal appearance that suggests
an intrinsic pineal parenchymal neoplasm. (b) Contrast-enhanced CT scan shows homogeneous enhancement in the mass, which assumes a triangular shape as it conforms to the contours of the pulvinar of the thalami and velum interpositum. (c) Axial proton-density-weighted MR image
shows the mass is homogeneously hyperintense; it is diamond shaped because it fills the two opposing triangles of the velum interpositum (anterior) and quadrigeminal plate cistern (posterior). (d) Sagittal T2-weighted image shows the mass is under the internal cerebral veins (arrow) and
extends anteriorly along the velum interpositum. The mass also extends interiorly, separating the cerebellum from the brain stem, and encroaches
on the superior medullary velum (the roof of the fourth ventricle). (From Smirniotopoulos et al., 1992, Fig. 11.)

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pediatric patients with primary intracranial yolk sac tumor,


embryonal carcinoma or mixed germ cell tumors containing yolk sac tumor components (Ushio et al., 1999).
(b) Pineal parenchymal tumors
A pineocytoma (Fig. 19.22) is composed of cells that
resemble mature pineocytes (Coca et al., 1992) and are
arranged in a glandular pattern. However, it may behave
like pineoblastoma, seeding via the CSF. In contrast, a
pineoblastoma is histologically identical to a medulloblastoma. It may invade adjacent brain structures spread
by the CSF and is considered a primitive neuroectodermal
tumor of the pineal region. These tumors have no sexual
predilection. Both tumors are malignant and may contain
intrinsic calcifications. In addition, pineal parenchymal
tumors might have ganglionic and astrocytic differentiation. Neither melatonin nor HIOMT are considered to be
useful markers for parenchymal tumors and also HCG
and -fetoprotein are usually negative. Tumoral pineal
cells differentiate either toward a neurosensory pathway
characterized by the presence of sensory elements
(vesicle-crowned rodlets or synaptic ribbons and fibrous

elements), or toward a neuroendocrine pathway with the


occurrence of many dense-core vesicles (Fetell and Stein,
1986; Smirniotopoulos et al., 1992; Jouvet et al., 1994;
Schut et al., 1996). Pineocytomas and a peneoblastoma
showed a decrease in the somatostatin receptor subtype
sst 2 and a complete loss of sst 5 expression (Champier
et al., 2003).
(c) Glial neoplasms
Glial neoplasms make up about one-third of the pineal
tumors. One-third of these tumors are benign; however,
astrocytomas may infiltrate the white matter along long
tracts. True glioblastomas rapidly become lethal (Fetell
and Stein, 1986; Smirniotopoulos et al., 1992).
(d) Cysts, tumors of supporting elements and
miscellaneous
The epiphysis often contains pineal cysts
1994), most of which are of glial origin.
they have an ependymal lining and there
cavities from the third ventricle (Duvernoy

(Fain et al.,
Occasionally
are vestigial
et al., 2000).

Fig. 19.23. Lipoma. (a) Axial CT scan shows a fatty attenuating mass in the pineal region that does not enhance. With its homogeneity and lack
of enhancement, the mass is most likely not a teratoma. It occupies most of the quadrigeminal plate cistern. (b) Sagittal T1-weighted MR image
shows a mass in the quadrigeminal plate cistern with homogeneous high signal intensity, similar to the signal intensity from the subcutaneous fat
and clival marrow. As with many other pineal region masses, it extends inferiorly (below the tentorium) and pushes the cerebellum away from
the brain stem. (From Smirniotopoulos, 1992, Fig. 14 with permission.)

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Moreover, malignant rhabdoid tumor (Muller et al, 1995)


and malignant melanoma are found. Melanoblasts are
present in most parts of the pia and may give rise to
tumors (Rubino et al., 1993). In addition, primary
myeloblastoma (Voessing et al., 1992), lipoma (Fig.
19.23), meningeomas, spindle cell carcinomas, choroid
plexus papilloma, hemangioblastoma, progonoma (a
melanocytic neuroectodermal tumor), chemodectomas
that presumably arise from sympathetic fibers that innervate the gland, and metastatic neoplasms should be
mentioned (Fetell and Stein, 1986; Smiriniotopoulos et
al., 1992).
(e) Clinical symptoms of pineal region tumors
Most patients with pineal region tumors have nonspecific symptoms of increased intracranial pressure,
i.e. headaches, nausea, vomiting, visual abnormalities,
papilledema and seizures. In addition, short stature,
obstructive hydrocephalus causing hypothalamic compression and anterior pituitary deficiency (growth
hormone deficiency, hypothyroidism, low cortisol),
diabetes insipidus, hypogonadism, high prolactin, and
precocious or delayed puberty are found. Precocious
puberty due to pineal tumor may be explained by: (i)
destruction of the pineal gland by the tumor, interfering
with its normal antigonadotropic effect; (ii) destruction
of hypothalamic sexual inhibitory centers; and (iii) ectopic
secretion of gonadotropins such as -HCG, which acts
like LH (Fetell and Stein, 1986; Rivarola et al., 1992,
2001; Smirniotopoulos et al., 1992).
There is indeed quite some evidence that hamartomas
have cells with the capacity of LHRH pulse generators
(see Chapter 19.3). In some cases either a lack of the
maximum night melatonin plasma value or higher-thannormal nocturnal melatonin concentrations could indicate
a pineal region tumor (Mandera et al., 1999).
A patient with histiocytosis that was present as a mass
in the pineal gland presented with incomplete ocular palsy
(Gizewski and Forsting, 2001).
19.8. Tuberous sclerosis (BournevillePringle
syndrome) and tumors of the hypothalamus
Tuberous sclerosis is an autosomal dominant hereditary
disease, although most cases probably arise sporadically.
Its presentation varies, showing lesions in brain and skin,
facial angiofibromas, retinal hamartomas, epileptic
seizures, mental retardation, autism and attention-deficit

hyperactivity disorder. Among the various epileptic


syndromes, Wests syndrome is the most typical (Crino
and Henske, 1999; Mizuguchi and Takashima, 2001;
Andres, 2003). Embryologically both the brain and the
skin are derived from ectoderm; tuberous sclerosis therefore belongs to the neurocutaneous syndromes (Morse,
1998) or phakomatosis with multisystem involvement
(Inoue et al., 1998b). Brain lesions in tuberous sclerosis
consist of cortical tubers, white matter abnormalities and
subependymal nodules that may also occur in the third
ventricular wall and that show calcification with
increasing age. The cortical tubers and subcortical heterotopic nodules are static, while the uncontrolled growth of
subependymal giant cell astrocytomas may lead to hydrocephalus and death (Crino and Henske, 1999; Mizuguchi
and Takashima, 2001). The prevalence of tuberous sclerosis is at least 1 in 10,000 (Inoue et al., 1998b; Crino
and Henske, 1999). The tumor-like growth may include
cells of more than one type, such as glioblasts and neuroblasts. Tuberous sclerosis is caused by mutations in the
tumor-suppressor gene TSC1 on chromosome 9q34 or in
TSC2 on 16p13.3 (Inoue et al., 1998b; Mizuguchi and
Takashima, 2001). TSC1 and TSC2 genes encode distinct
proteins, hamartin and tuberin, respectively. TSC2 mutations are more prevalent in sporadic cases (Crino and
Henske, 1999). Benign brain tumors are frequently seen
in tuberous sclerosis, which may also affect the hypothalamus. Giant cell astrocytomas occur in about 10% of
the children with tuberous sclerosis (Gunatilake and
Harendra De Silva, 1995). Subependymal giant cell
tumors have the tendency to enlarge and occur in 1015%
of tuberous sclerosis patients. Why such tumors occur
only in the area of the foramen of Monro is not clear
(Inoue et al., 1998b). A few tuberous sclerosis patients
have been described with a giant cell astrocytoma filling
the third ventricle (Turgut et al., 1996).
In his series of 60 autopsy cases with pathological
lesions of the hypothalamus, Bauer (1954) described one
patient with tuberous sclerosis whose corpora mamillaria were involved, and in whom precocious puberty,
convulsions and disturbed water balance were found.
Moreover, tuberous sclerosis of the hypothalamus has
caused obesity (Bastrup-Madsen and Greisen, 1963) and
has been associated in one case with a cavum septum
pellucidum (Bruyn, 1977). More recently, a case report
was published on a boy who developed precocious
puberty at 13 months and who had a hypothalamic
hamartoma and periventricular calcified lesions. The
manifestations of precocious puberty were based upon

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tuberous sclerosis and were effectively reduced by LHRH


(De Cornulier et al., 1993; cf. Chapter 19.3). In addition,
a child has been described who suffered from tuberous
sclerosis and laughing seizures due to a neoplasm rising
from the floor of the left lateral ventricle and extending
downwards into the hypothalamus. Ventricular dilatation
was noted on the left side as a result of the tumor causing
an obstruction of the foramen of Monro (Gunatilake and
Harendra De Silva, 1995). It is not known whether children with tuberous sclerosis so often suffer from sleep
disturbances because their hypothalamic systems are
affected. However, melatonin improves the total sleep
time in these patients (OCallaghan et al., 1999; Hoban,
2000).
Only a few cases have been reported of neuroendocrine
disturbances on the basis of tuberous sclerosis.
Bloomgarden et al. (1981) described hyperprolactinemia,
amenorrhea and galactorrhea in a female patient with
tuberous sclerosis. The hyperprolactinaemia was unresponsive to protirelin, chlorpromazine, levedopa,
bromocriptine mesylate or estrogen. It is not clear whether
the hyperprolactinemia was derived from the pituitary or
a hamartoma. Tinguy du Pouet et al. (1985) published a
case of tuberous sclerosis with diabetes insipidus, hyperprolactinaemia, growth hormone deficiency and delayed
puberty, based upon a hypothalamic periventricular
hamartoma. Microscopic examination revealed bizarre
giant cell clusters to be the main feature of the tubers.
These giant cells have both astrocytic and neuronal
features, suggesting that they are the product of a dysgenetic event in early development. In the white matter the
giant cells align in rows that appear to follow the path
of neuronal migration. Probably those cells that migrate
to the cortex form the tubers, and those that show incomplete migration give the white matter lesions. Some may
not migrate and produce subependymal nodules (Inoue
et al., 1998b).

85

frequently involving the pituitary stalk and hypothalamus.


These tumors may show rapid growth, differentiating the
lesion from a benign pituitary adenoma (Chong and
Newton, 1993). Also, brain tumors may give rise to hypothalamic metastases. For instance, Bauer (1954) reported
metastases to the third ventricle, infundibulum and
corpora mamillaria of a frontal lobe tumor. Metastasis
of the hypothalamic-pituitary region may also be an
atypical postmortem finding in systemic cancer. In symptomatic cases, diabetes insipidus due to a tumor in the
infundibulum or neurohypophysis is the usual clinical
manifestation, especially seen in the terminal stages
(Kimmel and ONeill, 1983; Schubiger and Haller, 1992;
Ten Bokkel Huinink et al., 2000). Serious loss of neurons
and gliosis may occur in the supraoptic and paraventricular nucleus when the stalk and neurohypophysis are
destroyed by metastases (Duchen, 1966). In addition,
circadian rhythm disturbances have been described in case
of localization of a metastasis of an adenocarcinoma of
the rectum in the suprachiasmatic region (Fig. 4.2).
Diabetes insipidus is a rare complication of acute
myeloid leukemia and acute lymphoblastleukemia. In
most cases a local leukemic infiltrate was found, most
often of the posterior lobe, but also in the hypothalamus
(Fig. 19.24). In some patients, however, overt leukemic
infiltrates were missing and scant thrombosis of small
vessels in the hypothalamus and posterior lobe of the
pituitary were seen. Moreover, some patients have been
described with diabetes insipidus established in the
preleukemic phase of acute myeloid leukemia. In one of
the patients, diabetes insipidus was a result of a hypothalamic lesion as judged from endocrine studies
(Puolakka et al., 1984). When one considers that the
posterior lobe, and not the anterior lobe, of the pituitary
is directly supplied by arterial blood from the systemic
circulation, the predilection for metastasis in this structure is understandable. The anterior lobe is supplied by
the portal system. When this system is obstructed by a
tumor, it is almost invariably by direct extension of the
tumor from the posterior lobe (Duchen, 1966), and
microinfarcts of the pituitary are the result (Kimmel and
ONeill, 1983).
Other clinical manifestations of metastases in this
region are anterior pituitary failure, and visual disturbances due to chiasmatic and optic nerve involvement
(Kimmel and ONeill, 1983). In fact, patients with tumors
who develop diabetes insipidus or hypopituitarism most
probably harbor pituitary metastases and not an adenoma
(Schubiger and Haller, 1992). Once a case with metastatic

19.9. Metastases
Brain metastases are common and often occur in patients
whose systemic cancer is quiescent. The most common
sources of metastatic tumors in the pituitary-hypothalamic region are carcinomas of the lungs or breasts,
and leukemia/lymphoma (Schubiger and Haller, 1992;
Chong and Newton, 1993). Metastatic carcinoma
originating from the gastrointestinal tract have also
been described. In cases of metastases, MR images
may show an enhancing lesion in the pituitary gland,
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Fig. 19.24. Female, 79 years of age, with chronic myeloide leukemia (NHB 88-093). Leukemic infiltration is present in the hypothalamus, just
above the supraoptic nucleus (SON). Bar represents 100 m.

spread of a small oat-cell carcinoma of the lung was


reported, involving both the posterior pituitary and the
pineal (Suganuma et al., 1994). It was proposed by way
of explanation that in both structures the bloodbrain
barrier is absent. In addition, violent hunger and obesity
have been reported as clinical evidence of hypothalamic
involvement in children with acute leukemia. Massive
diffuse leukemic infiltration was present in such cases at
the level of the ventromedial nuclei of the hypothalamus
(Heaney et al., 1954; Bastrup-Madsen and Greisen, 1963).
19.10. Other tumors
In the chiasmal and sellar region, approximately 10%
of the neoplasms are meningiomas. They may originate
from the superior leaf of the diaphragma sellae anterior
or posterior of the pituitary stalk or from the inferior
leaf of the diaphragma sellae (Beems et al., 1999).

Meningiomas of the inferior leaf of the sellar diaphragm


may produce primarily bitemporal hemianopsia and
hypopituitarism. Sometimes they grow around cranial
nerves. Sellar region meningiomas may produce hyperprolactinemia by mechanical effects on the pituitary stalk,
and may thus mimic prolactinomas. Meningiomas may
also cause diabetes insipidus or hypogonadism (Sheehan
and Kovacs, 1982; Horvath et al., 1997). Meningiomas
without dural attachment are rare (Beems et al., 1999),
but meningioma in contact with the pituitary stalk have
been described. As the pituitary stalk has no dura mater,
the tumor may have originated from the arachnoid
membrane of the pituitary stalk. The histological diagnosis was meningotheliomatous meningioma in one case
and meningioma in another (Hayashi et al., 1997).
Moreover, cases of meningioma of the third ventricle
have been described. Posterior third ventricular meningiomas usually originate from the falxtentorial junction

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or the connective tissue stroma of the pituitary gland.


Meningiomas in the anterior part of the third ventricle
usually result from the mesenchymal cell populations
belonging to the velum interpositum, the tela choroida
and the plexus choroidus. The patients have signs and
symptoms of increased intracranial pressures, diabetes
insipidus, motor disturbances, cranial nerve dysfunction
and, sometimes, short-term memory deficit (Pau et al.,
1996). Several data indicate that sex hormones may be
involved in the pathogenesis of meningiomas. The
majority of these tumors start to grow during the period
of maximum gonadal activity. These are the only common
intracranial tumors with a significantly higher incidence
in women, the female-to-male ratio being 2.5:1. In some
cases of meningiomas a relapsing course in relation to
pregnancy was found. In most cases these tumors were
located near the optic or oculomotor nerves. In addition,
there is an association between meningiomas and breast
cancer. Moreover, meningiomas have steroid hormonebinding sites for estrogens, progesterone, glucocorticoids,
mineralocorticoids and androgens (Poisson, 1984).
Juxtasellar or suprasellar subarachnoid cysts or arachnoidocele are benign. The subarachnoid space is formed
by an expansion of the intercellular space when the
cellular components of the meninx primitiva are removed.
The increase in the intercellular and primitive subarachnoid space are first observed at about 14 weeks of
gestation. Any abnormal event during this process may
result in the formation of an arachnoid cyst (Nishio et
al., 2001). The cysts may be asymptomatic and patients
may present with headache, optic-nerve compression,
disorders of growth, puberty, amenorrhea, obesity,
disturbed hypothalamopituitary function or hydrocephalus
(Adan et al., 2000; Todd et al., 2000). Rivarola et al.
(2001) and Starzyj et al. (2003) reported precocious
puberty in four children with a subarachnoid cyst.
Arachnoid cysts may also be found in autism (Tantam
et al., 1990). Fifteen percent of all arachnoid cysts are
parasellarly located. They can be congenital in origin,
develop from adhesions in the subarachnoid space or be
associated with another abnormality, such as a hamartoma. As they continue to expand slowly, they may push
against adjacent brain structures, cause hydrocephalus and
even remodel the adjacent skull. The differential diagnosis includes an epidymal cyst, a parasitic cyst or a
Rathkes cleft cyst (Chong and Newton, 1993; Nishio et
al., 2001). The minimally invasive treatment using stereotactic intracavitary irradiation of arachnoid cysts using
chromic colloidal phosphorus-32 proved to be safe and

87

Fig. 19.25. Coronal section of brain at midthalamus level with a chordoid


tumor obliterating the cavity of the third ventricle (arrow). Note
attachments of the mass to the roof of the ventricle and right thalamus,
and its downward extension to involve the hypothalamus. (From Vajtai
et al., 1999, Fig. 1 with permission.)

effective (Todd et al., 2000). Others have inserted a


cystperitoneal shunt (Nishio et al., 2001; Starzyj et al.,
2003).
Hypothalamic chordoma were reported in a few
patients. Chordoma are malignant neoplasms thought to
derive from fetal notochordal rests. Chordomas and chondromas are usually situated in the basis sphenoid behind
the posterior clinoid plate (Commins et al., 1994).
Third ventricle chordoid glioma arise from the hypothalamic (suprasellar) third ventricle region (Fig. 19.25).
The histology is reminiscent of chordoma or choroid
meningeoma. The tumor is composed of cords and clusters of epithelioid cells in a mucoid matrix and a
low-grade infiltrate of mature lymphocytes and plasma
cells. Russell bodies are present in the latter. Adjacent
brain tissue shows gliosis and numerous Rosenthal fibers.
The low-grade tumor arises preferentially in middle-aged
women. The symptoms may include forgetfulness,
headache, lethargy, homonymous hemianopsia, hypothalamic dysfunction and obstructing hydrocephalus.
Immunocytochemically, markers such as GFAP and
vimentin indicate that they are glia by nature. In imaging
studies, the tumor appears as a large, well-circumscribed
third ventricular mass, sometimes with a cystic component. The way the epithelioid cells are arranged in clusters
suggests a choroid plexus, or a meningothelial or notochordal derivation, but it may also be derived from the
subependymal tissue. The current treatment of choice is
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surgical resection (Brat et al., 1998; Vajtai et al., 1999;


Pomper et al., 2001; Kurian et al., 2002). Sometimes a
chordoma can mimic a pituitary adenoma and cause
bitemporal hemianopsia due to chiasmal compression and
hypopituitarism (Thodou et al., 2000).
Occasionally lipomas of 13 cm in diameter are found.
They might form a polyp hanging by a pedicle from the
undersurface of the tuber into the cisterna, or on the
ventral side of the mamillary bodies. Lipoma are usually
symptomless, located in the midline and found by accident. Macroscopically a lipoma might resemble a
hamartoma. Other lipoma might grow as a large mass
into the hypothalamus, replacing the entire tuberal region
and mamillary bodies. Histologically it is basically a
lipoma, but usually there are a few plaques of bone
embedded in the fat. Although the tumors are only
reported in adults, they are presumably congenital
(Sheehan and Kovacs, 1982; Kurt et al., 2002).

Malignant lymphoma is a condition of middle age and


affects both sexes equally. This is a type of tumor that
occurs more frequently in other parts of the brain than
in the hypothalamus and used to be called reticular
cell sarcoma. This tumor forms a pinkish solid mass in
the infundibulum and neighboring hypothalamus and
sometimes extends down the stalk to replace the posterior pituitary. Histologically it is diffuse and nonfollicular
in 6090% of the patients and consists of round or
polygonal cells with lobulated nuclei. In 98% of these
tumors the cells are derived from B lymphocytes.
Clinically the tumor is usually characterized by diabetes
insipidus and hypogonadism, sometimes also by
obesity, somnolence or psychiatric symptoms (Sheehan
and Kovacs, 1982). A case of primary hypothalamic
lymphoma was found to mimic neurosarcoidosis by
pleocytosis, increased spinal fluid protein, diabetes
insipidus, anterior lobe dysfunction, hepatic granuloma,

Fig. 19.26. A 24-year-old woman with a large adenoma of the pituitary (A) Mid-sagittal section. The optic chiasm (arrow) and anterior commissure (AC) are located on and above the adenoma, respectively. Anterior communicating artery complex (ACAC) is located closely in front of
optic chiasm and on the adenoma. (B) Coronal section. Optic chiasm (arrow) is flattened and displaced superiorly. (C) Axial section. Optic nerves
(arrows) are visible. (D) Axial section 3.5 mm above C. Optic tracts (arrow) and mamillary bodies (MB) are visible. (From Eda et al., 2002
Fig. 3.)

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to radiation therapy (Hasegawa et al., 1995). An endodermal cyst of the third ventricle has histological
similarities to the gastrointestinal epithelium and is
considered to be derived from the embryonic endodermal
layer, i.e. from the most cranial portion of the primitive
intestine (Bttner et al., 1997). A central neurocytoma
confined to the third ventricle presented clinically as
subarachnoid hemorrhage. It was a well-differentiated
neoplasm of neuronal origin, with a cystic component
and intratumoral hemorrhage. Synaptophysin, neuronspecific enolase, ultrastructurally identified synapses,
neurosecretory granules or neuritic processes demonstrated the neuronal lineage of these tumor cells.
Neurocytomas of the lateral ventricle may also spread
into the third ventricle. A gangliocytoma of the neurohypophysis is a very rare tumor (Chapters 19.3c, 22.1,
22.6). It may produce vasopressin and lead to inappropriate antidiuretic hormone secretion (Fehn et al., 1998;
Chapter 22.6). One patient with Cushings syndrome
appeared to have a gangliocytoma of the neurohypophysis containing ACTH-producing cells. The neurons
themselves did not express ACTH or CRH (Geddes
et al., 2000). In addition, ganglioglioma of the optic
chiasm were found most frequently as mixed glioneuronal tumors and more commonly in children
(Shuangshoti et al., 2000). Gliomatosis cerebri is
described in Chapter 19.4c.

hypercalcemia, elevated angiotensin-converting enzyme


(a carboxy-peptidase that hydrolyzes angiotensin I to
angiotensin II; produced, e.g. by epitheloid cells of the
sarcoid granuloma). The lack of response to prednisone
was, however, atypical for sarcoidosis, and emergency
transplenoidal resection disclosed a large B-cell
lymphoma, a disease that is usually also steroid-responsive (Bayrakdar et al., 1997).
A Large adenoma of the pituitary may push upwards
and produce pressure on the front of the chiasm,
or between the optic nerves (Fig. 19.26). The first
symptom is usually bitemporal hemianoptia, and there
is optic atrophy. Less often the tumor may impinge
on the back of the chiasma. Pressure on the hypothalamus may lead to fatigue and sleepiness, excessive eating
or anorexia, hypothermia, diabetes insipidus, hydrocephalus and hypopituitarism. The patient may also feel
cold due to hypothyroidism, perform less well and have
headaches (Sheehan and Kovacs, 1982; Harris et al.,
2002).
Gait disturbances and behavioral changes in a 51-yearold woman appeared to be due to a small, blackberry-like
subependymal tumor, i.e. a cavernoma behind the
interthalamic adhesion in the third ventricle. A huge,
mixed cavernous angioma and astrocytoma in the hypothalamus manifested by headache, visual field defect, gait
disturbance and convulsions, responded remarkably well

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)


The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved

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CHAPTER 20

Hypothalamic infections

20.1. Inflammatory conditions affecting the


hypothalamus

region. The granulomatous lesion was composed of


small cavities filled with necrotic material. The abscess
cavity was encircled by layers of collagen and florid
granulomatous tissue with giant cells (Fig. 20.1). There
was no evidence of systemic tuberculosis (Indira et al.,
1996). In the case of a hypophysial tuberculoma, a
thickened pituitary stalk in contrast MRI scans may be
useful for the differentiation from pituitary adenomas
(Sinha et al., 2000; Pramo et al., 2002). However, in
some developing countries, but also in the USA, patients
have been described with a hypothalamic tuberculoma,
causing the signs and symptoms of panhypopituitarism
(Flannery et al., 1993). Intracranial calcifications develop
in approximately one-third of the children who recovered
from tuberculous meningitis. The calcified lesions may
destroy hypothalamic or pituitary tissue and result, e.g.
in somatotropic or gonadotropic deficiencies or diabetes
insipidus (Asherson et al., 1965; Haslam et al., 1969).
Patients with tubercular meningitis may die suddenly,
probably due to hypothalamic apoplexia. Hypothalamic
damage secondary to infarction has been reported repeatedly. Other patients may develop panhypopituitarism due
to chronic scarring and calcification of the hypothalamus
(Indira et al., 1996).
In cholera cases, the hypothalamus showed a decrease
in Gomori-stained neurosecretory material. The paraventricular nucleus (PVN) was sometimes vacuolated
(Choudhury, 1969).

(a) Bacterial infections


One hundred years ago, tuberculosis was one of the
diagnoses most frequently made in the Western countries.
In 1893, Starr reported that 50% of all brain tumors
were due to tuberculosis, and, in the early years of
the last century, Cushing said that about 30% of all
space-occupying lesions within the cranium were attributable to tuberculosis (Scully et al., 1983). Tuberculous
meningitis may cause, e.g. epilepsy, hemiplegia, paraplegia, optic atrophy and blindness, deafness, mental
retardation, hydrocephalus and hypothalamopituitary
disorders such as diabetes insipidus, obesity, hypogonadism, and, when the periventricular portion of the
hypothalamus is involved, precocious sexual development
(Bauer, 1954; Lorber, 1958; Asherson et al., 1965). In
areas where tuberculosis is endemic, hypothalamic tuberculoma can still form an important radiologically
differential diagnosis to be distinguished, e.g. from astrocytoma, craniopharyngioma, hamartoma and germinoma.
A case report on a 10-year-old boy may serve as an
example. For 6 months this boy had had hypothalamic
symptoms, i.e. progressive loss of vision, headaches and
vomiting, and it was noticed that he gained weight
and ate and slept excessively for 4 months. There was
compression of the third ventricle with hydrocephalus.
He underwent placement of a ventriculoperitoneal shunt
prior to exploration. A biopsy of the suprasellar mass
revealed tuberculoma. Postoperatively the patient developed polyuria and hypothermia. The patient died on
the 7th postoperative day. At autopsy the suprasellar
mass was found to be occupying the entire hypothalamic

(b) Acute viral meningoencephalitis


Hypothalamopituitary symptoms such as hypopituitarism,
including hypogonadism, hyperprolactinemia and the
syndrome of inappropriate secretion of vasopressin may
be caused by acute viral meningoencephalitis (Bauer,
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Fig. 20.1. Tuberculosis of the hypothalamus (A). A histological preparation shows an abscess cavity field with caseous material bordered by poorly
formed granulomas with giant-cell reaction and fibrosis. (B) Higher magnification of the abscess wall shows epitheloid cells and Langerhans-type
giant cells. (From Indira et al., 1996, Fig. 3 with permission.)

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1954; Kupari et al., 1980; Lichtenstein et al., 1982;


Ishikawa et al., 2001b). According to Bauer (1954), the
periventricular portion of the hypothalamus can be
involved in various types of encephalitis and encephalomeningitis, including tuberculosis, which may result
in precocious puberty and diabetes insipidus. Acute
virus encephalitis frequently goes together with lesions
in the hypothalamus. A 12-year-old girl was diagnosed
as having acute disseminated encephalomyelitis. She
manifested hypersomnia and intense lesions in the
hypothalamus. The low hypocretin levels in the cerebrospinal fluid (CSF) of this patient explained the
hypersomnia (Kubota and Kabayashi, 2002; Chapter
28.4). Hypothalamic lesions have been reported, e.g.
following varicella-zoster, smallpox, measles, coxsackie
virus B, poliovirus and inoculation for rabies in patients
who died during the acute stage of encephalitis (Ishikawa
et al., 2001b).
A recent study using MRI confirmed the presence of
hypothalamopituitary abnormalities and dysfunctions in
rabies (Ishikawa et al., 2001b). Indeed, rabies is virtually
always fatal, once symptoms are evident (Pleasure and
Fischbein, 2000). Sexual manifestations of rabies, such
as priapism, penile hyperexcitability with erection, ejaculation on the slightest touch of the penis, and excessive
libido have been reported (Dutta et al., 1996). It has been
proposed that rabies may have played a key role in the
belief in vampires in the 18th century. Vampires allegedly
were dead people who left their graves and killed people
and animals (Gmez-Alonso, 1998). Rabies is a zoonosis
transmitted by a bite, scratch or inhalation of the virus.
Bat-borne rabies can be spread without traumatic exposure. Once inoculated, the virus spreads centripetally via
peripheral axons to the central nervous system (CNS),
where it is capable of transsynaptic spread. The intimate
relationship between the hypothalamus and the autonomous system (Buijs and Kalsbeek, 2002) may thus be
the explanation for the frequent involvement of the
hypothalamus. The untreated patient with furious (i.e.
encephalitic) rabies following dog bite frequently manifests a tendency to wander, to be restless, to show signs
of autonomic dysfunction, a hypersensitivity to stimuli,
a feeling of terror, persistent insomnia, an increasing
agitation, hydrophobia and muscular spasms. Paralytic
symptoms (dumb form) and coma may appear before
the patient dies. Rabies shows similarities to vampirism.
The muscle spasms may cause hoarse sounds, saliva
cannot be swallowed and vomiting of bloody fluid occurs.
Bat rabies is reported to give a high incidence of focal

93

brainstem signs and myoclonus, sometimes hemiparesis


or hemisensory deficits, ataxia, chorea or Horner
syndrome. The rabid patient may rush at those who
approach him, biting and tearing at them as if he were a
wild animal. Hypersexuality and violent rape attempts
may be striking manifestations of furious rabies. In some
men penile erection can last for several days. The literature reports cases of rabid patients who had intercourse
up to 30 times a day (Gmez-Alonso, 1998; Pleasure and
Fischbein, 2000).
Hypothalamopituitary insufficiency has been observed
following influenza A and herpes simplex encephalitis
(Kupari et al., 1980; Ishakawa et al., 2001). Following
herpes simplex encephalitis, MR images showed involvement of the substantia innominata and of the corpora
mamillaria in patients who were left with memory difficulties (Kapur et al., 1994). Hypothalamic encephalitis
has also caused a marked sinus bradycardia so severe
(with a heart rate of less than 30 beats per minute), that
a temporary pacemaker had to be implanted (Ishikawa et
al., 2001b).
(c) Post- and parainfectious encephalomyelitis
Hypothalamic lesions are a much less frequent occurrence
in the post- and parainfectious encephalomyelitis than in
the acute stages of encephalitis. A combination of hyperthermia, hyperphagia and secondary hypothyroidism has
been described in a boy after 1 year of high fever due to
a varicella infection. Diurnal fluctuations in temperature
and water excretion were abnormal, but diurnal fluctuations in serum corticosteroid levels were present.
Temperature regulation did not respond to the ordinary
regulatory stimuli. At autopsy, focal areas of gliosis and
lymphocytic infiltration were only found in the hypothalamus, particularly in the region of the supraoptic
nucleus (SON) and tuber cinereum (Lipsett et al., 1962).
A case of hypothalamic encephalitis with influenza
A/Netherlands/110/72, which was preceded by infectious
mononucleosis, showed a severe chronic inflammatory
reaction. There were round-cell accumulations in the
perivascular spaces, astroglial proliferation, foci of histiocytes, macrophages and edema; nerve cells were affected
(Ongerboer de Visser et al., 1976). In bulbar poliomyelitis,
diffuse inflammatory hypothalamic changes have been
observed in 85% of the cases. The SON is most severely
affected, whereas the tuberal and mamillary nuclei are
usually spared (Baker et al., 1952). In cases of bulbar
poliomyelitis where a prolonged hyperthermia is manifest,
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cell damage is the most severe in the rostral portion of the


hypothalamus. Because the PVN involvement alone is
reported to be exclusively associated with temperature elevations, the PVN has been proposed to be an essential
structure as far as lowering body temperature is concerned.
In cases of hypothermia, lateral and medial hypothalamic
nuclei are involved (Brown et al., 1953). A 3-year-old boy
developed obesity and had a fever for half a year. He died
of an allergic reaction to penicillin. Autopsy revealed a
severe bilateral drop of neurons in the ventromedial hypothalamic nuclei, with diffuse hyperplasia of astrocytes
(Wang and Huang, 1991; for ventromedial hypothalamus
syndrome, see Chapter 26.3).
(d) Fungal infections
Persistent fever of unknown origin may be due to a fungal
infection such as Candida albicans, aspergillus or mucor
species, or other fungi acting on the hypothalamus
(Barwick et al., 1994). Patients immunocompromised
by acquired immunodeficiency syndrome (AIDS), by
immunosuppressive drugs or treated by prolonged antibiotic therapy for gram-negative organisms are also
susceptible to central mycotic abscesses (see Chapter
20.3). Associated infections include, e.g. cryptococcosis.
Candida albicans causes meningitis, hydrocephalus,
cortical microscopic abscesses, cerebritis, granulomas and
vasculitis.
(e) Other hypothalamic infections
The hypothalamus is rather infrequently involved in bacterial infections such as -hemolytic streptococcus, pneumococcus and in the neonate Listeria monocytogenes.
Posterior lobe microabscesses are a common preterminal
incidental finding at autopsy (Horvath et al., 1997).
Hypothalamic pituitary deficiency has been described in
a case of Weils disease, which is due to leptospirosis.
Panhypopituitarism was found, but hypothalamic participation could not be demonstrated (Panidis et al., 1994).
Neurocysticercosis is a CNS infection caused by Taenia
larvae. In patients with such inflammatory lesions in the
anterior hypothalamus, obesity and hyperphagia were
observed (Lino et al., 2000). Lymes disease is a multisystem disorder caused by infection with the Borrelia
burgdorferi spirochete. Neuro-ophthalmic and ocular manifestations of Lymes disease, including papilledema,

increased intracranial pressure and optic atrophy, have frequently been reported (Balcer et al., 1997). Post-Lyme
syndrome is characterized by severe fatigue, malaise and
cognitive complaints. The latter component is more pronounced in Lymes disease than in chronic fatigue syndrome (Chapter 26.8a).
Whipples disease is a rare disease characterized by a
widespread, chronic granulomatous infiltration of the
gastrointestinal, cardiac, pulmonary and nervous systems.
There is a 6:1 male predominance. It is caused by the
rod-shaped baccillus Tropheryma whippelii, with a
delayed hypersensitivity as the underlying mechanism.
CNS involvement occurs in 1020% of cases. Lesions
consist of a gliovascular inflammatory reaction with a
predilection for hypothalamus, cingulate gyrus, basal
ganglia, insular cortex and cerebellum. Large numbers of
swollen, gemistocytic astrocytes and smaller collections
of the classic foamy macrophages are found. Perivascular
cuffs of mononuclear cells and lymphocytes are frequently
encountered also. Stuffed microglia frequently surround
nerve cells, a process accompanied by a definite loss
of neurons. CNS involvement may remain clinically
silent. Hypothalamopituitary involvement may include
symptoms of insomnia or hypersomnia, weight gain
and polydipsia, in combination with ophthalmoplegia.
Transient, almost complete sleep loss caused by cerebral
manifestation of this disease has been described.
Endocrine tests revealed flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin,
indicating that the suprachiasmatic nucleus was affected.
Whipples disease can be treated with antibiotics that
effectively cross the bloodbrain barrier, such as penicillin, TMP-SMZ or chloramphenicol (Mendel et al.,
1999; Voderholzer et al., 2002).
20.2. Encephalitis lethargica (Von Economos
encephalitis)
Encephalitis lethargica was first described by Constantin
von Economo in Vienna in 1917. Among the wounded
soldiers of World War I, he noted patients with peculiar
symptoms, including a remarkable sleepiness for which
the syndrome was named. The cause of the epidemic,
which affected 5 million victims, was never determined.
The histopathology of the acute cases included inflammated cells, congested blood vessels, hemorrhages, cellular necrosis, chromatolysis, neuronophagia and gliosis.
The mesencephalic and basal ganglia were the most

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frequent sites of the lesions, but the hypothalamus, too,


appeared to be one of the predilection sites, which might
relate to some of the neuropsychiatric symptoms, e.g.
sleep and circadian disturbances (see Chapter 4), disturbances of sexual behavior (Chapter 24.5), mood (Chapter
26.4), obsessive and compulsive behavior (Chapter 26.6)
and aggression (Chapter 26.9). The lethargy resembled
abnormally profound sleep. Often the patient could be
roused, would answer a question intelligently and then
relapse into a stupor. Insomnia and marked disturbances
of the diurnal pattern were also reported.
Von Economo broadly divided encephalitis lethargica
into the somnolence-ophthaloplegia type with lesions in
the posterior wall of the third ventricle near the oculomotor nucleus and the choreatic-insomniac type, due
to an anterior lesion in the lateral wall of the third
ventricle near the corpus striatum. In postencephalitis
parkinsonism, oculogyric crises were found. They were
linked to obsessive and compulsive behavior. Some
patients had compulsive sexual or violent thoughts along
with oculogyric deviation. Mood disorders were striking,
including recurrent mania, episodic depression and bipolar
mood disorders (Cheyette and Cummings, 1995). Among
the neurological disorders that developed months to years
after the acute infection, a 10% incidence of morbid
obesity was found. Whether these patients indeed had
lesions in the mediobasal hypothalamus was not established (Nagashima et al., 1992). Children tended to
manifest somewhat different symptoms in cases of
encephalitis lethargica than adults. They were more likely
to display an inversion of the sleep rhythm: they often
had insomnia at night and slept during the day. Many
children displayed behavioral disturbances, including
sexual precocity, exhibitionist tendencies and sexual
aggression. Although a number of the behavioral symptoms indicate hypothalamic involvement, no relationship
has developed between particular hypothalamic lesions
and behavioral disturbances in encephalitis lethargica
(Cheyette and Cummings, 1995).
More recently two patients were described with
acute encephalitis, the features of which including
parkinsonism, fever, lethargy, fluctuations of consciousness, pupillary abnormalities, oculogyric crises, delusions,
loss of temperature regulation, profuse sweating, disturbances of the sleep cycle and severe dyskineas suggested
encephalitis lethargica. Both patients responded rapidly
and dramatically to intravenous methylprednisolone,
although some hypothalamic symptoms remained in one
patient. The cause is not known (Blunt et al., 1997).

95

20.3. Acquired immunodeficiency syndrome (AIDS)


Hypothalamic disturbances, such as endocrine or autonomic dysfunction, hyper- or hypothermia and vegetative
symptoms, have frequently been reported in patients with
AIDS. These include adrenal insufficiency, hyperprolactinemia, central diabetes insipidus and changes in the
hypothalamopituitary gonadal axis (Croxson et al., 1989;
Dluhy, 1990; Merenich et al., 1990; Sullivan et al., 1992;
Moses et al., 2003) as well as weight loss, fever, and
fatigue (Hellerstein et al., 1990). Frank hypopituitarism
due to destruction or infiltration of the hypothalamic
region is rare in patients with AIDS: only a few cases of
hypopituitarism have been described in AIDS patients.
More subtle defects, due to the human immunodeficiency
virus (HIV), or other HIV-mediated factors of hypothalamopituitary function, occur frequently, although in a
routine H&E staining generally no obvious signs of local
inflammation are observed in the region of the PVN.
In some patients periventricular cuffs are present in the
hypothalamus (Fig. 20.2). In addition, no obvious difference was seen for leukocyte-common antigen (LCA) or
GFAP staining between hypothalamic sections of groups
of controls and AIDS patients (Purba et al., 1993). When
AIDS causes endocrine problems, the focus in literature
is generally on the endocrine end-organs, i.e. the thyroid,
adrenal glands, gonads and kidneys, and not on the
possible causes on the level of the pituitary, and certainly
not on the level of the hypothalamus (Merenich, 1994).
However, cytokines such as interleukin-1 (IL-1), IL-6
and tumor necrosis factor (TNF), which are produced by
immune cells, may affect hypothalamic corticotropinreleasing hormone (CRH) neurons (Freda and Bilezikian,
1999). Cytomegalovirus (CMV) involvement has sometimes been found in the adenohypophysis, neurohypophysis and hypothalamus (Sullivan et al., 1992; Purba
et al., 1993; Merenich, 1994). In the neurohypophysis,
Cryptococcus sp., Aspergillus sp., Toxoplasma sp. and
Pneumocystes carinii were observed in AIDS patients
(Figs. 20.3). In addition to endocrine and autonomic dysfunctions, also visual loss may occur in AIDS. An AIDS
patient has been described with a chiasmatic mass due to
a primary central nervous system lymphoma (Lee et al.,
2001).
Vasopressin
Central diabetes insipidus has been found in a patient
with AIDS due to cytomegalovirus infection of the
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Fig. 20.2. Perivascular cuff in the hypothalamus in a case of AIDS ( 42 years). Bar = 200m.

hypothalamus. The patient did not have polyuria because


of the accompanying glucocorticoid deficiency. In addition, low testosterone, follicle-stimulating hormone (FSH)
and luteinizing hormone (LH) were found (Moses et al.,
2003). Central diabetes insipidus has also been reported
in a few AIDS patients in whom anterior pituitary function was preserved. Desmopressin resulted in complete
resolution of this symptom (Merenich, 1994). The number
of vasopressin-expressing neurons in the PVN in a group
of AIDS patients was, however, not significantly lower
than in controls (Purba et al., 1993), indicating that, due
to destruction of the SON and PVN, hypothalamic
diabetes insipidus must be a rare phenomenon. In
addition, several AIDS patients with the syndrome of
inappropriate antidiuretic hormone secretion have been
reported (Merenich, 1994). Hyponatremia occurs in
3050% of AIDS patients (Sellmeyer and Grunfeld,
1996).

Oxytocin
We observed a 40% drop in the number of oxytocinexpressing neurons in the PVN in AIDS patients (Purba
et al., 1994). However, no decrease in oxytocin-messenger
RNA (mRNA) of the PVN was measured by quantitative in situ hybridization in AIDS patients (Guldenaar
and Swaab, 1995), suggesting differences in oxytocin
precursor processing in AIDS. If this is indeed the case,
it may be of importance for those autonomic functions
that are regulated by oxytocin fibers projecting from the
PVN to the brainstem (Chapter 30).
Oxytocin receptors are present in AIDS-related
Kaposis sarcoma, an intensely angioproliferative disease,
possibly of vascular origin. Oxytocin treatment of Kaposi
cells led to a significant increase in cell proliferation and
could therefore be considered a possible relevant growth
factor involved in Kaposis sarcoma progression (Cassoni
et al., 2002).

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Fig. 20.3. Toxoplasmosis infection in the hypothalamus in a case of AIDS. Bar = 200 m.

hyperactivity (see above) to subclinical disturbances to


frank adrenal insufficiency (Freda and Bilezikian, 1999).
Data concerning ACTH secretion are conflicting, which
may at least be partly due to the stage of infection
(Lortholary et al., 1996). In a group of HIV-positive
homosexual men in relatively good health, no difference
in cortisol levels was found (Kertzner et al., 1993). This
negative finding was presumed to be due to the relatively
early stage of the disease (Rotterdam and Dembitzer,
1993), but an attenuated ACTH and cortisol response to
a cold stressor challenge was observed in asymptomatic
HIV-1 positive persons (Kumar et al., 2002). The HPA
axis can show abnormalities in different directions. On
the one hand, the adrenal gland is known to be a common
site of opportunistic infections (Rotterdam and Dembitzer,
1993). On the other hand, there are studies that report
that cortisol is elevated at all stages of infection and
particularly in AIDS patients (Christeff et al., 1997).

Hypothalamopituitaryadrenal (HPA) axis


Increased serum cortisol levels are the most common
finding as AIDS progresses (Grinspoon et al., 1994;
Merenich, 1994; Savastano et al., 1994; Lortholary et al.,
1996; Sellmeyer and Grunfeld, 1996, Christeff et al.,
1997; Freda and Bilezikian, 1999). There has even been
a report of a case of Cushings syndrome associated with
AIDS (Savastano et al., 1994). It has been proposed that
the HIV virus may stimulate CRH or corticotropin
(ACTH) either directly or indirectly via stimulation of
cytokines. In addition, HIV is a major life stressor. HIV
viral load is also immediately high in the hippocampus,
which inhibits CRH. Moreover, the POMC promotor is
100% homologous to a region of the HIV-1 genome, and
HIV viral protein R can interact with corticosteroid receptors. Which of these putative mechanisms is of clinical
importance has to be investigated (Kumar et al., 2002).
Abnormalities of the HPA axis in AIDS may range from
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Adrenal insufficiency also results in low cortisol levels,


and a blunted cortisol response to ACTH stimulation has
been observed in AIDS patients, accounting, at least
partly, for weight loss, general weakness, anorexia
(Savastano et al., 1994), and hypotension or hyponatremia, which are all Addison symptoms, in spite of
elevated cortisol levels. In fact, 12% of the AIDS patients
are glucocorticoid-resistant (Grinspoon et al., 1994;
Merenich, 1994; Norbiato et al., 1997). Although histological modification of the adrenal glands has often been
described during the late stages of HIV infection, reports
of adrenal insufficiency are rare (Lortholary et al., 1996).
Suppressed circadian secretion of ACTH in association
with increased basal cortisol levels has also been observed
in a small number of patients with AIDS. On the other
hand, normal and elevated ACTH and cortisol levels have
been found in others with preserved adrenal function.
Moreover, the development of cortisol resistance has been
presumed (Grinspoon et al., 1994; Merenich, 1994). So
far, however, there are no direct observations available
on activity changes of the CRH neurons in the PVN of
AIDS patients. In contrast to cortisol, the serum dehydroepiandrosterone (DHEA) levels generally decreased in
each later stage of HIV infection. The increased cortisol
levels and the decreased levels of DHEA, an antiglucocorticoid compound, may, at least partly, provoke a drop
in CD4+ cells and a shift from type 1 to type 2 cytokine
production (Christeff et al., 1997; Clerici et al., 1997). A
fall in DHEA levels predicts progression to AIDS, independent of CD4 cell counts (Sellmeyer and Grunfeld,
1996). Antiglucocorticoid drugs may be helpful in HIV
disease, as they antagonize the immunosuppression
induced by increased levels of cortisol (Norbiato et al.,
1997). Whether DHEA administration may influence the
disease process favorably has not been studied.
Circulating levels of alpha-melanotropin (MSH are
elevated in HIV-infected patients (Catania et al., 2000).
Hypothalamopituitarythyroid axis
Thyroid function is normal in most patients with HIV
infection (Grinspoon et al., 1994). Opportunistic infections of the thyroid have been found, but most of the
patients did not present with thyroid dysfunction
(Sellmeyer and Greenfeld, 1996). Hypothyroidism has
been seen in AIDS patients but is considered to be due
to altered peripheral metabolism of thyroid hormone and
not to changes on the level of the pituitary or hypothalamus. In the terminal phases of AIDS, thyroid hormone
axis changes are similar to those observed in other serious

conditions, i.e. those of the euthyroid sick syndrome


(Merenich et al., 1990; Merenich, 1994; Sellmeyer and
Grunfeld, 1996; Fliers et al., 1997; Chapter 8.6).
Hypothalamopituitarygonadal axis
In the early stages of AIDS, total and free testosterone
are elevated and the LH response to LHRH is exaggerated (Merenich et al., 1990). This may be explained
by a direct stimulatory effect of the HIV virus on the
pituitary or hypothalamic level. However, as AIDS
progresses, one-third of the men develop hypogonadism,
with lower testosterone levels and higher LH and FSH
levels. These changes may affect cognition, mood, libido
and energy levels (Croxson et al., 1989; Ng et al., 1994).
Testicular atrophy is a common finding in AIDS (Rogers
and Klatt, 1988). Some of the medications used may also
affect gonadal function (Sellmeyer and Grunfeld, 1996).
Prolactin levels are normal or mildly elevated (Croxson
et al., 1989; Merenich et al., 1990). The gonadal axis has
not been studied adequately in women with AIDS, but
menstrual irregularities, decreased libido and hair loss
have been reported (Merenich, 1994).
Growth hormone
Two cases of growth hormone deficiency in AIDS have
been reported that were coupled to sex steroid deficiency.
One of the cases was associated with gonadotropic failure.
The patients had evidence of dysfunction at the hypothalamic, pituitary and end-organ level (Ng et al., 1994).
In HIV-infected men who did not show signs of wasting,
normal growth-hormone secretion, insulin-like growth
factor-1 (IGF-I) and IGF-binding protein-3 concentrations
were found (Heijligenberg et al., 1996).
Circadian changes
When HIV-infected males are compared with controls,
significantly higher levels are found for cortisol, and lower
ones for DHEA, DHEA-S and ACTH. Plasma testosterone
levels decreased in a later stage of HIV infection (Villette
et al., 1990). Analysis of the circadian rhythm of plasma
hormone levels clearly indicated an altered adrenal
hormonal state in HIV-infected male patients, even during
the asymptomatic period of the infection. For instance,
plasma cortisol at 04.30 h was more than twice as high
in HIV-infected patients than in time-matched controls
(Villette et al., 1990). Abnormal ACTH and cortisol
circadian rhythms have also been reported in stage IVc
AIDS patients (Lortholary et al., 1996). Although such
data might point to early changes in the suprachiasmatic

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nucleus, these authors did not take into consideration that


comparisons were made between HIV-infected men, some
of whom were homosexual, whereas sexual orientation of
the controls was not specified (Villette et al., 1990). The
difference in the suprachiasmatic nucleus in homosexual
men as compared to heterosexual men (Swaab and
Hofman, 1990) may thus have biased these observations.
Circadian growth hormone secretion in asymptomatic HIV
infection and AIDS without wasting is not different from
that in healthy subjects.

99

The external envelope of the HIV virus contains a glycoprotein (gp 120) that has been shown to be neurotoxic and
to cause learning deficits in rats. Vasoactive-intestinal
polypeptide (VIP) was found to block the gp 120-induced
neurotoxicity in culture, and a VIP receptor antagonist
displayed toxic properties to neurons in culture. Possible
repercussions of these observations for the VIP cells in the
suprachiasmatic nucleus (SCN) (Chapter 4c, d) of the
hypothalamus in HIV-infected patients have never been
studied.

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)


The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved

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CHAPTER 21

Neuroimmunological disorders

21.1. Neurosarcoidosis of the hypothalamus

led to the diagnosis of schizophrenia, schizoaffective


disorder and dementia. Also, mental status associated with
delirium, euphoria, depression, aggression, apathy and
cognitive deficits have been described. If neurosarcoidosis
occurs, it has a striking predilection for the hypothalamus
and pituitary, i.e. in 1026% of cases (Robert, 1962;
Turkington and Macindoe, 1972; Stern et al., 1985;
Vanhoof et al., 1992; Oksanen, 1994; Guoth et al., 1998;
Schielke et al., 2001). Central diabetes insipidus occurs
in about 25% of patients with neurosarcoidosis (Bullmann
et al., 2000) and can be the first manifestation of the
disease (Konrad et al., 2000). Hyperprolactinaemia may
be present (Molina et al., 2002). Other manifestations
of hypopituitarism are hypoglycemia, dwarfism, panhypopituitarism, hypogonadism, obesity, and weight gain or
weight loss (Bell, 1991; Murialdo and Tamagno, 2002;
Randeva et al., 2002). Symptoms also attributed to
hypothalamic involvement in sarcoidosis are somnolence,
insomnia, hypothermia, extreme variations in body
temperature, intolerance to cold, anorexia, hyperphagia,
and progressive obesity and personality changes (Robert,
1962; Branch et al., 1971; Bell, 1991; Sommer et al.,
1991; Vanhoof et al., 1992). In addition, a patient
with hypothalamic sarcoidosis was described who
had polyuria, inappropriate vasopressin (VP) release
and excessive thirst. The patients fitted the criteria of
SchwartzBartter (Chapter 22.6a) and the neurosarcoidosis was confirmed by autopsy (Kirkland et al., 1983).
Up to 20% of neurosarcoidosis patients have psychiatric manifestations. These can range from mild apathy
to severe mental deterioration (Vanhoof et al., 1992;
OBrien et al., 1994). In addition, memory loss associated
with confusion has been described (Sharma, 1997).
A 67-year old woman who had neurosarcoidosis,
which damaged the anteromedial hypothalamus with an

The etiology of sarcoidosis is unknown. Environmental


factors, infectious agents or hereditary factors may be
involved. The seasonal clustering reported for various
types of sarcoidosis (Wilsher, 1998) suggests that circannual fluctuations in the immune system or in infections
may be important. Melatonin may mediate circannual
immunological fluctuations (Nelson and Demas, 1997).
Since a patient developed neurosarcoidosis 22 years after
augmentation mammoplasty through the injection of
silicone gel (Yoshida et al., 1996), it has been suggested
that immunomodulations by foreign bodies such as
silicone may also be a pathogenic risk factor in
sarcoidosis.
(a) Clinical presentation
Neurological involvement is rather rare; it occurs in about
5% of the sarcoidosis patients and leads to death in
1218% of all cases (Vanhoof et al., 1992; OBrien
et al., 1994; Sharma, 1997). Criteria for the diagnosis of
possible, probable and definitive neurosarcoidosis have
been proposed (Zajicek et al., 1999). Neurosarcoidosis
may be confused clinically with multiple sclerosis,
Lyme disease, Bechets disease, histiocytosis-X,
Wegeners granulomatosis, Whipples disease, lymphomatosis, meningeal carcinomatosis and a variety of
infections, including cryptococcal meningitis, tuberculosis, syphilis, toxoplasmosis, and fungal infections. The
diagnosis of isolated neurosarcoidosis, can only be established by biopsy (Graham and James, 1988; Sommer
et al., 1991; Zajicek et al., 1999; Randeva et al., 2002;
Chapters 20.1, 21.3). In addition, neurosarcoidosis has
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extension into the mamillary bodies, did not only have


hyperphagia and hyperdipsia, but also had severe memory
failure, characterized by spontaneous confabulations,
disorientation and severely impaired free recall with
preserved recognition. The authors argued that damage
of the anterior hypothalamus rather than of the mamillary bodies was responsible for the confabulary amnesia
(Ptak et al., 2001). The exact role of hypothalamic and
other lesions in the psychiatric symptoms (see Chapter
26) has to be better defined. The optic nerve is, after the
facial nerve, the second most commonly involved cranial
nerve in neurosarcoidosis. MR images may show optic
nerve enhancement. The characteristic picture is that of
an atypical optic neuritis often subacute in onset, which
might recover following steroids or cause permanent
visual impairment (Zajicek et al., 1999). The optic nerve
is affected in some 5% of the patients with sarcoidosis
(Sharma and Anders, 1985; Stern et al., 1985; Graham
and James, 1988; Westlake et al., 1995; Fig. 21.1). The
optic chiasm is also frequently affected (Walker et al.,
1990). Space-occupying sarcoid lesions may lead to
papilledema and optic nerve atrophy (Sharma and Anders,
1985; Katz et al., 2003). Most of the cases in which
sarcoidosis is manifested as an optic nerve tumor were
mistaken for optic nerve meningioma (Macafee et al.,
1999). Diplopia has also been reported (Molina et al.,
2002). One case has been described that presented in a
very unusual manner, with anosmia and visual changes.
Noncaseating granulomata were subsequently found in
the respiratory epithelium and submucosal (Kieff et al.,
1997). Once an association was described between a
Rathkes cleft cyst and sarcoidosis lesions scattered
around it, causing an intra- and extracellular mass and
hypopituitarism without diabetes insipidus (Cannav et
al., 1997).
Sudden death resulting from hypothalamic sarcoidosis
has been reported a few times. In one case, autopsy
revealed neurosarcoidosis with secondary hydrocephalus.
The other case was a 23-year-old woman who had experienced 6 months of amenorrhea and a 50-pound weight
gain. She had an extensive infiltration of the hypothalamus, including the pituitary stalk, the median
eminence/infundibular nucleus, the right optic nerve,
mamillary bodies, the supraoptic nucleus and the walls
of the third ventricle, including the paraventricular
nucleus (PVN). The PVN showed a marked cell loss.
Death was proposed to be due to the loss of PVN neurons
that innervate autonomic centers, leading to cardiopulmonary arrest (Gleckman et al., 2002).

(b) Pathology
Neurosarcoidosis is due to noncaseating granulomas infiltrating the hypothalamus (Graham and James, 1988; Bell,
1991). The granulomas are initially made up of loosely
organized epithelioid cells derived from macrophages
that are surrounded by a ring of T-lymphocytes. In older
granulomas large numbers of epithelioid and giant cells
are surrounded by a small number of lymphocytes (Bell,
1991). Around the granulomas nerve cells may disappear,
demyelination and gemistocytic reactive astrocytes are
found (Robert, 1962). In addition, space-occupying
sarcoid lesions can be found at the base of the brain
and in the floor of the third ventricle. They may also
manifest themselves as a pituitary pseudotumor (Robert,
1962; Timsit et al., 1993) or, e.g. Rathkes cleft cyst
(Cannav et al., 1997). Whereas earlier postmortem findings pointed mainly to partial or total destruction of the
pituitary by granulomas, later examination of both the
pituitary and the hypothalamus showed extensive and
preferential infiltration of the hypothalamus by granulomatous inflammation or granulomas, and little, if any,
involvement of the pituitary itself (Bell, 1991; Fig. 21.2).
Autopsy was only performed on a few patients with
neurosarcoidosis and showed granulomata diffusely scattered in the median eminence and bilaterally throughout
the hypothalamus (Selenkow et al., 1959; Turkington and
MacIndoe, 1972). In addition, late stages of hyalinized
granulomata have been reported throughout the hypothalamus. They consisted of multiple discrete, round to
oval masses of 100300 m (Branch et al., 1971). One
patient has been reported presenting with diabetes
insipidus. He had a posterior pituitary mass but no other
abnormalities in the pituitary, infundibulum and hypothalamus. The mass showed complete repression after
corticosteroid treatment, but diabetes insipidus persisted
(Loh et al., 1997).
The most common MRI abnormality in cases of
neurosarcoidosis is the presence of multiple white-matter
lesions (Zajicek et al., 1999). MRI may demonstrate hypothalamic periventricular and meningeal lesions (Bell,
1991) and thickening of the pituitary stalk that extends
toward the optic chiasm (Walker, 1990). Only rarely does
neurosarcoidosis present itself as an intracranial mass
lesion. An example is the case described by Grand et al.
(1996; Fig. 21.3) with a lesion resembling a bunch
of grapes on MR images, extending from the right
frontotemporal area toward the midline, involving the
hypothalamus. The arachnoid covering the optic chiasm,

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Fig. 21.1. Sarcoidosis involving the optic nerve and hypothalamus. Top: T1-weighted coronal magnetic resonance imaging scan showing asymmetrical thickening of the chiasm (solid arrow). Center: Following gadolinium enhancement, an increased signal can be seen in the hypothalamus,
third ventricle (open arrow) and meninges (solid arrow), due to sarcoidosis. Bottom: Sagittal cut showing enhancement in the hypothalamus and
pituitary stalk (open arrow), with enlargement of the pituitary gland (solid arrow). (From Westlake et al., 1995, Fig. 1 with permission.)

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Fig. 21.2. Sarcoidosis nodules scattered through the hypothalamus (H&E). (From Sheehan et al., 1982, Fig. 3.45 with permission.)

pituitary stalk and floor of the third ventricle may be


opaque, thickened and sprinkled with many miliary
nodules (Robert, 1962; Vanhoof et al., 1992). Periventricular enhancement indicates active inflammation (Bell,
1991) and involvement of the ependymal lining often
leads to complete obliteration of the third ventricle and
to hydrocephalus (Robert, 1962; Scott, 1993).
(c) Endocrine changes
The prevalence of neuroendocrine disturbances due to
neurosarcoidosis has a peak around 3039 years of age.
Hypogonadotropic hypogonadism, polyuria and polydipsia are the most frequently occurring symptoms in
patients with sarcoidosis of the hypothalamus and pitu-

itary (Murialdo and Tamagno, 2002). Whereas the symptoms of diabetes insipidus were initially attributed to
diabetes insipidus caused by vasopressin deficiency
(Selenkow et al., 1959; Robert, 1962; Branch et al., 1971;
Stern et al., 1985), later studies indicated that they more
often result from primary polydipsia and possibly from
destruction of the osmoreceptors, without vasopressin
deficiency (Bell, 1991). The displacement of the pituitary
bright spot to the upper infundibulum in neurosarcoidosis
(Walker et al., 1996) correlates with the presence of
diabetes insipidus. A patient has been described
with diabetes insipidus and a large posterior pituitary
mass that was most probably due to sarcoidosis. A
complete regression of the posterior pituitary mass was
found after corticosteroid therapy, but the diabetes

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Fig. 21.3. (a, b) Sagittal and (c) coronal T1 images after i.v. gadolinium: sarcoidosis of the hypothalamus. Multiple nodular enhancement resembling a bunch of grapes in the right temporal lobe; extension toward the hypothalamohypophyseal region. (d) Axial T2 image: lesions of the
intermediate intensity signal surrounded by extensive edema. (From Grand et al., 1996, Fig. 2 with permission.)

insipidus persisted and the patient continued to need his


intranasal vasopressin therapy during the 12-month
follow-up (Loh et al., 1997). Inappropriate secretion of
vasopressin has also been described in neurosarcoidosis
(Stern et al., 1985).
Deficiency of anterior pituitary hormones most often
occurs on the basis of hypothalamic dysfunction, although
the pituitary might sometimes be primarily involved as
well (Selenkow et al., 1959; Robert, 1962; Stern et al.,
1985; Graham and James, 1988; Bell, 1991). Patients
may have hypothyroidism, hypogonadism, changes in
pubic hair and body hair, loss of libido, secondary amenorrhea, hypoadrenalism, panhypopituitaris, increased
serum prolactin and, less often, galactorrhea (Robert,
1962; Turkington and MacIndoe, 1972; Stern et al., 1985;

Graham and James, 1988; Verhage et al., 1990; Bell,


1991; Lipnick et al., 1993, Westlake et al., 1995; Molina
et al., 2002; Murialdo and Tamagno, 2002; Randeva et
al., 2002). However, it should be noted that Munt et al.
(1975) were unable to confirm by radioimmunoassay the
high incidence of hyperprolactinemia in patients with
neurosarcoidosis involving the hypothalamus.
Normally, hypoglycemia stimulates rapid increase
of hormones such as catecholamines, glucagon, cortisol
and growth hormone to act in concert to increase
plasma glucose concentration. This action is regulated
by the ventromedial region of the hypothalamus. A
patient has been described who had complete loss of the
counterregulatory response to hypoglycaemia due to a
hypothalamic sarcoid infiltration (Fry et al., 1999).
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(d) Therapy
Administration of oral corticosteroids, 4080 mg/day,
is the usual first line of therapy for neurosarcoidosis,
and often corticosteroids are given long-term, despite the
absence of controlled studies of their efficacy and
the high frequency of serious side effects (Murialdo
and Tamagno, 2002; Randeva et al., 2002).
Methylprednisolone pulse therapy has also been applied
(Molina et al., 2002). In general, neurosarcoidosis is more
resistant to therapy than the pulmonary variety and longterm, high-dose corticosteroid therapy is generally not
very well tolerated and not very effective. Methotrexate,
cyclosporine-A and cyclophosphamide seem to be more
effective (Murialdo and Tamagno, 2002). Recently, the
TNF- antagonist infliximab has been tried with some
success in the treatment of systemic sarcoidosis and
in optic disc swelling in sarcoidosis (Katz et al., 2003).
However, in over half of the neurosarcoidosis patients
the disease progresses despite corticosteroid or other
immunosuppressive therapies (Zajicek et al., 1999).

21.2. Multiple sclerosis (MS) and the hypothalamus


MS is an inflammatory demyelinating disease of the
central nervous system. It is generally a disease of young
adulthood with a peak age of onset between 25 and 30
years of age. The initial course of MS is often characterized by spontaneous relapses and remissions, but it can
also run a primary progressive course. Although the exact
etiology of the disorder is unknown, there is clinical and
laboratory evidence suggesting that it is a multicausal
disease with genetic, autoimmune and environmental
components (Duquette and Girard, 1993). The premenstrual period triggers exacerbations. In fact, 45% of all
exacerbations seem to start in this period (Zorgdrager and
De Keyser, 2002). There is a decreasing NorthSouth
gradient in risk and there are race and sex differences
in predisposition (Limburg, 1950; Kurtzke et al., 1979;
Sadovnik and Ebers, 1993). Seasonal fluctuations in peak
exacerbation rate depend on the region. Exacerbations
of optic neuritis and MS have the highest frequencies
in spring and the lowest in winter. The seasonal fluctuations are presumed to be related to a dysregulation of
interferon- and viral infections (Balashov et al., 1998;
Jin et al., 2000). In addition, stressful life experiences
are considered to be risk factors (Goodin et al., 1999;
Martinelli, 2000). However, an Israeli paper shows that,

contrary to expectation, the number of relapses during a


war and the following months may even be significantly
lower (Nisipeanu and Korczyn, 1993). Several genetic
factors seem to be involved in the risk of developing
MS and in the course of the disease. HLA-DRB1*1501
alleles and estrogen receptor polymorphisms are of importance in this connection and may also be the basis of
the sex differences in the prevalence of MS (Kikuchi
et al., 2002). In addition, single-nucleotide polymorphism
(SNP) in interleukin-1 (IL-1), - and in the IL-1
receptor antagonist influence long-term prognosis in MS
(Mann et al., 2002). Apolipoprotein E (ApoE) is involved
in the transport of lipids necessary for membrane repair,
and is encoded by a gene on chromosome 19q13. MS
patients with an ApoE 3/4 genotype have a more severe
disease course, according to some studies (Fazekas et al.,
2000, 2001), while later onset of chronic progressive MS
was observed in patients carrying the ApoE2 allele
(Ballerini et al., 2000). However, other studies did not
find an association between ApoE4 and adverse outcome
in MS (Masterman et al., 2002). An SNP haplotype near
ApoE is associated with MS susceptibility (Schmidt
et al., 2002). Several other polymorphisms have also been
implicated in the susceptibility and course of MS (Cocco
and Marrosu, 2000).
(a) Autonomic, behavioral and neuroendocrine
symptoms
A number of autonomic and neuroendocrine functions
that are often found to be disturbed in MS point to hypothalamic involvement in this disease. Such autonomic
functions include disturbed functions of the bowel and
bladder, and of sexual behavior (Matthews, 1991; Hulter
and Lundberg, 1995; Mattson et al., 1995), as well as
sweating, and respiratory and cardiovascular regulation
(Anema et al., 1991; Fowler et al., 1992; Howard et al.,
1992), disturbed temperature regulation (Lammens et al.,
1989; Tsui et al., 2002), such as acute and chronic
hypothermia (Sullivan et al., 1987, White et al., 1996)
and poikilothermy (Kurz et al., 1998) and sleep disturbances (Campbell et al., 1982; Clark et al., 1992;
Ferini-Strambi et al., 1994; Tachibana et al., 1994; Tsui
et al., 2002). One patient had asymmetric sweating of the
right forehead and shoulder, due to MS lesions in the
left hypothalamus (Ueno et al., 2000). An MS patient
was described with a new plaque in the hypothalamus
who developed acute hypersomnia and undetectable
CSF hypocretin levels (Iseki et al., 2002). A significant

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reduction in tremor has been reported among MS patients


after subthalamic ventral intermediate nucleus brain stimulation (see Chapter 15.1). However, patient satisfaction
with this procedure was variable (Berk et al., 2002).
Sexual dysfunction in patients with MS is typically
characterized by diminished libido, erectile and ejaculating dysfunction in men, and poor lubrication and
anorgasmy in women. Hypersexual behavior and paraphilias are distinctly uncommon in this group of patients,
but have been described associated with focal brain
lesions in the hypothalamic and septal regions (Frohman
et al., 2002).
Some endocrine disturbances in MS are also related to
hypothalamic alterations. They include: abnormal testosterone levels (Grinsted et al., 1989; Markianos and Sfagos,
1989), which may lead to hypothalamic hypogonadism,
decreased libido and impotence, and may be treated with
testosterone (Bourdette et al., 1988); hyperprolactinemia,
in five of nine cases accompanied by hypothalamic lesions
(Kira et al., 1991; Tsui et al., 2002); altered growth
hormone and TSH levels (Klapps et al., 1992); and
inappropriate antidiuretic hormone secretion (Apple
et al., 1978; Tsui et al., 2002). Alpha-melanotropin
(MSH) levels are increased in patients with a greater
inability score (Catania et al., 2000). A failure of suppression of cortisol levels was observed following
dexamethasone treatment (Reder et al., 1987; Grasser
et al., 1996; Fassbender et al., 1998; Kmpfel et al., 1999;
Then Bergh et al., 1999), indicating a hyperactive
hypothalamopituitaryadrenal (HPA) axis. Cortisol levels
in postmortem CSF of MS patients are elevated by some
80% in comparison with controls, which is another
indication of an increased HPA activity (Erkut et al.,
2002). A severe impairment of the ACTH and metapirone
test was reported by some authors (Brambilla et al., 1974),
while others did not find a difference in the plasma cortisol
response to corticotropin (ACTH) in MS patients (Wei
and Lightman, 1997; Kmpfel et al., 1999). The latter
group also reported lower dehydroepiandrosterone sulfate
(DHEAS) secretion in MS patients. It should be noted
that the pathophysiology of hypercortisolism in MS seems
to be different (see below) from that in depression. MS
is presumed to be associated with increased prominence
of hypothalamic VP secretion (Michelson et al., 1994;
Michaelson and Gold, 1998; cf. Chapter 26.4). Indeed,
the entire increase in corticotropin-releasing hormone
(CRH)-expressing neurons in MS appeared to be due to
an increase in those CRH neurons that colocalize VP
(Erkut et al., 1995; Fig. 21.4). Not only do the CRH

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neurons play an essential role in cortisol regulation, they


also influence mood (Chapters 21.2b, 26.4), and it is therefore of particular interest that treating relapsing-remitting
MS patients with a combination of corticosteroids and
the antidepressant moclobemide favors normalization of
the HPA axis (Then Bergh et al., 2001). It has been
proposed that the pineal gland may be implicated in the
relapsing-remitting nature of the disease. Melatonin was
even claimed to be able to cause acute exacerbation of
symptoms. Abnormal plasma melatonin levels were found
in half of the MS patients during exacerbations. Most of
them had nocturnal levels that were below the daytime
values. There was also a significant relation between
melatonin levels, age of onset of symptoms and the
duration of illness. Pineal calcification was found in nearly
all the MS patients. These observations were hypothesized to be related to the occurrence of seasonal variations
in MS, the influence of climatic variables, and the low
incidence of MS in African and American black populations (Sandyk and Awerbuch, 1992). Exactly how the
pineal function is related to the MS disease process should
be investigated further. Since fatigue and sleep disturbances are frequent and disabling symptoms inMS,
and because of the presumed disturbed pineal function,
we investigated whether these symptoms might be
due to disrupted circadian sleep/wake regulation.
However, no evidence was found for a generalized
circadian disturbance in MS patients, which indicates
that the suprachiasmatic nucleus will generally not be
seriously affected in this disease (Taphoorn et al., 1993).
Vasopressin levels in CSF, but not in plasma, were found
to be decreased in MS (Olsson et al., 1987). It is not
clear what exactly the source of this diminished amount
of CSF vasopressin is, since we did not find an indication
for an activity change in the vasopressin neurons of the
PVN in MS (Purba et al., 1995). In addition, Michelson
and Gold (1998) presume that MS is associated with
increased hypothalamic vasopressin secretion and Erkut
et al. (1995) showed that the entire increase in the number
of CRH-expressing neurons in MS was due to those
CRH neurons that coexpress vasopressin. Desmopressin
(DDAVP, nasal spray) is a vasopressin agonist that is
effective both in the treatment of nocturnal enuresis and
in the treatment of increased daytime urinary frequency,
which often seriously disrupts work and social activities
in MS patients. A side effect of this therapy might be
the development of hyponatremia. Although the patient
should be warned about the symptoms of side effects due
to hyponatremia, i.e. malaise, headache and nausea
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(Hoverd and Fowler, 1998), long-term use of DDAVP


has been shown to be safe and effective by others (Tubridy
et al., 1999).
Lower levels of CSF somatostatin have been found in
MS patients during relapse, and a strong relationship has
been found between cognitive decline and decrease in
CSF somatostatin levels (Roca et al., 1999). It is not
known which brain area is responsible for the changes
in somatostatin levels.
(b) Mood changes
Although euphoria was mentioned as the dominant
emotional change in MS in an old paper (Cottrell and
Wilson, 1926), a fact that is generally known in clinics,
more recent literature has repeatedly shown that depression is the major mood change in these patients (Rao

Fig. 21.4. Increased numbers of corticotropin-releasing hormone (CRH)


and vasopressin (VP) in multiple sclerosis (MS). Numbers of CRH
neurons that do not localize VP (CRH-only) or that colocalize VP (CRH
+ VP) in the PVN of 8 MS patients and 8 controls. Tissue was obtained
from the Netherlands Brain Bank (Amsterdam, the Netherlands).
Clinicopathological data (mean SEM), age, 51.0 3.8 years (MS), 52.6
5.0 years (controls); postmortem delay 12.9 5.6 h (MS), 13.9 3.9
h (controls); fixation time 49 14 h (MS), 36.7 4.3 h (controls);
duration of MS, 23 years; primary progressive MS 2/8 and secondary
progressive MS, 6/8. Neurons are counted in the PVN after immunocytochemical double-staining of VP and CRH as described (Erkut
et al., 1995). The difference in numbers of CRH/VP neurons between
the MS and the control group is significant (p = 0.046). (Based upon
Erkut et al., 1995, Fig. 3). Note that the increase in CRH-expressing neurons in MS is solely due to an increase in CRH cells coexpressing VP.

et al., 1992). MS patients are frequently depressed,


irritable and short-tempered (Dalos et al., 1983; Schubert
and Foliart, 1993; Fassbender et al., 1998). There is a
significant interaction between the level of neurological
impairment and depression in patients with MS (Mohr et
al., 1997b). However, comparison of MS patients with a
group of traumatic paraplegics as disease controls also
showed a significantly higher incidence of emotional
disturbances in the MS patients, especially during periods
of relapse (Dalos et al., 1983), and a boost of depression
in MS may even occur shortly before neurological symptoms develop (Whitlock et al., 1980; Joffe et al., 1987;
Minden and Schiffer, 1990; Millefiorini et al., 1992). so
that the mood changes do not only seem to be due to the
presence of a neurological disability alone. In agreement
with this idea, Fassbender et al. (1998) found that both
affective and neuroendocrine disorders in MS were related
to the inflammatory disease and not to disability. A relationship is presumed between the hyperactive HPA axis
(see previous section) and depression in MS and, indeed,
a combined treatment with corticosteroids and the antidepressant moclobemide normalizes HPA axis function
in relapsing-remitting MS patients (Then Bergh et al.,
2001). A relationship has also been observed between
MS lesions in the left arcuate fasciculus, i.e. in the
suprainsular white matter and depression in MS (Pujol et
al., 1997), while major depression is known also to result
from left cortical lesions. The higher levels of depression
in MS are associated with sleep complaints (Campbell et
al., 1992). The very high rate of depression among MS
patients does not have a genetic basis (Sadovnick et al.,
1996). Although interferon--1B reduces the frequency
and severity of exacerbations of MS in patients with the
relapsing-remitting form, it also causes flu-like symptoms
and increases depression within the first 6 months after
starting this therapy. Subsequent treatment of depression
improves the adherence to interferon therapy (Mohr et
al., 1997a; Walther and Hohfeld, 1999).
(c) The HPA axis in relation to susceptibility and
recovery
As shown by animal models, the HPA axis, which is a
central system in the regulation of immune responses
(Rivest, 2001), may influence susceptibility to and
recovery from MS. Studies on experimental allergic
encephalomyelitis (EAE), the most extensively studied
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Sobel et al., 1988; McDonald, 1994; Rodriguez and


Scheithover, 1994), have indicated that the activity of the
HPA axis may be crucial in these processes. In certain
rat strains, such as the Lewis rat, low corticosteroid levels
are accompanied by a high susceptibility to EAE,
whereas, once the disease has been established, elevation
of corticosteroid levels is required for spontaneous
recovery (MacPhee et al., 1989; Sternberg et al., 1989;
Mason et al., 1990; Villas et al., 1991; Kuroda et al.,
1994). In line with these findings, glucocorticoids, CRH
and urocortin are capable of suppressing EAE in Lewis
rats (Bolton and Flower, 1989; Poliak et al., 1997).
In relation to the possibility that low corticosteroid
levels may lead to increased susceptibility to MS, it is
of interest to note that, from the fourth decade of life
onwards, CRH neurons become gradually more activated
(Chapter 8.5b; Figs. 8.26, 8.27). This is also the age
at which MS prevalence starts to decline in the population. Both markers for activity of these neurons,
the total number of paraventricular nucleus cells and the
proportion of VP-expressing CRH neurons show an
age-dependent increase (Raadsheer et al., 1994a, b).
No data are available as yet on age-related changes in
CRH mRNA in the human PVN. As animal experiments
have shown that an increased HPA axis activity may
lead to decreased susceptibility to EAE, the age-related
increase in CRH activity suggests that this may be an
important factor leading to decreasing prevalence of MS
with age. Data on CRH neuron activity before the age
that MS prevalence increases are at present not available.
It has been observed that from 12 to 20 years of age the
saliva cortisol level gradually increases (Walker et al.,
2001), but the peak age of onset occurs one decade later.
Of course it is not known whether those young subjects
who have lower HPA axis activity are indeed at risk to
contract MS. However, the observation that in EAE
the HPA axis is six-fold increased in activity and in MS
only 2.5 times (Wei and Lightman, 1997) was proposed
to point to a relative deficiency of the HPA axis in
MS patients. It is questionable, though, whether these
observations in two different species with a different
time course in the disease process can indeed be compared
so easily. However, this possibility agrees with the observation that the insulin-induced cortisol increase in
MS patients was lower than in healthy controls (Teasdale
et al., 1967).
CRH neurons are clearly activated in MS patients, as
appears from the 2.4-fold increase in the number
of neurons expressing CRH (Purba et al., 1995) and

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the 4.5-fold increase in neurons coexpressing CRH and


VP (Erkut et al., 1995; Fig. 21.4). In fact, the latter study
showed that the entire increase in CRH cell numbers in
MS was due to an increase in those CRH neurons that
colocalized VP, which is different from the situation in
depression (see Chapter 26.4). VP potentiates both the
peripheral and central effects of CRH (see Chapter
8.5). Our data agree with the increase in plasma levels
of corticosteroids reported in MS (Millac et al., 1969;
Reder et al., 1987; Michelson et al., 1994) and the
presence of an enlarged adrenal gland in this condition
(Reder et al., 1987, 1994). Moreover, postmortem CSF
cortisol level in MS is elevated by 80%. Cortisol levels
in CSF appeared to reflect postmortem serum cortisol,
since these levels were highly correlated (Erkut et al.,
2002). The dexamethasoneCRH-suppression tests indicated hyperactivity of the HPA axis only in primary and
secondary progressive MS, while relapsing-remitting
patients had response patterns similar to controls (Heesen
et al., 2002).
The increased HPA axis activity may be seen as an
effort to suppress the disease process. Indeed, exogenous
corticosteroids improve the rate of recovery from acute
exacerbations of MS and attacks of monosymptomatic
optic neuritis. However, there is at present no convincing
evidence that glucocorticoid therapy reduces the
frequency of MS exacerbations or delays the progression
of neurological disability (Milligan et al., 1987; Miller
et al., 1992; Frequin et al., 1994; Wenning et al., 1994;
Andersson et al., 1998). The strong increase in CRHneuron activity thus seems compatible with the idea that
the brain defends itself against the disease process
(MacPhee et al., 1989), although it is not entirely
successful in this. Indeed, an endocrine paper concluded
that the HPA axis activation in MS is a reaction to the
disease process, since it correlates with a marker for
the acute phase response, white blood cell counts and with
gadolinium enhancement in MRI (Wei and Lightman,
1997; Fassbender et al., 1998). The enhanced response
in the dexamethasone-suppression test in MS correlated
with disease activity and with the clinical subtype of MS
in such a way that increased HPA axis activity relates
to an increased disease activity or severity (Wei and
Lightman, 1997; Then Bergh et al., 1999). In agreement
with this idea, Millac et al. (1969) and Grasser et al.
(1996) found increased cortisol levels in MS only during
exacerbations and a heterogeneity of the HPA system
function, possibly at the corticosteroid receptor level.
Although the presence of a partial glucocorticoid receptor
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deficiency in some MS patients can, at present, not be


excluded as the reason for a different course of HPA
axis activation, there does not seem to be any gross
disorder of the HPA axis in MS (Millac et al., 1969).
In line with this conclusion is the observation that,
after cessation of the corticosteroid therapy for relapses,
HPA axis function is normal and corticosteroid replacement therapy seems unnecessary (Mir et al., 1990).
In addition, it has been observed that cortisol release
induced by the dexamethasoneCRH test, is negatively
associated with the presence and number of gadoliniumenhancing lesions and positively associated with
ventricular size. This suggests a protective effect of
the HPA axis drive on acute lesion inflammation in
MS. These observations can, however, also be explained
in a different way. The observation that prolonged treatment with prednisolone significantly decreases brain
volume (Hoogervorst et al., 2002) is another reason to
have reservations about long-term corticosteroid therapy
in MS.
CRH itself may also be directly involved in the defense
against the disease process, because it has a neuroprotective effect (Fox et al., 1993) and immunomodulating
actions (Webster et al., 1998). Moreover, CRH has
analgesic properties (Lariviere and Melzach, 2000).
It is remarkable that the condition of most women
with MS stabilizes or improves during pregnancy, but
after delivery they run an increased risk of suffering a
relapse. It is estimated that the risk that the condition
takes a turn for the worse is between 20% and 75%.
However, it is not clear what factors determine susceptibility changes during pregnancy and postpartum (Birk
et al., 1990), although steroid hormones are presumed
to be implicated. Hormonal changes preceding the
menstruation may worsen symptoms in a subgroup of
women with relapsing-remitting MS (Zorgdrager and De
Keyser, 1997).
(d) Inflammation, demyelination and hypothalamic
structures
MS is an immune-mediated disease characterized by
inflammatory demyelinating perivascular lesions in the
white matter, disseminated in time and space (Raine,
1994). In addition, brain weight is decreased (Jelliffe and
White, 1935; Erkut et al., 1995). Although ample literature
covers the neuropathology of MS, little reference has
been made to the hypothalamus. Hypothalamic lesions as

mentioned by Brownell and Hughes (1962) are said to


make up only 1% of the total lesions, which does not
agree with our observations, which showed a large number
of demyelinated plaques to be present in hypothalamic
and adjacent structures in a high proportion of MS
patients (Huitinga et al., 2001). Moreover, acute unilateral
optic neuritis is generally not included in hypothalamic
involvement, while, within 5 years, in some 30% of
patients, it was followed by clinically definite MS.
Corticosteroids did not influence this risk, nor the degree
of neurological disability in a 5-year follow-up study
(Optic Neuritis Study Group, 1997). Unilateral optic neuritis occurs often as an initial manifestation of MS. Acute
bilateral optic neuritis is less common. Swelling and
demyelinating lesions in myelinated bundles can be shown
by MRI, also following gadolinium enhancement (Fig.
21.5), and pathology has confirmed the inflammatory
nature and demyelination. The optic radiations are almost
always involved (Newman et al., 1991; McDonald and
Barnes, 1992). MS lesions are mentioned by Bignani
(1961) and Peters-Bonn (1958) to be present not only
around the walls of the lateral ventricles, but also around
those of the third ventricle. Early periventricular lesions
are situated around subependymal veins, causing focal
perivenous demyelination. The lesions subsequently
coalesce with neighboring lesions (Adams et al., 1987).
A limited number of other papers mentions the involvement of the hypothalamus in MS: Zimmerman and Netzky
(1950) found that the paraventricular nucleus of the
hypothalamus is sometimes involved in MS; Bignani
et al. (1961) described fresh plaques throughout the whole
hypothalamus in a patient with a depression, profuse
sweating and hyperthermia. An MS patient has been
described with acute relapses associated with drowsiness
and hypothermia. Although MRI, endocrine and autonomic
studies failed to localize a lesion in the hypothalamus,
subsequent necropsy showed plaques of demyelination
throughout the hypothalamus, including the area of the
posterior hypothalamic nucleus (White et al., 1996). In
addition, a woman with MS who had presented with
hypothermia, dysphagia, lethargy, dysrhythmicity and
bronchopneumonia, showed a large, mature, gray, translucent gliotic plaque involving the hypothalamus at the
postmortem. At the microscopic level, there was evidence
of current activity in a proportion of that plaque. In
addition to gliosis, lymphocytic cuffing of vessels and
occasional macrophages containing lipid debris were seen
(Edwards et al., 1996a). Kamalian et al. (1975) reported
a malignant case of MS in which the disease began with

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in body temperature, depression and an activated HPA


axis (see above) we investigated the possible presence of
MS lesions in 16 MS patients using myelin Klver
hematoxylin staining, CR3/43 (anti-HLA-DR, -DP, -DQ)
as a marker for activated microglial cells (Graeber et al.,
1994), glial fibrillary acidic protein (GFAP, marker for
astrocytes), KP1 (recognizes macrophages and microglial
cells) and amyloid precursor protein (APP, detects axonal
damage; Ferguson et al., 1997). The myelinated bundles
in and around the hypothalamus analyzed were the optic
system (optic nerves, optic chiasm and optic tract), the
fornix, internal capsule and anterior commissure. We
distinguished between active demyelinating lesions
containing foamy macrophages and microglial cells and
chronic, inactive hypocellular gliotic lesions (De Groot
et al., 2001; Huitinga et al., 2001; Figs. 21.621.10). The
hypothalamus of 16 of 17 MS patients contained demyelinated lesions (Fig. 21.6). The incidence of active lesions
was high (60%) and outnumbered chronic inactive gliotic
lesions in the internal capsule. In 4 out of 17 MS patients,
axonal damage was observed and in 3 of 17 MS patients
gray matter lesions were apparent. Duration of MS was
inversely related to the active hypothalamic MS lesion
score. Since comparison of hypothalamic lesions with MS

rapid weight loss and terminated after 17 months with


generalized muscle wasting and cachexia. Demyelinating
lesions were found in the lateral hypothalamus and a
relationship was proposed between the clinical symptoms
and the localization of the lesions, because lesions in the
lateral hypothalamus may cause aphagia and anorexia (see
Chapter 23). The optic nerves and chiasm were almost
completely demyelinated and there was intense reactive
astrogliosis. The fornix showed a patchy loss of myelin.
A plaque-like sclerotic lesion was located in the left lateral
hypothalamus. The plaque showed almost complete loss
of myelin, a moderate, diffuse astrogliosis and occasional
small lymphocytic infiltrates. The right lateral hypothalamus showed slight myelin loss. The dorsomedial and
ventromedial nuclei appeared to be unaltered. An old
plaque with its pronounced fibrillary astrogliosis continued into the left mamillary body and fornix, surrounded
by more cellularly active lesions. There were also
subacute lesions with perivascular infiltrates along the
third ventricle. In MS patients with hyperprolactinemia,
hypothalamic lesions were present in 5 of 9 patients (Kira
et al., 1991; Tsui et al., 2002).
Because MS patients show hypothalamic signs and
symptoms such as fatigue, sleep disturbances, changes

Fig. 21.5. Multiple sclerosis patient with optic chiasmal neuritis. MR. T1-weighted images after gadolinium enhancement. Coronal (A) and axial
(B) views demonstrating a thickened optic chiasm with focal enhancement (arrows). (From Newman et al., 1991, Fig. 2 with
permission.)

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Fig. 21.6. Multiple sclerosis (MS) lesions in the human hypothalamus. A and B: Kluver staining of the hypothalamus of a control subject (82016, (A) and a MS patient (93-051, (B). Myelin is stained blue. Note that, in the control subject the myelinated bundles (IC: internal capsule, FX:
fornix, OS: optic system) can easily be distinguished, whereas, in the MS patient, myelin bundles contain large white spots or are even barely
visible (i.e. the OS in MS patient 93-051) because of demyelinating MS lesions (*). In the control subject, the anterior commissure (AC) is not
present at this level. The left FX in the MS patient is partly demyelinated. IF: infundibulum, P: PVN. Magnification: 4.5 . C and D: Human
leukocyte antigen (HLA-DR, -DP, -DQ) staining of an active MS lesion in the internal capsule in MS patient 95-065 (C) and a (p)reactive lesion
also in the internal capsule of MS patient 96-026 (D). Note the foamy character of the HLA-positive macrophages in the active lesion in (C),
indicative of myelin phagocytosis, and the ramified character of the HLA-positive macrophages in the (p)reactive lesion in (D), indicative of
activated microglial cells. Arrow points at perivascular leukocyte cuffing. Magnification: 400 . bv = blood vessel. Tissue was obtained from the
Netherlands Brain Bank. (From preparation by I. Huitinga.)

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disease severity in MS (Schrijver et al., 1999) and because


priming with IL-1 suppresses EAE in the Lewis rat
(Huitinga et al., 2000b).
Since demyelinating lesions in fiber bundles in and
adjacent to the hypothalamus (i.e. the fornix, anterior
commissure, internal capsule and optic system) may
be the basis for autonomic and endocrine alterations
in multiple sclerosis (MS) patients, we investigated the
relationship between the presence of hypothalamic lesions
and the state of activation of CRH neurons in MS patients
(n = 15). The state of activation of CRH neurons was
determined by quantifying the number of CRH neurons
that did or did not contain vasopressin, as well as the
amount of CRH mRNA expressed in the paraventricular
nucleus. The state of activation of CRH neurons in the
MS group was compared with that in controls (n = 14).
Hypothalamic MS lesions were determined as described
above. As found previously (Erkut et al., 1995; Purba
et al., 1995), numbers of CRH neurons that colocalize
vasopressin are significantly increased in MS. In line with
these findings we also found increased levels of CRH
mRNA in MS. Interestingly, there was a strong, significant negative relationship between the numbers of
CRH neurons that colocalize vasopressin (the population
of CRH neurons that is increased in MS) and active MS
lesions in the hypothalamus. There was no relation
between CRH single positive neurons and the active
lesion score. The effect was thus neuron-specific. The
chronic inactive lesion score did not correlate with the
numbers of CRH that colocalize VP in MS; the effect
thus concerns only the immunologically active lesions.
The same negative relationship was seen between the
amount of CRH mRNA expression and the active lesion
score in MS. This relationship, too, concerned only
immunologically active lesions and not the chronic
inactive gliotic lesions. Interestingly, controls also showed
a negative relationship between HLA score (activated
microglial cells) and the amount of CRH mRNA expression, indicating that the relationship between activated
microglial cells and the decreased activation of CRH
neurons is not MS specific. Thus, whereas as a group MS
patients have activated CRH neurons, the presence of
active lesions and activated macrophages and microglial
cells in or around the hypothalamus of MS patients
induces a significant decrease in the activation of CRH
neurons. Apparently, MS patients with many active
lesions in the hypothalamus have a diminished activity
of the HPA system (Huitinga et al., 2002). The clinical
consequences of such an impaired activity of the HPA

Fig. 21.7. Active and chronic inactive lesion scores (bars) and the incidence of active and chronic inactive lesions per fiber bundle (numbers
on top of the bars) in the hypothalamus of multiple sclerosis patients:
the internal capsule (IC), anterior commissure (AC), fornix (FX) and
optic system (including optic nerve and optic chiasm, OS). Note that
the AC and the FX were not present in the sections studied in all
patients. The active lesion score includes (p)reactive and active lesions
and the chronic inactive lesion score includes only chronic inactive
hypocellular gliotic lesions. Bar represents the mean SEM. (From
Huitinga et al., 2001, Fig. 2 with permission.)

lesions in other areas of the brain in the same patients


(n = 7) showed a great similarity as both stage and appearance were concerned, this negative relation in all
likelihood reflects the clinical consequences of high
disease activity throughout the whole brain. In controls
no demyelinating lesions were seen, but, in 11 control
cases, HLA expression was observed that was lower than
in MS patients. Thus, systematic pathological investigation of the hypothalamus in MS patients reveals an
unexpectedly high incidence of active lesions.
Preactive lesions were also found in the neurosecretory
supraoptic nucleus (SON) (Fig. 21.11). In the oxytocin
neurons of the PVN and accessory nuclei, IL-1 was
found (Fig. 21.12). In MS patients fewer neurons in the
PVN were found to be positive for this cytokine (Huitinga
et al., 2000a; Fig. 21.13). This finding may be of particular
interest in relation to MS, since a specific combination
of IL-1 and IL-1 receptor antagonist is associated with
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Fig. 21.8. Microphotographs of multiple sclerosis (MS) lesions. A: CD68-positive foamy macrophages in an active lesion in the internal capsule
(IC) of MS patient 95-065. B: Klver staining of an active lesion in the OS of MS patient 95-065. Arrows point at two foamy macrophages at
the edge of the lesion. Arrowheads point at luxol fast blue-positive particles in the macrophages. C: Gliosis in a chronic active lesion in the IC
of patient 95-065. Arrows point at glial fibrillary acidic protein (GFAP)-positive hypertrophic astrocytes. D: human leukocyte antigen (HLA-DR,
-DP, -DQ)-positive microglial cells (arrow) and HLA-positive leukocytes (arrowhead) in the VirchowRobin space around a blood vessel (Bv),
indicative of a (p)reactive MS lesion in the IC of MS patient 96-026. E: A chronic inactive lesion in the OS of patient 93-051. Arrows point at
HLA-DR, -DP, -DQ-positive microglial-like cells and arrowheads point at isomorphic gliosis and widened extracellular spaces typical for gliotic
tissue. F: Perivascular accumulation of CD3-positive T cells near an active lesion in the IC of patient 95-065. Bar = 15 m. (From Huitinga et
al., 2001, Fig. 3 with permission.)

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Fig. 21.9. Microphotograph of axonal damage and HLA expression in the supraoptic nucleus (SON) and the median eminence. A: Bodian staining
of the optic system (OS) of MS patient 93-051. Note the reduced density of axons as compared to the axonal density in Fig. B. B: Bodian staining
of the OS of MS patient 96-026. There is no sign of axonal damage in the OS of this MS patient. C: amyloid precursor protein (APP)-immunoreactive axons in the IC of MS patient 91-070. Note the large-diameter (57 m) of the APP-immunoreactive axons. Adjacent to this area is an
active MS lesion (not shown). D: HLA-DP, -DQ, -DR-positive microglial cells in the SON of MS patient 96-026. Arrow points at an HLA-positive microglial-like cell that seems to be in close contact with an SON neuron. E: HLA-DR, -DP, -DQ-immunoreactive microglial-like cells in the
median eminence of control 93-085. Arrows point at HLA-reactive microglial-like cells in close vicinity of blood vessels (Bv). F: HLA-DR, -DP,
-DQ-immunoreactive cells in the median eminence of MS patient 95-095. Arrow points at a small lesion of HLA-positive cells. Bar = 15 m.
(From Huitinga et al., 2001, Fig. 4 with permission.)

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Fig. 21.10. The relationships between the duration (in years) of multiple sclerosis (MS) and the active lesion score (left panel, p = 0.001, r =
0.719) and chronic inactive lesion score (right panel, p = 0.102, r = 0.410) in the hypothalamus. Note that there is a significant inverse correlation between the active lesion score and the duration of MS, i.e. leading to death, but not between the chronic inactive lesions score and the
duration of MS. (From Huitinga et al., 2001, Fig. 5 with permission.)

system in a subgroup of MS patients should be studied


further.
(e) Differential diagnosis of optic neuritis
Acute optic neuritis in MS should be differentiated from
Lebers hereditary optic neuropathy. In children, optic
neuritis is often bilateral. It usually follows infections
such as measles, chicken pox and infectious mononucleosis in nearly half of cases, and there is a seasonal
fluctuation, with the greatest number presenting in April.
While the risk of MS after childhood optic neuritis is low
(some 15%), the risk factor for adults is 75% (McDonald
and Barnes, 1992).
The diagnosis of MS has often been applied to patients
with a syndrome that has recently been renamed recurrent
optic neuromyelitis with endocrinopathies. It has been
described in Antillean women from Martinique and
Guadeloupe. Myelopathic symptoms and visual problems
recurred. Spinal cord involvement consisted of a band-like
sensory loss and MRI shows caviation-like images. The
endocrinopathies consisted of amenorrhea, galactorrhea,

diabetes insipidus, hypothyroidism or hyperphagia. In


the spinal cord, demyelinizing lesions with diffuse
spongiosis are found with thickened blood vessel walls
without evidence of inflammation. Autonomic abnormalities are present in half of cases. Demyelination of the optic
tracts is observed; the optic neuromyelitis is probably
of postinfectious origin. In three cases MRI revealed
lesions in the pituitary and inferior hypothalamus (Vernant
et al., 1997).
21.3. Langerhans cell histiocytosis
(HandSchllerChristian disease; histiocytosis-X)
HandSchllerChristian disease, with its granuloma
that are preferentially located in the hypothalamus and
pituitary (Gagel, 1941; Treip, 1992; Fig. 21.14) is also
known as Langerhans histiocytosis or histiocytosis-X
(Kepes and Kepes, 1969; Schneider and Gthert, 1975).
The terms Gagels granuloma, eosinophilic granuloma,
Ayalas granuloma, LettererSiwe disease and hypothalamic granuloma have all been used (Horvath et al., 1997;

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Fig. 21.11. Microphotograph of a (p)reactive lesion in the optic nerve (on) and in the supraoptic nucleus (son) in multiple sclerosis (MS) patient
96-307. A: HLA-DP, -DQ, -DR-positive cells in the ON and SON (arrowheads point at HLA-DP, -DQ, -DR-negative SON neurons) in section
601. B: Interleukin-1(IL-1)-staining of section 599. The same area as in A, containing the son and a rim of the on. Arrowheads point at IL1-negative and the arrow points at an IL-1-positive neuron in son. In the on, arrowheads point at IL--ir glial cells. C: Magnification of HLA-DP,
-DQ, -DR-positive cells in the on; D: magnification of interleukin-1 (IL-1)-ir cells in the on. Note: in the gray matter in the son, as well as in
white matter in the on, HLA-DP, -DQ, -DR-ir glial cells are present that are indicative of a (p)reactive MS lesion in both areas, whereas
IL-1-ir cells are only present in the on and not in the son. Bar: 45 m in A, B; 15 m in C, D. (From Huitinga et al., 2000a, Fig. 4 with
permission.)

Rosenzweig et al., 1997). The disease may represent an


uncontrolled immunological reaction to an unknown
antigen (DAvella et al., 1997; Schmitz and Favara, 1998).
In a very small number of families, recurrence of the
disease has been reported (Arico and Egeler, 1998). There
is a unifocal benign form of the disease in which the
hypothalamus and pituitary are spared. It is characterized
by a solitary lytic bone lesion. The multifocal form is
more aggressive and, in childhood, presents with the

clinical triad diabetes insipidus, exophthalmus and lytic


bone disease secondary to granulomas in the hypothalamus and pituitary gland. On MR images the pituitary
stalk is thickened symmetrically. However, after a few
years there is a complete reversal of the pituitary stalk
enlargement in a large percentage of the patients. The
normal high MRI signal density in the posterior lobe is
frequently absent. Associated involvement of the temporal
bone supports the diagnosis (Chong and Newton,
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Fig. 21.12. Microphotograph of interleukin-1 (IL-1)-ir neurons in the paraventricular nucleus (PVN) in two control cases and two multiple sclerosis (MS) patients illustrative of IL-1 staining intensity in the control versus the MS group. Per patient the rank number in estimated numbers
of IL-1-ir PVN neurons in the group (see Fig. 21.13) are given in parentheses: A: control 96-163 (3rd), B: MS 90-246 (1st), C: control 96-019
(9th), D: MS 96-352 (9th). Arrows point at IL-1-positive neurons containing a nucleolus and arrowheads point at IL-1-negative neurons containing
a nucleolus. Bar = 15 m. (From Huitinga et al., 2000a, Fig. 6 with permission.)

1993; Fig. 21.15; Rami et al., 1998; Leger et al., 1999;


Czernichow et al., 2000).
The classic triad of diabetes insipidus, exophthalamus
and lytic bone disease is present in only 25% of the cases.
Visual disturbances and endocrine dysfunctions such as
delayed or precocious puberty, hypogonadism, growth
retardation, growth hormone deficiency in the insulin
hypoglycemic tolerance test, hypothyroidism, hypoadrenalism, panhypopituitarism, diabetes insipidus, morbid
obesity and modest hyperprolactinemia may also be present (Ober et al., 1989; Chong and Newton, 1993; Lin et

al., 1998; Rami et al., 1998; Modan-Moses, 2001; Beswick


et al., 2002; Harris et al., 2002). A few cases with polyneuropathy have been described. One such an atypical
case is a patient with Langerhans cell histiocytosis and
polyneuropathy, diagnosed 12 years after the development
of diabetes insipidus following head trauma (Malko et
al., 2000). A girl with Langerhans cell histiocytosis developed diabetes insipidus and central precocious puberty at
7.5 years of age (Municchi et al., 2002).
In a late stage of the disease, vegetative disorders,
short-term memory deficits, psychic disturbances, disor-

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since then agreement has been reached about the role of


the Langerhans cell, a cell with features similar to the
Langerhans cell of the epidermis, which is now considered to be the principal proliferating cell in the disease
(Ober et al., 1989; Schmitz and Favara, 1998). The normal
epidermal Langerhans cell is a dendritic, antigenpresenting cell characterized by the intracytoplasmic,
tennis racket-shaped Birbeck granule of 200400 nm
in width and by expression of CD1a and S-100.
Tissue damage is caused by excessive production of
cytokines and prostaglandins (Rosenzweig et al., 1997).
Lymphocytes and plasma cells, eosinophils, giant cells
and microglia are also found. In one case an adult male
with Langerhans cell histiocytosis diabetes insipidus
occurred 5 years before the skin lesions and the hypothalamic mass became evident (Catalina et al., 1995;
Horvath et al., 1997). By using positron-emission tomography (PET), both increased and decreased glucose
metabolism was found in cases of Langerhans cell
histiocytosis. The increased activity probably represents
an active, ongoing disease process, and areas of decreased
activity either represent a burnt-out brain lesion caused
by the disease or a decreased brain metabolism of other
origin (Calming et al., 2002).
An unusual case of isolated histiocytosis presented as
a solitary mass in the pineal gland with incomplete ocular
palsy (Gizewski and Forsting, 2001). Spreading may occur
through portal vessels or via the systemic circulation
(Wilke, 1956). A primary phase of histiocyte proliferation is followed by brain atrophy or demyelination and
gliosis of unknown origin (Barthez et al., 2000).
Apart from corticosteroids (Harris et al., 2002),
chemotherapy and low-dose radiotherapy have been
reported to be successful treatments for Langerhans
cell histiocytosis masses in the hypothalamus (Catalina
et al., 1995). At least in those patients with shortterm polyuria or polydipsia, and with an abnormality in
water-deprivation tests, rapid treatment with hypothalamopituitary radiation therapy seems justified. However,
there seems to be no rationale for treating patients with
full diabetes insipidus, as there is no evidence that patients
in later stages of the disease will respond to this therapy
(Rosenzweig et al., 1997). Although chemotherapy may
cause a regression of the Langerhans cell histiocytosislesion, even in some cases with good therapeutic results,
hormone deficiencies are usually irreversible (Rami et al.,
1998).
In the case of a solitary hypothalamic granuloma, where
Langerhans cell histiocytosis was found with diabetes

Fig. 21.13. Total numbers of interleukin-1-immunoreactive (IL-1-ir)


neurons in the paraventricular nucleus (PVN). Bars indicate the median.
Triangles indicate individual cell counts. Note the high interindividual
variation. The total number of IL-1-ir neurons in the PVN was significantly decreased in the multiple sclerosis (MS) group as compared to
the control group (p < 0.05). In addition to the reduction in numbers of
IL-1-ir neurons in the PVN, also the IL-1 staining intensity was
strongly reduced in most MS patients. (From Huitinga et al., 2000a,
Fig. 7 with permission.)

ders of temperature regulation and hypersomnolence have


been described (Schneider and Gthert, 1975; Yen, 1993;
Kaltsas et al., 2000). The disorder may have a waxing
and waning course. About 50% of the patients with
hypothalamic diabetes insipidus due to histiocytosis-X
had antibodies against VP neurons. In a patient who
became pregnant, diabetes insipidus remitted at about
the 28th week of gestation and recurred after delivery.
Improvement of the disease during pregnancy supports
the notion of an autoimmune pathogenesis (Scherbaum,
1992).
The disease is neuropathologically characterized by
infiltration of the hypothalamus and pituitary, including
the pars distalis by lipid-laden histiocytes or foam cells
that appear to be involved in the autoimmune process
(Scherbaum et al., 1986). Autoimmunity to hypothalamic
vasopressin cells may be present in a large percentage of
patients with central diabetes insipidus and Langhanss
cell histiocytosis (Pivonello et al., 2003). The X in the
term histiocytosis-X indicated an unknown cell, but
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Fig. 21.14. Gagel granuloma (Langerhans histiocytosis). Sagittal section of the pituitary gland, showing enlargement of the stalk and posterior
lobe (on the right) by granulomatous infiltration. Hematoxylin & eosin.  5.5. (From Treib et al., 1992, Fig. 16.11 with permission.)

insipidus and panhypopituitarism, complete microsurgical


excision was performed (DAvella et al., 1997). Some
clinicians advocate the combination of surgical excision
with postoperative radiation (olak, 1998). However,
surgical resection and chemotherapy with prednisolone
and vinblastine have also been effective (Lin et al., 1998).
Dynamic evaluation of pituitary function was not a useful
predictor of late endocrine sequelae, with the possible
exception of the progressively decreasing thyrotropin
(TSH) response to thyrotropin-releasing hormone (TRH)
(Lin et al., 1998; Maghnie et al., 1998b).
ErdheimChester disease, first described in 1930 as
lipoid granulomatosis, is a rare condition, predominantly

of middle-aged males. The pathological hallmark of this


disease consists of xanthogranulomatous infiltrations of a
wide variety of tissues by cells of macrophage or histiocyte lineage. Symmetrical predominantly sclerotic bone
lesions sparing the epiphysis and the predominance of
lipid-laden histiocytes or foam cells in the patients
retroperitoneal tissues was considered as a diagnostic of
ErdheimChester disease. This entity is distinct from
histiocytosis-X, but the two diseases may represent a
disease spectrum. Patients have been described with multiorgan involvement, thrombocytopenia, central diabetes
insipidus, panhypopituitarism, hyperprolactinemia, gonadotropin insufficiency, decreased insulin-like growth factor

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Fig. 21.15. Histiocytosis. Sagittal (A) and coronal (B) precontrast and postcontrast-enhanced MR scans. The pituitary stalk (arrows) is markedly
enlarged. Prominent contrast enhancement of the stalk is noted. (From Chong and Newton, 1993, Fig. 23 with permission.)

I levels and bilateral adrenal enlargement, suggesting


hypothalamic-pituitary dysfunction. The high-intensity
signal of the posterior pituitary on T1-weighted images
may be absent on MR images, the pituitary stalk and dura
may be thickened and a hypothalamic mass has been
described. The diagnosis of the rare cranial localizations
is usually made on the basis of a biopsy (Tritos et al.,
1998a; Oweity et al., 2002; Perras et al., 2002).

21.4. Other neuroimmunological hypothalamic


disorders and lesions
The idiopathic hypothalamic dysfunction syndrome of
childhood (Chapter 32.1) may be based upon a nonmetastatic paraneoplastic syndrome related to the presence
of an occult neural-crest tumor. The tumor probably
produces antineuronal antibodies that lead to extensive
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Fig. 21.16. Granular ependymitis of the third ventricle in a case of sudden death (NHB 96-077, 68). Bar = 400 m.

lymphocytic/histocytic infiltrates in the hypothalamus


and other brain areas. Lymphocytic hypophysitis and
autoimmune diabetes insipidus are discussed in Chapter
22.2.
Granular ependymitis are periventricular lesions characterized by raised pyramidal granulations with focal
gliosis in the subependymal region. The overlying
ependyma is trophic, eroded or absent (Fig. 21.16). Some
of the cases with ependymitis or subependymal gliosis
are active, in the sense that they contain lymphocytic

infiltrates. Granular ependymitis is generally associated


with ventricular dilatation or meningitis. Although granular ependymitis is more frequently seen in MS, it is
certainly not specific for this disease and also found in,
e.g. Parkinsons disease, vascular disease and senile
atrophy. In addition, it is found in, e.g. meningococcal
or pneumococcal meningitis. In MS, granular ependymitis
may provide a possible route for the exchange of inflammatory agents between the brain and the CSF (Adams
et al., 1987).

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infections such as viral encephalitis, i.e. following infections with the Epstein-Barr or the Varizella zoster virus
(Merriam 1986; Fenzi et al., 1993; Salter and White,
1993; Mller et al., 1998b). Perivascular inflammatory
infiltrates and microglial proliferation of nodular type
were observed in the hypothalamus (Fig. 28.1), in particular the floor of the third ventricle and in the
periaqueductal gray. In two previous cases, inflammatory
changes were present in the hypothalamus and in the
temporal lobe or they were confined to the thalamus.
Prevalence of T-lymphocytes in the affected area was
suggestive of an unknown viral antigen responsible
for the immuneresponse and is consistent with the
observation that in 35% of the KleineLevin cases
the onset is preceded by respiratory disease or vaccination
(Fenzi et al., 1993). In addition, the increased (HLA)DQB1*0201 allele frequency was significantly increased
in KleineLevin syndrome. This, together with the young
age of onset, the recurrence of symptoms and the frequent
infectious precipitating factors suggests an autoimmune
etiology for KleineLevin syndrome (Dauvilliers et al.,
2002).

In GuillainBarr syndrome, inappropriate vasopressin


secretion (Chapter 22.6a) and undetectable CSF levels of
hypocretin (Ripley et al., 2001; Kanbayashi et al., 2002;
Chapter 28.4) have been described, pointing to hypothalamic involvement.
Paraneoplastic encephalitis is characterized by personality changes, irritability, depression, seizures, memory
loss and sometimes dementia. It is due to antineuronal
antibodies. Patients with anti-Ta (anti-Ma2) antibodies
frequently have hypothalamic involvement, as appears,
e.g. from diabetes insipidus, loss of libido, hypothyroidism, hypersomnia, hyperthermia and panhypopituitarism.
The tumor should be treated (Gultekin et al., 2000; Chapter
19.1b, 32.1).
For the possible autoimmune destruction of the
orexin/hypocretin system in the lateral hypothalamus in
case of narcolepsy, see Chapter 28.4.
In anorexia and bulimia nervosa patients, autoantibodies against -MSH, ACTH and luteinizing hormonereleasing hormone (LHRH) have been found (Fetissov
et al., 2002; Chapters 22.2b, 23.2), but their function has
not yet been elucidated.
KleineLevin syndrome (periodic somnolence and
morbid hunger, see Chapter 28.1) may follow viral

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)


The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved

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CHAPTER 22

Drinking disorders

As to the function of the posterior lobe, the experimental


evidence is unequivocal. Its removal causes no symptoms.
Moreover, its structure is nonglandular. Camus and Roussy
were quite justified in speaking of it as an atrophied nervous
lobe . . . We have, therefore, no evidence that pituitrin is
anything more than a pharmacologically very interesting
extract (Bailey and Bremer, 1921; from Anderson and
Haymaker, 1974).

stretch receptors, which send inhibitory signals to the


hypothalamus via an as yet unidentified neuronal pathway.
The osmotic threshold for thirst is similar to that for
vasopressin release. That a rapid fall in thirst takes place
before any significant change in plasma osmolality occurs
can be considered as a defense mechanism which protects
against overhydration (McKenna and Thompson, 1998).
Histamine, produced in the tuberomamillary nucleus
(TMN), elicits drinking, increases the release of vasopressin and decreases urine output via H1 and H2
receptors (Brown et al., 2001). Animal experiments have
revealed a number of peptides that regulate drinking
behavior, such as angiotensin II (Chapter 30.5) and
orexin-A, which is also involved in eating (Chapter 23).
The kidney concentrates or dilutes urine under the
influence of vasopressin. The segmental permeabilities
in the nephron correlate with the expression of different
members of the aquaporin family, seven members of
which have been identified in the kidney. Vasopressindependent expression of aquaporin-2 is found in the apical
membrane of the principal cells of the collecting duct
(King and Yasui, 2002).

Osmoregulation and thirst. Plasma osmolality is precisely


maintained within a remarkably narrow range of 282298
mosmol/kg, which is achieved by the close integration of
the antidiuretic action of vasopressin and the sensation
of thirst. Plasma osmolality is the most important physiological determinant of vasopressin secretion (Robertson,
2001; Chapter 8.e). Changes in osmolality were always
thought to be detected in the circumventricular organs
that are said to send information to the vasopressinproducing neurons (see Chapter 8), but the identification
of water channels, or aquaporins, in the supraoptic and
paraventricular nucleui (SON and PVN) has challenged
this traditional theory. The presence of messenger RNA
(mRNA) for aquaporins in the SON and PVN may indicate that these nuclei have osmoreceptors that are
independent of the osmoreceptors in the circumventricular organs, such as the subfornical organ and the
organum vasculosum laminae terminalis (see Chapter
30.5). Data from a patient with defective osmoregulation
of thirst with preservation of osmoregulation of vasopressin release (Hammond et al., 1986) provides
corroborative evidence of separate osmoreceptors of thirst
and vasopressin release.
The osmotic threshold at which secretion of vasopressin
begins is 284.3 mosmol/kg. During drinking there is an
almost instantaneous suppression of vasopressin secretion, probably due to the activation of oropharyngeal

22.1. Pathology of the neurohypophysis


The neurohypophysis consists of: (1) the pars nervosa
(neural or posterior lobe); (2) the infundibular process
(pituitary stalk), which contains the nerve tracts from the
supraoptic and paraventricular nucleus (SON and PVN),
a thin tongue of anterior pituitary tissue (pars tuberalis,
containing predominantly gonadotrophs, while somatotropic, mammotropic, corticotropic and thyrotropic cells
are rare) (Baker, 1977; Osamura and Watanabe, 1978)
and the vessels of the portal system (see Chapter 17.1);
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and (3) the pars infundibularis (infundibulum). The neurohypophysis is characterized by its rich vascularity, nerve
endings, Herring bodies and pituicytes, which are specialized astrocytes that are, at least in part, glial fibrillary
acidic protein (GFAP)-positive (Velasco et al., 1982). The
capillaries have fenestrated endothelial cells and extensive perivascular spaces.
Clinically, pathology of the neurohypophysis may
lead to diabetes insipidus (see Chapter 22.2) or to
inappropriate secretion of vasopressin (SchwartzBartter
syndrome; see Chapter 22.6). Apart from disturbances of
water metabolism, abnormalities in the posterior pituitary,
particularly space-occupying lesions, may cause symptoms such as headache and visual disturbances. In
addition, the intracranial pressure may increase, producing
anterior-pituitary compression. Damage to the pituitary
stalk may interrupt the portal circulation and lead to
infarction of the anterior lobe and thus to endocrine
impairments.
Congenital malformations in the neurohypophysis have
also been described, such as agenesis of the posterior
lobe of the pituitary in a fetus in the progeny of a mother
who used alcohol during pregnancy (Konovalov et al.,
1997), and persistence of the infundibular recess by which
the third ventricle is protruding into the neurohypophysis.
The infundibular recess in the neurohypophysis normally
disappears in human embryos by the 45-mm stage
(Cabanes, 1978). Moreover, duplication of the pituitary,
of the adenohypophysis as well as the neurohypophysis,
have been reported (Hori, 1983). The pituitary stalk is
rarely duplicated in holoprosencephaly (Sarnat and
Flores-Sarnat, 2001). Loss of the infundibulum or pituitary stalk due to traumatic damage has been reported
(Grossman and Sanfield, 1994). Dystopia of the neurohypophysis may either be asymptomatic or accompany
anterior pituitary anomalies (Aydan and Ghatak, 1994;
Chapters 18.4, 18.6). Twin boys, born at 35 weeks
of gestation, with hypopituitarism, hypoplasia of the
anterior pituitary gland, an ectopically localized posterior
pituitary at the base of the median eminence, had a
paracentric inversion of the short arm of chromosome 1.
The smooth appearance at the base of the median
eminence and the absence of the pituitary stalk in these
boys implied a developmental alteration. However, the
causal relationship to the chromosome 1 anomaly remains
to be determined (Siegel et al., 1995). Dystopia of the
neurohypophysis is frequently accompanied by growth
hormone and other pituitary deficiencies and is now
generally considered to be a developmental disorder or

disconnection rather than an interruption of the stalk


due to complications at birth (Mszros et al., 2000; see
also Chapters 18.4, 18.6). In the empty-sella syndrome,
the intrasellar CSF does not seem to influence posterior
lobe function (Zucchini et al., 1995), while hypogonadotropic hypogonadism and growth hormone deficiency
frequently occur (Cannav et al., 2002).
The following histological and histopathological
phenomena may be found in the neurohypophysis (for
some reviews, see also Kovacs, 1984; Treip, 1992;
Horvath et al., 1997, 2000). Basophilic corticotropin
(ACTH) and beta-melanotropin (MSH)-containing cell
invasion (Osamura and Watanabe, 1978; Horvath et al.,
2000) is generally not present before the age of 20 years
and does not occur before puberty. This phenomenon is
frequently (in 30%) seen in older subjects, especially in
aging men. ACTH and -endorphin (or pro-opiomelanocortin) cell hyperplasia occurs in 29% of men and
14% of women. Eighty percent of the male and 77% of
the female subjects with this hyperplasia were over 50
years of age (Horvath et al., 1999). These cells are generally not related to any endocrine abnormality (Sheehan
and Kovacs, 1982; Sano et al., 1993; Horvath et al., 1999).
Although some authors consider these cells to be one of
the possible origins of basophil pituitary adenomas, in
the literature only two cases of basophil adenomas in the
posterior lobe have indeed been recorded (Kuebber et al.,
1990). In addition, a gangliocytoma (Chapter 19.3c)
containing ACTH-producing cells and inducing Cushings
syndrome has been found in the neurohypophysis (Geddes
et al., 2000).
Glandular structures (Rasmussen, 1933), i.e. ectopic
salivary gland tissue resembling serous acinar and duct
cells (Schochet et al., 1974; Osamura and Watanabe,
1978; Horvath et al., 1997) and lymphocytic foci are
common incidental findings in the posterior lobe or stalk
without clinical consequences, but they are sometimes
found in septicemia.
The commonest finding in the infundibular stem and
process is acute hemorrhage, often petechial, but sometimes large enough to cause appreciable damage to the
infundibular process. Necrosis within the infundibular
process itself is very rare. Hemorrhages and necroses may
be associated with postpartum necrosis of the anterior
pituitary, increased cranial pressure, shock, disseminated
intravascular coagulation, septicemia and various hematological disorders. Traumatic brain injuries such as a
gunshot wound may damage the pituitary stalk,
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insipidus (Alaca et al., 2002). Accumulation of neurosecretory material and retraction bulbs are evidence of
ruptured axons. In case of thrombotic thrombocytopenic
purpura, vessels in the neural lobe may contain hyaline
thrombi. Agonal thrombi may also be seen in the vessels
of the infundibular stem. Chronic changes following
lesions are atrophy and loss of pituicytes. Hemosiderin
deposition may be found in longstanding cases and can
appear within 8 days of injury (Chapter 25.4).
Chronic inflammation with infiltration of lymphocytes,
predominantly of the T-cell and CD4+ type, and plasma
cells are found in cases of lymphocytic infundibuloneurohypophysitis and may cause diabetes insipidus.
This disorder mainly occurs in women and most often
in the later stages of pregnancy. It is characterized by
thickening of the pituitary stalk, enlargement of the neurohypophysis, absence of the hyperintense MRI signal of
the posterior pituitary, diabetes insipidus, visual
disturbances and anterior pituitary deficiencies, while
sometimes a large mass may involve the hypothalamus,
infundibulum, optic nerves, chiasm and tracts (Kamel
et al., 1998; Maghnie et al., 1998b; Tubridy et al., 2001;
Ouma and Farrell, 2002; see Chapter 22.2b).
An autoimmune-mediated process is presumed and
the disorder may respond to corticosteroids (Ouma
and Farrell, 2002). Panhypopituitarism and diplopia,
secondary to fourth nerve palsy, have been described.
Fibrosis following infections may also be found in the
neurohypophysis.
Cystic changes in the infundibular process have been
described, as well as squamous keratin positive cell nests
(Asa et al., 1981), which are frequently found in the
pituitary stalk.
Hypovolemic shock of the mother at the time of
delivery may not only cause pituitary necrosis, but
also affect the tuber cinereum, pituitary stalk, SON and
PVN. Hypopituitarism of pregnancy may be accompanied by diabetes insipidus of sudden onset following
severe postpartum hemorrhage. However, true diabetes
insipidus is rare in Sheehans syndrome, and lesions may
be present in the posterior lobe without corresponding
clinical symptoms. In fact, 50% of the Sheehans
syndrome patients did not get diabetes insipidus for more
than 30 years after the causative event (Otsuka et al.,
1998). Probably the amount of damage to the SON and
PVN will determine whether or not diabetes insipidus
will occur in Sheehansyndrome, but other factors are
certainly not excluded (Sheehan and Kovacs, 1982).
Indeed, in some cases of postpartem hypopituitarism,

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considerable degeneration in the SON and PVN has


been reported. The estimated numbers of remaining
SON neurons was often only some 2025%. The
accessory SON may also disappear. The PVN is sometimes as strongly affected as the SON, but sometimes
retains its normal neuronal values. In addition, nearly all
cases had petechial hemorrhages in the hypothalamus,
apparently related to the terminal coma (Whitehead,
1963).
Granulomas may be present on the basis of tuberculosis
(see Chapter 20.1), neurosarcoidosis (Loh et al., 1997;
see Chapter 21.1), syphylis, a small-vessel vasculitis such
as Wegeners granulomatosis (Woywodt et al., 2000;
Chapter 22.2) or granulomatous hypophysitis, histologically characterized by infiltration of multinucleated giant
cells, plasma cells and lymphocytes (Fujiwara et al.,
2001). The neurohypophysis is also frequently involved
in histiocytosis. Diabetes insipidus may be an early sign
of this disease (Catalina et al., 1995). On MR images a
thickened stalk may be seen as expression of preclinical
histiocytosis (Zucchini et al., 1995; see Chapter 21.3).
Numerous eosinophilic leukocytes and lipid-laden foamy
macrophages may be present or fibrosis may prevail.
ErdheimChester disease is probably a distinct form of
histiocytosis (Tritos et al., 1998a).
Granular cell tumors (termed choristomas by
Sternberg in 1921, and granular cell myoblastomas or
tumorettes by Shanklin in 1947) are the most common
primary neurohypophysial tumors. The term choristoma
is confusing, as it is also used for the unrelated neuronal
choristomas or gangliocytomas or ectopic ganglion cells
(see Chapter 19.3c). They occur in some 517% of
pituitaries (Sano et al., 1993; Fig. 19.16). Granular cell
tumors are a special form of glioma (Chapter 19.4c) that
are found after the second decade in some 6% of the
pituitary glands (Luse and Kernohan, 1955). They consist
of large cells with granular, lightly eosinophylic cytoplasm (Fig. 22.1). They are mostly small, 12 mm
or even smaller, and are not evident from a glancing
inspection. They grow slowly, are histologically benign,
well demarcated, but unencapsulated. The majority
remain asymptomatic. In those rare cases where granule cell tumors are symptomatic, they may cause
diabetes insipidus, hypopituitarism, visual impairment or
headache (Symon et al., 1971; Massie, 1979; Barrande
et al., 1995; Ji et al., 1995) (see Chapter 19.4c). A
case has been described of a granular cell tumor of the
neurohypophysis that most probably causes acromegaly.
The presumed growth hormone-releasing hormone-like
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compound has, however, not been identified in the tumor


(Losa et al., 2000). Histologically, granular cell tumors
are composed of large, spherical, oval or polygonal cells
with eccentrically located nuclei and abundant acidophilic
cytoplasm, containing PAS positive neuramic acid and
carbohydrate-containing granula that appear to be lysosomes under the electron microscope (EM). The brown
cytoplasmatic granules (Fig. 22.1) may be sufficiently
numerous to import a brown pigmented appearance to
the tumor (Massie, 1979). The cells are presumed to originate from pituicytes (Luse and Kernohan, 1955; Jenevein,
1964; Massie, 1979; Mller et al., 1980; Horvath et al.,
1997). Granular cell tumors label with lectin, S-100, and
not with neuron-specific enolase, myelin basic protein,
vimentin, keratin or desmin, but mostly not with GFAP.
Some showed reactivity, however, for -1-antitrypsin, 1-antichymotrypsin and cathepsin B. The latter marker
suggests a lysosomal disorder. The fact that GFAP does
not usually label the tumors does not support the pituicyte as a progenitor of granular cell tumors, but it does
not exclude this possibility either (Nishioka et al., 1991;
Losa et al., 2000). Indeed, Barrande et al. (1995) and
Lafitte et al. (1994) have both reported a granular cell
tumor to be positive for GFAP.
Metastatic carcinomas in the posterior pituitary
constitute the most important neoplasms. They may be
derived from, e.g. carcinomas of the bronchus, breast,
colon or prostate, or from malignant melanoma, sarcomas,
lymphoma, Hodgkins disease or leukemia, and may
give rise to diabetes insipidus (Schubiger and Haller,
1992; Ten Bokkel Huinink et al., 2000) (see Chapter
19.9).
Only seldom are other neoplasms found in the
neurohypophysis, i.e. gliomas, pituitary astrocytomas
or pituicytomas, which may be derived from pituicytes.
Immunocytochemically they may be positive for GFAP,
vementin and epithelial membrane antigen. The presence
of intermediate filaments in a concentric way (fibrous
body), and secretory granules in one case, suggested
the possibility that the tumor might also arise from
folliculostellate cells of the adenohypophysis (Cenacchi
et al., 2001). MRI scans show extension of the tumor
into the pituitary stalk. Panhypopituitarism may be an
early manifestation of this tumor, while diabetes insipidus
may be absent, suggesting vasopressin release to take
place above the level of the tumor (Nishizawa et al.,
1997). In addition, gangliogliomas, hamartomas (Chapter
19.3; Fig. 19.9), epidermoids, suprasellar germinomas
(Chapter 19.2), craniopharyngiomas (Chapter 19.5) and

lipomas have been reported (Hurley et al., 1994).


Gangliocytoma or ectopic ganglion cells of the neurohypophysis have been described that produce vasopressin
(Fehn et al., 1998; Horvath et al., 2000; Chapter 22.6),
ACTH (Geddes et al., 2000) or -endorphin (Horvath et
al., 2000). It is not clear whether they should be considered the result of abnormal migration during embryonic
life, differentiation/maturation of neuroblasts, or transdifferentiation from proliferating pars intermedia cells
(Horvath et al., 2000). Germinomas of the neurohypophysis and median eminence may cause diabetes
insipidus, multiple deficiencies of the anterior pituitary
compression of the optic chiasm and hypothalamus. This
tumor can develop simultaneously with a similar tumor
in the pineal region (Saeki et al., 1999). The first abnormal
MRI sign in cases of germinoma in children and adolescents is pituitary stalk thickening (Mootha et al., 1997).
Two cases of a meningioma of the pituitary stalk has
been described that must have originated from the arachnoid membrane, since it had no dura attachment (Hayashi
et al., 1997; Beems et al., 1999). Neoplasms of the
infundibulum are described under various names, i.e.
infundibuloma, hamartoma, glioma or astrocytoma (see
Chapter 19.4). Extremely rare is a pituitary adenoma
located entirely outside the sella turcica arising from the
pars tuberalis, causing visual disturbance (Hamada et al.,
1990).
An early stage of cytoskeletal alterations as revealed
by antibodies against abnormally phosphorylated tau (e.g.
AT8, PHF-1 or Alz-50) are found in fibers and Herring
body-like swellings in some aged patients, even if the
brain is devoid of Alzheimer changes. Such changes are
hardly detectable with sensitive silver methods. The relationship of these early Alzheimer changes in the
neurohypophysis, and those in the SON, PVN and the
rest of the brain, should be further investigated. In addition, the functional implications of these cytoskeletal
changes are not yet clear (Schultz et al., 1997).
For stalk sectioning lesions, see Chapters 18.4, 18.6
and 25.4. The pituitary stalk may also be absent, because
it was never formed in development (e.g. Den Ouden et
al., 2002; Chapters 18.4, 18.6). A thin or invisible pituitary stalk on MR images may be found in children with
prenatal or perinatal-onset hypothalamic hypopituitarism
who gradually develop growth hormone and ACTH deficiency (Miyamoto et al., 2001). A very thin stalk ending
in a neurohypophysis without the normal MRI hypertensisity (see below) was found in a child with a persistent
large craniopharyngeal canal and an enlarged empty sella

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Fig. 22.1. Cells of a granular cell tumor in the neurohypophysis. Note the brown-pigmented cytoplasmic granules (NHB 92-001).
Bar = 100 m.

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turcica filled with CSF (Ekinci et al., 2003). A thickened


pituitary stalk on MR images may indicate the presence
of Langerhans histiocytosis (Czernichow et al., 2000;
Chapter 21.3), lymphocytic hypophysitis (Iglesias and
Dez, 2000; Chapter 22.2b), lymphocytic infundibuloneurohypophysitis (Takahashi et al., 1999; Chapter
22.2b), a germinoma (Leger et al., 1999; Czernichow et
al., 2000; Chapter 19.2) or a hypophyseal tuberculoma
(Sinha et al., 2000; Pramo et al., 2002).
Pathological states of the neurohypophysis may be
reflected in a disappearance of the MRI high-intensity
signal of the posterior pituitary that is normally present
in 90% of subjects (Brooks et al., 1989; Tien et al., 1991).
This MRI signal was first thought to be caused by fat
within the sella turcica. The source of the hyperintense
MRI signal is now presumed to be the neurosecretory
granules containing vasopressin (Fujisawa et al., 1989),
but no attention has been paid so far to the contribution
of oxytocin-containing granules. It should also be noted
that, in the case of persistent elevation of vasopressin
plasma levels as found in diabetes mellitus and hemodialysis, the hyperintense MRI signal in the neurohypophysis
may be decreased, possibly due to depletion of vasopressin storage. When treating for hyperglycemia, plasma
levels of vasopressin promptly decrease and the hyperintense MRI signal reappears within 12 months (Sato et
al., 1995; Fujisawa et al., 1996; Chapter 22.5; Fig. 22.1).
The high intensity MRI signal is frequently absent in case
of macroadenoma of the anterior pituitary, craniopharyngioma, traumatic stalk transsection, patients with
empty sella syndrome and diabetes insipidus. In both
primary central diabetes insipidus (Chapter 22.2a) and
secondary diabetes insipidus due to, e.g. germinoma,
teratoma (Mootha et al., 1997; Chapter 19.2), Wolframs
syndrome (see Chapter 22.7) or histiocytosis-x, the
normal high-intensity MRI signal was not detected. In
some patients with macroadenomas, a small, high signal
intensity region was seen above the pituitary gland
without any high intensity from within the gland itself
(Colombo et al., 1987; Fujisawa et al., 1987b), suggesting
the presence of a newly formed miniature-posterior lobe
above the level of the neurohypophysis. The presence of
a high-intensity MRI signal on the pituitary adenoma
surface in the case of a supradiaphragmatic extension
is supposed to be due to blockage of the hypothalamoneurohypophysial fibers, with an accumulation of
neurosecretory granules. It generally predicts functional
integrity after removal of the large pituitary adenoma
(Salehi et al., 2002).

22.2. Diabetes insipidus


The brain secretes thoughts as the kidney secretes urine
(Jakob Moleschott,18221893)

Diabetes insipidus was distinguished from diabetes


mellitus in 1674 by the English physician Thomas Willis
(for references see Sawin, 2000). Diabetes insipidus is
characterized clinically by polyuria (defined as the
passage of amounts of diluted urine in excess of 2 l/m2
per 24 h or approximately 40 ml/kg per 24 h) in older
children or adults) and polydipsia, and biochemically by
inappropriately diluted urine in the face of rising plasma
osmolality. Diabetes insipidus may be due to vasopressin
deficiency in familial central diabetes insipidus, to a defect
in the mechanism of kidney receptors for vasopressin, or
to mutations in the vasopressin-regulated water channel
of the renal collecting duct aquaporin-2 (Deen et al., 2000,
Chapter in nephrogenic diabetes insipidus; Fig. 1.14) or
to primary polydipsia (Chapter 22.3). Approximately 3%
of the aquaporin-2 in collecting ducts is excreted into
urine, and the urinary excretion of this water channel
protein correlates positively with plasma vasopressin
levels (Ishikawa, 2000). The simultaneous measurement
of plasma vasopressin and plasma osmolality in a dehydration test is the most powerful diagnostic tool in the
differential diagnosis of diabetes insipidus and primary
polydipsia (Diederich et al., 2001). Thirst is the most
prominent symptom of hypothalamic diabetes insipidus
and is the necessary stimulus to replace urinary losses.
The mechanism of regulation of thirst is normal in the
vast majority of patients with central diabetes insipidus.
On the other hand, the combination of diabetes insipidus
and hypodipsia has also been described in association
with surgery to the anterior communicating artery
aneurysms, head injury, tumors, sarcoidosis, hydrocephalus and toluene exposure. Since patients with adipsia
and vasopressin deficiency in response to osmotic stimuli
may have entirely normal vasopressin responses to nonosmotic stimuli, such as hypotension and apomorphine, the
site of the lesion in these patients seems to be the osmoreceptor (Bayliss and Cheethan, 1998; McKenna and
Thompson, 1998). Central diabetes insipidus with thickened pituitary stalk on MR images may indicate the
presence of Langerhans histiocytosis (Chapter 21.3)
or germinoma (Leger et al., 1999; Chapter 19.2). The
old treatment, pitressin in oil, given intramuscularly,
was effective for 24 h, but the injection was often painful. Desmopressin (1-desamino-8-arginine vasopressin,

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DDAVP), however, does not have the pressor effect


as seen with pitressin and lysine vasopressin (LVP)
treatment and is effective when given as a nasal
spray twice daily. DDAVP is now also available in
tablet form. Patients with central diabetes insipidus
have an increased heart rate, left ventricular contractility
and impaired diastolic function. These alterations, which
can be reversed by DDAVP, are probably due to
stimulation of the sympathetic nervous activity induced
by hypovolemia. In children with diabetes insipidus, the
incidence of complications of DDAVP treatment is
high, especially in those that are cortisol-deficient or
treated with carbamazepine also. Children may develop
water intoxication with seizures, as well as asymptomatic
hyponatremia, and may even die (Rizzo et al., 2001).
The normal high MRI signal of the posterior lobe is
generally not detected in familial diabetes insipidus
and secondary diabetes insipidus, e.g. due to germinomas,
teratomas, Langerhans cell histiocytosis, or Wolframs
syndrome (Fujisawa et al., 1987b; Tien et al., 1991;
Rutishauser et al. 1996; Maghnie et al., 2000; Flck
et al., 2001; see Chapter 21.3, 22.1, 22.7), although
there seem to be exceptions to this rule (Miyamoto,
1991; Maghnie et al., 1992; Hansen et al., 1997). Increased
release due to persistent elevation of plasma vasopressin
levels, as found in diabetes mellitus (Chapter 22.5), may
also accompany a decreased MRI signal intensity of the
neurohypophysis (Fujisawa et al., 1996). The source of
the hyperintense MRI signal of the posterior pituitary is
most probably the neurosecretory granules that contain
vasopressin (Fujisawa et al., 1989), although the contribution of oxytocin and its precursor to the bright spot is
not known. The presence of a bright spot in diabetes
insipidus seems to depend on the type of mutation, the
turnover of neuropeptides in the neurohypophysis and
possibly also the amount of oxytocin that is present.

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substitution therapy with exogenous vasopressin or


analogues. Urine production may amount to some 20
l/day. The urinary excretion of the renal collecting duct
water channel aquaporin-2 in central diabetes insipidus
is one-eighth of that of controls (Ishikawa et al., 2000).
Most mutations are presumed to impair the folding and
intracellular trafficking of the preprohormone for vasopressin. In the long run, the mutant precursor seems to
be toxic for the neuroendocrine neurons. As an example
of the autosomal dominant form of familial diabetes
insipidus, members of a Dutch family may be mentioned,
who appeared to have a point mutation in one allele of
the affected gene, based upon a G to T transversion
at position 17 of the neurophysin encoding exon B on
chromosome 20p13 (Bahnsen et al. 1992; Fig. 22.2b).
Some 40 different mutations have now been found in
kindreds with familial hypothalamic diabetes insipidus
(Fig. 22.3), including six mutations in the part that
encodes the signal peptide, and the rest, in different loci
in the neurophysin II moiety, i.e. in exon 1 or 2, including
two in vasopressin itself, five nonsense mutations (premature stopcodons) in exon 2 or 3, and one trinucleotide
deletion in exon 2 (Ito et al., 1991; Miller, 1993; Yuasa
et al., 1993; Nagasaki et al., 1995; Rittig et al., 1996;
2002; Hansen et al., 1997; Grant et al., 1998; Heppner
et al., 1998; Calvo et al., 1999; Rutishauser et al., 1999;
Siggaard et al., 1999; Abbes et al., 2000; Fuji et al., 2000;
Skordis et al., 2000; Flck et al., 2001; Nijenhuis et al.,
2001; Boson et al., 2003). All the dominant mutations
contrast with the recessive mutation in vasopressin itself.
The mutated form of vasopressin is a weak agonist
with approximately 30-fold reduced binding to the vasopressin receptor (V2) (Willants et al., 1999). A familial
autosomal dominant form of neurohypophysial diabetes
was also described that is based upon a missense mutation encoding the vasopressin moiety, leading to a
substitution of histidine for tyrosine at position 2 in vasopressin. The pituitary bright spot on MR images was
absent. The polyuria and polydipsia started between the
ages of 6 months and 3 years in this family (Rittig et al.,
2002).
The few available postmortem histological observations in families with hereditary hypothalamic diabetes
insipidus point to severe neuronal death in the SON and
PVN, associated with a loss of nerve fibers in the posterior pituitary (Hanhart, 1940; Braverman et al. 1965;
Green et al., 1967; for the mutation of this kind, see
Bergeron et al. 1991; Mahoney et al., 2002; Fig. 22.4),
suggesting that the mutated product might be toxic to the

(a) Familial central diabetes insipidus


Familial hypothalamic diabetes insipidus is transmitted
as an autosomal dominant or X-linked recessive disorder
(Fig. 22.2a). The gene responsible for the X-linked form
of diabetes insipidus has not yet been cloned (Hansen
et al., 1997).
Familial central diabetes insipidus is a rare disease that
accounts for about 5% of all cases of diabetes insipidus
(Bayliss and Cheetham, 1998). Affected individuals have
low or undetectable levels of circulating vasopressin and
suffer from polydipsia and polyuria, and they respond to
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Fig. 22.2. (a) Pedigree of a Dutch family with hereditary hypothalamic diabetes insipidus, comprising five generations. Black symbols denote
affected individuals, women are indicated by circles and men by squares. Samples were available from individuals marked by arrows. (From
Bahnsen et al., 1992, Fig. 1 with permission.) (b) DNA sequencing gel, demonstrating the difference in exon B between the normal and the mutated
vasopressin-neurophysin gene allele of the individual IV-3. The missense mutation G-T is indicated by arrows. Numbering of the deduced amino
acid sequence corresponds to human neurophysin. (From Bahnsen et al., 1992, Fig. 2 with permission.)

neurosecretory cell. Slowly acting toxicity would also


explain the variable age at onset of the disease (Schmale
et al., 1993); we observed that diabetes insipidus may not
strike until an individual reaches the age of approximately
89 years (Bahnsen et al., 1992). Other observations, too,
indicate that vasopressin secretion is normal for the first
few years of life, or even up to school age, and that
diabetes insipidus then develops rapidly, after which it
may continue to aggravate slowly for a decade or more
(McLeod et al., 1993; Hansen et al., 1997; Grant et al.,
1998; Siggaard et al., 1999; Mahoney et al., 2002). Family
members with a mutation in vasopressin replacing Pro7

of mature vasopressin with Leu were asymptomatic


for at least the first year of life, although no normal
vasopressin was produced. Leu-vasopressin had apparently sufficient in vivo activity to delay the symptoms.
As for the claim of Mahoney et al. (2002), that in
autosomal dominant central diabetes insipidus the magnocellular vasopressin neurons are lost, but the parvocellular
neurons that supply vasopressin and corticotropinreleasing hormone (CRH) to the median eminence
are preserved, no direct postmortem evidence is available
with double staining. Also, Bergeron et al. (1991)
presumes that the smaller vasopressin neurons that are

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Fig. 22.3. Schematic diagram of the coding regions of the arginine vasopressinneurophysin II (AVP-NPII) gene and the primary structure of the
preprohormone, showing the location and type of mutations identified in familial hypothalamic diabetes insipidus. (From Rittig et al., 1996, Fig.
1 with permission.)

neurosecretory cells in the various types of familial


diabetes insipidus.
When the mutant of the Dutch kindred was stably
expressed in a mouse pituitary cell line, the mutant
precursor was synthesized, but processing and secretion
were dramatically reduced and the protein did not seem
to reach the trans-Golgi network (Olias et al., 1996).
Studies in which various other human mutant vasopressin
precursors were expressed in cell lines also showed an
accumulation of the mutated vasopressin precursor in the
endoplasmic reticulum, a reduced viability of the cells
(Ito et al., 1997; Nijenhuis et al., 2001) and a reduced
vasopressin expression (Iwasaki et al., 2000). Mutant
vasopressin precursors do not fold correctly and probably
cannot be processed and routed normally so that they do
not move from the endoplasmic reticulum to the Golgi
apparatus and neurosecretory granules. By mis-sorting,
the mutations interfere with the expression of the normal
allele, explaining the dominant nature of the disease. It
has been shown in cell culture that the mutant precursor
accumulates in the endoplasmic reticulum. Homo- and

preserved may project to nonpituitary targets. However,


these smaller neurons may well be degenerating neurons,
and there is no proof that these neurons do or do not
project to the neurohypophysis.
The onset of the symptoms and the severity of the
polyuria vary considerably within the families. One
missense mutation in neurophysin (1665T>G) is associated with early-onset diabetes insipidus. One index case
developed the symptoms at 1 month of age (DiMeglio et
al., 2001). On the other hand, in a postmortem case of a
44-year-old man with hereditary diabetes insipidus, no
clear cell death was found in the SON and PVN, but
immunocytochemically the neurons hardly stained for
vasopressin in the PVN (Nagai et al., 1984), which indicated very late degeneration of the vasopressin neurons.
One can perhaps consider this as an early phase of degeneration, although the history and several hormonal
functions were atypical in these patients (Hansen et al.,
1997). More systematic data from age-related studies and
postmortem observations using quantitative methods are
needed in order to establish the natural history of the
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Fig. 22.4. Supraoptic nucleus (SON), medial portion. Severe loss of vasopressin-expressing (VP) neurons in hereditary diabetes insipidus (b, d) as
compared to age-matched control (a, c), with only rare immunoreactive cells (arrows). Slight gliosis and attenuation of the capillary network is
also evident (d). VP immunostain; a, b  80, c, d  250. (From Bergeron et al., 1991, Fig. 2 with permission.)

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heterodimer formation between wild-type and mutant


precursor formation occurs and impairs intracellular
trafficking of wild-type precursor from the endoplasmic
reticulum to the Golgi apparatus, and may interfere with
the production of other proteins that are essential for
survival of the neurons. The mutant proteins accumulate
in the endoplasmic reticulum and aggregates will form
that also contain the wild-type molecules, resulting in the
activation of a general degradation system, autophagy,
resulting in vasopressin deficiency (Sinha et al., 2000).
The swollen autophagic vesicles contain cathepsin D (a
lysosomal protease), endolin (a marker for late endosomes) and lysosomal-associated membrane protein-1,
suggesting that they may be degradative autolysosomes,
as shown in transgenic rats that express a Japanese mutant
vasopressin gene (Davies and Murphy, 2002). The facts
that most mutations do not affect the vasopressin moiety
itself and the slow development of the misfolding neurotoxicity is the mechanism (Eubanks et al., 2001;
Nijenhuis et al., 2001) that causes the neurosecretory
neurons in hereditary hypothalamic diabetes insipidus to
degenerate seem to explain why children do not develop
diabetes insipidus until later, and why in adulthood degeneration of vasopressin neurons is found. However, the
premature 87STOP mutation may have a different pathogenetic mechanism (Eubanks et al., 2001).
Central diabetes insipidus is associated with increased
baseline ACTH and cortisol secretion, and increased
responsiveness of these two hormones to CRH administration. Replacement with DDAVP completely normalizes
the ACTH and cortisol response to CRH, but not the
baseline secretion of ACTH and cortisol (Pivonello et al.,
2002).

135

the vasopressin cell bodies (Scherbaum, 1992), but ultimately their presence seems to go together with partial
or complete diabetes insipidus (De Bellis et al., 1994,
2002). A longitudinal study of patients with endocrine
autoiommune diseases but without overt diabetes
insipidus showed that the clinical phase can be preceded
by a long subclinical period characterized by antibodies
against vasopressin cells without impairing the posterior
lobe function. However, the presence of such antibodies
indicates a high risk of developing overt diabetes
insipidus. The hyperintense MRI signal of the posterior
pituitary can persist even in the early phase of the development of diabetes insipidus and only disappear later.
Consequently, this is not a useful tool for the prediction
of the progression of autoimmune diabetes insipidus
(De Bellis et al., 1999, 2002). The pituitary stalk is
often thickened on MR images (Maghnie et al., 2000; De
Bellis et al., 2002; Pivonello et al., 2003). Interestingly,
DDAVP treatment of patients with partial central diabetes
insipidus for 1 year showed recovery of posterior lobe
function and disappearance of the antibodies against
vasopressin cells. These results are in line with the
isohormonal therapy given in preclinical stages in some
other endocrine autoimmune diseases (De Bellis et al.,
1999). Infundibulohypophysitis usually presents with
diabetes insipidus and is often associated with disturbances of vision (Tubridy et al., 2001; Ouma and Farrell,
2002). The infiltrate is predominantly composed of
lymphocytes and plasma cells and may involve the hypothalamus, infundibulum, optic nerves, chiasm and tracts.
A dramatic improvement may take place following
administration of corticosteroids (Ouma and Farrell,
2002). Patients with lymphocytic infundibuloneurohypophysitis presenting as diabetes insipidus may have
autoantibodies to vasopressin and on MR images show a
normal pituitary with a focal nodular thickening of the
infundibulum, stalk thickening, and lack of hyperintense
signal of the normal neurohypophysis (De Bellis et al.,
2002). In fact, most patients with idiopathic central
diabetes insipidus have lymphocytic neurohypophysitis
(Pivonello et al., 2003).
Apart from diabetes insipidus, loss of hyperintense
posterior lobe signal and thickened pituitary stalk,
lymphocytic hypophysitis can also manifest itself with
anterior pituitary disorders. Some 90% of cases with
lymphocytic hypophysitis are female and at least 65%
are associated with pregnancy. Sixty percent of cases have
symptoms such as headache and visual defect, and 40%
have hyperprolactinemia with functional involvement of

(b) Autoimmune diabetes insipidus


Idiopathic diabetes insipidus is associated with autoimmunity in one third of the cases. Indeed, autoantibodies
against the vasopressin-cell surfaces have been found
(Fig. 22.5). Autoimmune central diabetes insipidus is very
likely in young patients with a clinical history of autoimmune diseases and radiological evidence of pituitary stalk
thickening (Scherbaum, 1992; De Bellis et al., 1999,
2002; Pivonello et al., 2003). Conversely, the low titer
autoantibodies in patients with non-idiopathic central
diabetes insipidus probably represents an epiphenomenon.
Autoantibodies are never found in familial central
diabetes insipidus (Pivonello et al., 2003). It has not yet
been established whether the autoantibodies observed in
diabetes insipidus are indeed cytotoxic and might destroy
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Fig. 22.5. (a) Autoantibodies to hypothalamic vasopressin cells. An unfixed 7-m cryostat section of human hypothalamus at the level of the
supraoptic nucleus (SON) was incubated with native serum from a patient with idiopathic hypothalamic diabetes insipidus and stained with FITClabeled anti-human IgG. Note that the cytoplasm of large cells is stained. It is shown by the four-layer, double-fluorochrome immunofluorescence
test with antivasopressin in the second sandwich that vasopressin cells were stained ( 250). (b) The same area of the SON as in (a) incubated
with normal human serum and FITC-labeled polyvalent anti-human immunoglobulin. Note that the background is brighter than the dark neurosecretory cell bodies ( 400). (c) The same area of the SON as in (a) incubated with the serum of a patient with systemic lupus erythematosus
containing the rare anti-ribosomal antibodies visualized by FITC-labeled anti-human IgG, which may, in very rare cases disturb the detection of
vasopressin-cell antibodies. Note the coarsely granulated cytoplasmic staining of the two large cell bodies ( 400). (d) Cryostat section (7 m) of
human hypothalamus at the level of the SON. The specimen was obtained from a donor aged 50 years. The section was incubated with normal
human serum and FITC-labeled polyvalent anti-human immunoglobulin. The autofluorescent lipofuscin deposits in the cell bodies of large
neurosecretory cells hamper the evaluation of test results ( 250). (From Scherbaum, 1992, Fig. 1 with permission.)

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the anterior pituitary (Iglesias and Dez, 2000; Tubridy


et al., 2001).
Stereotactic biopsies of the neurohypophysis or pituitary stalk revealed chronic inflammation with infiltration
lymphocytes predominantly of the CD4+ subpopulation
and plasma cells. The natural course of the lymphocytic
infundibuloneurohypophysitis generally seems to be selflimited, but glucocorticoid therapy has been given to
reduce intracranial hypertension. This therapy is presumed
to contribute to the reduction of the mass, although proof
of such an effect is lacking (Imura et al., 1993; Koshiyama
et al., 1994; Paja et al., 1994; Chico et al., 1998; Kamel
et al., 1998; Maghnie et al., 1998a).
Specific subtypes of the major histocompatibility
complex (MHC), the human leukocyte antigens (HLA),
can be correlated with this disease and other autoimmune
endocrine disorders. The differential diagnosis of a
thickened pituitary infundibulum includes sarcoidosis,
tuberculosis, germinoma, infiltrations from pituitary
adenoma, hypothalamic glioma or teratoma, and mass
lesions such as craniopharyngioma, Rathkes pouch cyst,
tumor of the pituitary infundibulum, metastases, and
Langerhans cell histiocytosis (Kamel et al., 1998). In
fact, autoimmunity to vasopressin-producing cells may be
present in a large percentage of patients with central
diabetes insipidus associated with Langerhans cell histiocytosis (Pivonello et al., 2003). An 8-year-old child who
presented with acute-onset diabetes insipidus followed by
an acquired growth hormone deficiency had an enlarged
pituitary stalk and absence of posterior pituitary hyperintensity as shown by MRI. At the age of 15 years,
a large hypothalamic mass and panhypopituitarism
ere found. The perivascular inflammatory lymphocytic
infiltrates suggested the presence of a lymphocytic
infundibuloneurohypophysitis that reacted favorably to
glucocorticoids (Maghnie et al., 1998a). Transient
diabetes insipidus associated with lymphocytic infundibuloneurohypophysitis and a thickened pituitary stalk shown
on MR images has also been described in a 77-year-old
woman (Takahashi et al., 1999). A case of diabetes
insipidus caused by nonspecific chronic inflammation of
the hypothalamus was reported that had acute multifocal
placoid pigment epitheliopathy with an immunogenic
predisposition as well as HLA class I antigen A2 and
class II antigen DR4, which might also be a case of
autoimmune reaction (Watanabe et al., 1994).
Cases with necrotizing infundibulohypophysitis and a
combination of diabetes insipidus and hypopituitarism
have been described. It is possible that this disorder, as

137

described by Ahmed et al. (1993), represents an end stage


of lymphocytic infundibulitis, but alternatively it may be
a unique syndrome. Wegeners granulomatosis is a
systematic necrotisizing vasculitis with neurological
symptoms in some 50% of cases. Antineutrophil cytoplasmic antibodies are present. A few cases have been
described in which the disease remained confined to the
anterior and posterior pituitary, causing hypopituitarism
and diabetes insipidus. The patients did not respond to
immunosuppressive therapy with cyclophosphamide, but
in some patients corticosteroids gave a clinical remission
(Rosete et al., 1991; Roberts et al., 1995; Berthier et al.,
2000; Woywodt et al., 2000). Transient diabetes insipidus
has also been described in GuillainBarr syndrome
(Pessin, 1972). It should also be mentioned that iatrogenic antibodies may be raised by treatment with
vasopressin, making the patients refractory to treatment
with vasopressin and causing diabetes insipidus (Bisset
et al., 1976).
On the basis of the limited literature on autoimmune
diabetes insipidus, it seems certainly worthwhile to
look for autoimmune processes that may be directed
toward other hypothalamic neurons and might be an
explanation for hypothalamic symptoms in other neurological, psychiatric or neuroendocrine diseases (see, e.g.
idiopathic hypothalamic dysfunction syndrome of childhood (Chapter 19.1; 32.1), adipsia (Chapter 22.3),
anorexia and bulimia nervosa (Fetissov et al., 2002;
Chapter 23.2), obsessive-compulsive disorder (Chapter
26.6), KleineLevin syndrome (Chapter 28.1) and
narcolepsy (Chapter 28.4).
(c) Pregnancy-induced diabetes insipidus
During pregnancy a transient form of diabetes insipidus
sometimes occurs. The central form may respond to
DDAVP but not to vasopressin, because the vasopressin
analogue is much less susceptible to degradation to placental vasopressinase (Hansen et al., 1997). Vasopressinase
during pregnancy is the same enzyme as cystine-aminopeptidase or oxytocinase. It may, at least partly, be
responsible for the fact that the metabolic clearance of
vasopressin during pregnancy increases fourfold. The
enzyme decreases to undetectable levels in several days
postpartum. Cases have been described with a transient diabetes insipidus during pregnancy due to extraordinarily
high plasma vasopressinase activity. However, a more
likely cause of polydipsia and polyuria during pregnancy
is the unmasking of subclinical forms of either central
or nephrogenic diabetes insipidus (see Chapter 22.2e).
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Apart from the presence of vasopressinase, a decreased


threshold for thirst contributes to the aggravation of diabetes insipidus. When, during pregnancy, thirst increases,
more water is consumed and the urine volume becomes
unacceptable. The lowering of the thirst threshold is accompanied by a similar lowering of the osmotic threshold for
the release of vasopressin. The result is that pregnant
women drink more water, which may subsequently be
retained. The exact mechanism for the altered osmoregulation in pregnancy is obscure, but the combination of
changes in water homeostasis and vasopressin metabolism
that occurs in normal pregnancy seems to provide an explanation for the transient expression of diabetes insipidus in
pregnant women, especially in the case of latent forms of
neurogenic or nephrogenic diabetes insipidus (Durr et al.,
1987; Iwasaki et al., 1991; Robinson and Amico, 1991;
Treip, 1992; Williams et al., 1993; Van der Post et al.,
1994; Lindheimer and Davison, 1995; Naruki et al., 1996).
On the other hand, a partial central diabetes insipidus, e.g.
due to an asymptomatic craniopharyngioma, should also
be considered in cases of pregnancy-induced diabetes
insipidus (Fluteau-Nadler et al., 1998). The safety of
DDAVP treatment for the child during pregnancy still
has to be established (cf. Linder et al., 1986). In case
of pregnancy-induced diabetes insipidus, the oxytocin
levels may be normal, depending on the exact cause of this
disorder (Sende et al, 1976; Shangold et al., 1983).
(d) Other causes of central diabetes insipidus
Diabetes insipidus has also been observed as part of a
midline developmental anomaly, e.g. in septo-optic
dysplasia (see Chapter 18.3), holoprosencephalic syndromes in which the development of the SON and
PVN is disturbed (Sztriha et al.,1998; Robertson, 2001;
Sarnat and Flores-Sarnat, 2001) and in dystopia of the
neurohypophysis (Chapter 18.4). Structural lesions of
the hypothalamus in children may accompany weight
gain, diabetes insipidus, osmoreceptor dysfunction
(hypernatremia with absent thirst), pituitary deficiencies
and hyperprolactinemia (Cianfarani et al., 1993). Partial
central diabetes insipidus with an elevated threshold of
thirst and enhanced renal water handling to maintain body
water was found in a woman who, as a 4-year-old child,
had had meningitis, followed by a ventriculoperitoneal
shunt operation because of normal-pressure hydrocephalus (Fukagawa et al., 2001). In addition, diabetes
insipidus can be present in hypothalamic Langerhans
cell histiocytosis (Czernichow et al., 2000; Modan-Moses
et al., 2001; Municchi et al., 2002; Chapter 21.3),

ErdheimChester disease (a distinct form of histiocytosis)


(Tritos et al., 1998a), Wolframs syndrome (Chapter
22.7) and in association with LaurenceMoon/Bardet
Beidl syndrome (Chapter 23.3), hypoxic/ischemic brain
damage, hemorrhage, infarcts, Sheehans syndrome (see
Chapter 17.2), inflammation and abscess formation
(see Chapter 20) and tumors of the hypothalamus,
including metastases (see Chapter 19), or of the pituitary.
In cases of pituitary adenomas with supradiaphragmatic
extension that lead to permanent diabetes insipidus, no
high-intensity MRI signal is observed (Saeki et al., 2002).
Following craniotomy for a pituitary tumor, a patient
developed central diabetes insipidus, with absence of
the posterior pituitary bright spot. She survived the severe
hyponatremia, but developed permanent (6 months)
disorientation to time and place, even after DDAVP
administration (Gomez-Daspet et al., 2002). Diabetes
insipidus may also be found following traumatic injuries
(Chapter 25.1) or be due to toxins (snake venom,
tetrodotoxin; Robertson, 2001) and result from surgical
manipulations affecting either the SON and PVN or,
more frequently, following sectioning of the hypothalamoneurohypophysial tract (see Chapter 25.4) and in
GuillainBarr syndrome (Treip, 1970b; Pessin, 1972;
Rudelli and Deck, 1979; Stern et al., 1985; Fujisawa et
al., 1987b; Bell, 1991; Laing et al., 1991; Arisaka et al.,
1992; Catalina et al., 1995; Bayliss and Cheetham, 1998).
Diabetes insipidus may also occur in neurosarcoidosis
(see Chapter 21.1), in idiopathic giant cell granulomatous hypophysitis, which is histologically characterized
by infiltration of multinucleated giant cells, plasma cells
and lymphocytes (Fujiwara et al., 2001), and in paraneoplastic limbic encephalitis, due, for instance, to anti-Ta
(= anti-Ma2) antibodies (Gultekin et al., 2000). Lesions
of the neurohypophysis alone may not result in diabetes
insipidus when the neurosecretory nuclei remain intact.
A syndrome of partial diabetes insipidus has been reported
in anorexia nervosa, where vasopressin seems to be
secreted erratically, independent of plasma sodium levels
(Gold et al., 1983). Although uncommon, central diabetes
insipidus may develop following spinal trauma and/or
surgery; it is thought that the sympathetic tone is then
disturbed and vascular dilation may cause a drop in blood
flow in the neurohypophysis and median eminence
(Kuzeyli et al., 2001).
(e) Nephrogenic diabetes insipidus
Nephrogenic diabetes insipidus can be inherited or
acquired. It is characterized by an inability to concentrate

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urine despite normal or elevated plasma vasopressin levels


(Barberis et al., 1998). About 9095% of patients with
nephrogenic diabetes insipidus are males with the Xlinked recessive form of the disease (OM1M 304800),
who have mutations in the vasopressin receptor-2 gene,
located on Xq28 (Van den Ouweland et al., 1992;
Birnbaumer, 2000; Morello and Bichet, 2001; Fig. 22.6).
Severe disease of this X-linked form is expressed in
hemizygous boys, whereas heterozygous girls may have
moderate expression to no symptoms at all. Sporadic cases
are frequent and they usually represent X-linked recessive nephrogenic diabetes insipidus rather than the
autosomal form (Bichet et al., 1988; Holtzman et al.,
1993; Ala et al., 1998; Deen and Knoers, 1998; Wildin
et al., 1998; Rocha et al., 1999; Wildin and Cogdell,
1999). Over 155 mutations within the vasopressin receptor
(V2) gene may cause inherited nephrogenic diabetes
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loss-of-function vasopressin receptor mutation R137H,


which is associated with familial nephrogenic diabetes
insipidus, induces constitutive arrestin-mediated desensitization. The binding of arrestins to phosphorylated
receptors mediates the agonist-dependent desensitization
and internalization of G-protein-coupled receptors. The
affinity of arrestin for the phosphorylated G-proteincoupled receptor regulates the ability of the internalized
receptor to be dephosphorylated and recycled back to the
plasma membrane. Unregulated desensitization can thus
induce nephrogenic diabetes insipidus (Barak et al., 2001).
Other vasopressin receptor mutants cause nephrogenic
diabetes insipidus by other mechanisms, e.g. by a lack
of vasopressin binding or signaling, by retention in the
endoplasmic reticulum or by a lack of binding of the
mutated receptor with the molecular chaperone calnexin
(Morello et al., 2001). A large number of vasopressin V2
receptor mutants have been identified (Arthus et al.,

Fig. 22.6. Schematic representation of the V2 receptor and identification of 155 putative disease-causing AVPR2 mutations. A solid circle indicates the location of (or the closest codon to) a mutation; a number indicates more than one mutation in the same codon. There are 78 missense
mutations, 42 frameshift mutations, 6 in-frame deletions or insertions and 3 splice site mutations. Eight large deletions and one complex mutation
are not shown. (From Morello and Bichet, 2001, Fig. 7 with permission.)

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2000), causing defects in its intracellular trafficking, its


membrane localization, ligand-binding affinity and selectivity (Albertazzi et al., 2000; Pasel et al., 2000; Postina
et al., 2000).
In less than 10% of families, nephrogenic diabetes
insipidus has an autosomal-recessive or autosomal dominant (OM1M 222000 and 125800, respectively) mode of
inheritance, caused by mutations on chromosome 12q13
in the gene of the water channel protein aquaporin-2
(Deen and Knoers, 1998; Rocha et al., 1999; Wildin and
Cogdell, 1999; Morello and Bichet, 2001; Fig. 22.7). One
mutant protein leading to the autosomal dominant form
was able to form heterotetramers with the wild-type
aquaporin-2, in contrast to the mutants found in the recessive form (Kamsteeg et al., 2000). Normally, after binding
of vasopressin to the V2 receptor, the receptor activates
the G-protein Gs that stimulate a phosphorylation
cascade, which promotes translocation of presynthesized
aquaporin-2 water channels, which are then inserted into
the apical membrane of the renal collecting duct cells
and make them permeable for water. Mutations in
the aquaporin-2 water channel makes the collecting

duct impermeable for water, as do mutations in the


V2 receptor, resulting in nephrogenic diabetes insipidus
(Fig. 8.6; Deen and Knoers, 1998; Birnbaumer, 1999;
Deen et al., 2000). With the aquaporin-2 mutants, all
cases of nephrogenic diabetes insipidus were identified,
a unique feature for a genetic disease (Birnbaumer, 2000;
Lin et al., 2002a). One mutant was studied in more
detail. The mutant protein was mainly retained in the
Golgi apparatus (Kamsteeg et al., 2000). Another mutant
in a family with dominant nephrogenic diabetes insipidus
revealed a single-nucleotide deletion in one aquaporin-2
allele. The mutated protein appeared to be localized in
the basolateral membrane and late endosomes/lysosomes,
whereas the wild-type protein was expressed in the
apical membrane. Upon coexpression, the wild-type and
mutated protein complex mistargeted to late endosomes/
lysosomes, resulting in an absence of the wild-type protein
in the apical membrane. Misrouting after heteroligomerization, rather than a lack of function, thus seems to
be the cause of nephrogenic diabetes insipidus in this
family with a deletion in the aquaporin-2 gene (Marr
et al., 2002).

Fig. 22.7. A. Schematic representation of the aquaporin-2 (AQP-2) protein and identification of 26 putative disease-causing AQP2 mutations. A
monomer with six transmembrane helices is represented. The location of the protein kinase A phosphorylation site (Pa) is indicated. This site is
possibly involved in the arginine vasopressin-induced trafficking of AQP2 from intracellular vesicles to the plasma membrane and in the subsequent stimulation of endocytosis. Solid circles indicate the locations of the mutations. B. Representation of the six-helix barrel of the AQP1 protein
viewed parallel to the bilayer. (From Morello and Bichet, 2001.)

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Nephrogenic diabetes insipidus generally manifests a


few days after birth. It will usually result in profound
polyuria and consequent dehydration, vomiting, constipation, fever, irritability and a failure to thrive in infancy.
Episodes of dehydration can cause brain damage, permanent mental retardation and even death. There may be a
history of hydramnios (Bayliss and Cheetham, 1998; Jonat
et al., 1999; Van Lieburg et al., 1999; Wildin and Cogdell,
1999). Nephrogenic diabetes insipidus is characterized by
normal or elevated concentrations of vasopressin and an
insensitivity to exogenously administered vasopressin
analogues. It may be partially controlled by thiazide
diuretics, amiloride or indomethacin (Hansen et al., 1997).
Polyuria in nephrogenic diabetes insipidus may be
completely concealed by concomittant adrenal failure.
Polyuria starts immediately after corticosteroid replacement, probably because of an intrarenal mechanism.
Cortisol seems to be required for an optimal excretion of
water (Iwasaki et al., 1997; Bayliss and Cheetham, 1998).
On the other hand, we observed strongly decreased vasopressin staining in the SON and PVN following
corticosteroid treatment (Erkut et al., 1998), indicating a
lack of free vasopressin that may also contribute to
unmasking nephrogenic diabetes insipidus. Selective
nonpeptide V2-renal vasopressin receptor antagonist
rescued the function of V2-renal receptor mutants by
promoting their proper folding and maturation. Such
compounds may thus have potentially therapeutic effects
(Paranjape and Thibonnier, 2001).
In addition, nephrogenic diabetes insipidus may be
based on osmotic diuresis (diabetes mellitus; see Chapter
22.5), hypercalcemia, and hypocalcemia (both of which
impair the action of vasopressin on the distal nephron),
chronic renal disease, drugs such as lithium and demeclocycline, postobstructive uropathy, solute washout from
the renal medulla and primary polydipsia (Bayliss and
Cheetham, 1998; Chapter 22.3).
In rare cases of Gitelmans syndrome, growth hormone
deficiency or multiple pituitary hormone deficiencies are
associated with empty sella and diabetes insipidus. The
disease is caused by mutations in the gene encoding TSC
(SLC12A3) of the distal convoluted tubule (Bettinelli et
al., 1999).
Cases of transient vasopressin (DDAVP)-resistant
diabetes that developed during gestation have been
reported. A pathogenetic factor, such as increased production of prostoglandin E2, may cause resistance to
DDAVP. The hyperprostoglandin E-syndrome is a variant
of Bartters syndrome and may be induced by lithium or

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hydronephrosis (Jin-No et al., 1998). Indomethacin and


hydrochlorothiazide normalize prostoglandin E levels
and decrease urine volumes. A T1-weighed MR image
of the posterior pituitary may reveal decreased intensity
due to increased vasopressin release. The syndrome
remitted in the puerperium (Barron et al., 1984; Ford and
Lumpkin, 1986; Jin-No et al., 1998). These thus appear
to be cases of nephrogenic diabetes that were unmasked
by pregnancy.
Defective urine-concentrating ability due to a complete
deficiency of aquaporin-1 was described in a few
unrelated subjects. Aquaporin-1 is the archetypal waterchannel protein that is abundantly present in the renal
proximal tubular epithelium, the thin descending limb of
the loop of Henle and the descending vasa recta of the
kidney. The gene for aquaporin-1 is localized on chromosome 7. The two subjects with a complete deficiency
of aquaporin-1 did not have polyuria, but both had an
impaired ability to concentrate their urine maximally
when deprived of water. People with a complete deficiency of aquaporin-1 have thus unidentified mechanisms
of fluid readsorption in the proximal tubules that compensate for the deficiency of aquaporin-1 (King et al., 2001).
22.3. Primary polydipsia and adipsia
(a) Primary polydipsia
Primary polydipsia is characterized by thirst, excessive
fluid intake and hypotonic polyuria, despite preservation
of the ability to secrete appropriate amounts of vasopressin in response to osmotic stimuli. A physiological
inhibition of vasopressin is present due to excessive
drinking. This condition was reported for the first time
by Nothnagel in 1881. He described a man who was
kicked by a horse, causing him to fall backward onto the
back of his head. Within half an hour he developed a
fierce thirst, drank 3 l of water and beer within half an
hour and only then did he start to urinate. The thirst
persisted for 4 days (Anderson and Haymaker, 1974). The
simultaneous measurement of plasma vasopressin and
plasma osmolality in a dehydration test is the best
diagnostic tool in the differential diagnosis of primary
polydipsia and diabetes insipidus (Diederich et al., 2001).
In addition to psychiatric disorders, primary polydipsia
may be associated with neurosarcoidosis or with congenital absence of the corpus callosum. In the case of tumors
in the pineal or suprasellar region, a transient polydipsia
can precede a state of adipsia (Zazgornik et al., 1974).
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In a patient who suffered from polydipsia secondary to


sarcoidosis, a normal reaction to vasopressin was found.
Following treatment with vasopressin, abrupt cessation of
thirst occurred when serum osmolality had been lowered
to 275 mosmol/kg (normally below 290 mosmol/kg). This
patient thus had an abnormal sensation of thirst (Mellinger
and Zafar, 1983). Polydipsia, polyuria and an increased
thirst sensation can also be present during untreated thyrotoxicosis (Harvey et al., 1991).
Primary polydipsia is an isolated clinical abnormality
characterized by abnormal thirst. Compulsive waterdrinking is sometimes also called dipsogenic diabetes
insipidus. However, the term dipsogenic polydipsia is
generally used for somatic patients. The disorder is
known to occur in association with damage to the hypothalamus, such as closed head trauma, neurosarcoidosis,
infections, multiple sclerosis or medicines such as lithium,
or carbamazepine (Robertson, 2001). The vasopressin
levels of compulsive water-drinking psychiatric patients
are higher, at any given level of osmolality, but vasopressin secretion can only account for hyponatremia
not for polydipsia, the primary problem. Angiotensin II,
a known dipsinogen in animals, has also been proposed
as a possible etiological factor. Neuroleptics increase
angiotensin II, induce thirst in animals and release vasopressin (Verghese et al., 1993), but there are no reports
on changes in this peptide with respect to primary polydipsia in patients. The syndrome is characterized by
excessive water drinking, explained by the patient as
having severe, persistent and unquenchable thirst, and
which leads to the production of hypotonic polyuria. A
hyperintense T1-weighted MRI signal is clearly present
in the neurohypophysis of patients with this syndrome.
Three distinct abnormalities of the control of thirst appreciation have been identified in clinical studies. First, the
osmotic threshold for thirst appreciation is lowered to
such an extent that patients are thirsty even at plasma
osmolalities so low that they are associated with a
complete lack of vasopressin secretion. The second abnormality is that patients drink more than healthy controls
in response to a given rise in plasma osmolality. Finally,
their thirst is not suppressed even while they are drinking;
they continue to feel thirsty even when imbibing large
quantities of water. It has been suggested that primary
polydipsia is caused by abnormal function of the osmoreceptors that govern thirst, but the failure of the action
of drinking to suppress thirst indicates that nonosmotic
control of thirst is also abnormal. It therefore seems likely
that there is a second abnormality in the integration of

osmotic and nonosmotic control of thirst in primary polydipsia (Thompson et al., 1991; McKenna and Thompson,
1998).
(b) Psychogenic polydipsia
Primary polydipsia may be associated with psychiatric
disorders and is then generally termed psychogenic polydipsia (Thompson et al., 1991). The criterion used for
polydipsia is 2.5 l of urine per day, and a urine specific
gravity of less than 1008. In one patient with psychogenic diabetes insipidus a normal posterior pituitary
MRI bright spot was detected (Chiumello et al., 1989),
indicating storage of vasopressin. Aquaporin-2 excretion
in the urine is not changed in these conditions (Ishikawa,
2000). Associated disorders such as sporadic convulsive
seizures, comatose states, hydronephrosis, enuresis,
urinary incontinence, projectile-type vomiting and malnutrition may be present (Blum et al., 1983). Polydipsia and
water intoxication cause considerable morbidity and
mortality in chronic psychiatric patients. Polydipsia in
psychiatric patients has been described prior to the use
of neuroleptics. Many names are being used in literature
for this disorder, which include psychogenic polydipsia
or compulsive water drinking, intermittent hyponatremia,
polydipsia syndrome and self-induced water intoxication.
Water intoxication occurs in 50% of the polydipsic
patients, due to cerebral edema caused by hyponatremia.
The symptoms include headache, blurred vision, anorexia,
nausea, vomiting and diarrhea, muscle cramps, restlessness, confusion, exacerbation of psychosis, convulsion,
coma and death. Polydipsia and water intoxication
are strongly associated with chronicity of the illness;
80% of the patients suffer from schizophrenia, others
from affective disorders, alcohol abuse, mental retardation, organic brain disorders and personality disorders
(Chiumello et al., 1989). For unknown reasons, patients
with psychogenic polydipsia and intermittent hyponatremia have larger ventricle to brain ratios. Since this
ratio and the lateral ventricle volume decrease during
water loading, water loading does not account for the
diminished brain volume observed in these patients
(Leadbetter et al., 1999).
(c) Adipsinogenic disorders
Inappropriate lack of thirst, with consequent failure to
drink in order to correct hyperosmolality, is characteristic of adipsinogenic disorders (Robertson, 2001). The

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patient denies thirst or does not drink spontaneously.


Plasma osmolality and plasma sodium are elevated and
blood volume is contracted with a raised blood urea. Poor
cerebration and drowsiness are common symptoms and
the condition can progress to somnolence, fits, hemiplegia,
coma, rhabdomyolysis and acute renal failure. Four
main patterns of abnormal osmoregulatory function have
been described. Type A is characterized by an upward
resetting of the osmotic thresholds for both thirst and
vasopressin release. This rare condition is sometimes
referred to as essential hypernatremia. Patients will
usually respond to advice to drink approximately 2 l of
fluid daily. Type B is characterized by subnormal thirst
and vasopressin release to osmotic stimuli. They are able
to secrete some vasopressin and the disorder may be due
to partial destruction of the osmoreceptors. Type B adipsia
has been described in association with microcephaly and
dysplasia of the corpus callosum, early puberty and
aggressive behavior, and increased renal sensitivity to
vasopressin. Complete destruction of the osmoreceptor is
classified as type C osmoreceptor dysfunction. Surgery
for ruptured aneurysms associated with clipping of the
anterior communicating artery of the circle of Willis, ablation of tumors, granulomata, toluene exposure and head
injury may cause this condition. As these patients secrete
normal amounts of vasopressin in response to nonosmotic
stimuli, the site of the lesion is the osmoreceptor, rather
than the SON or PVN. Because thirst and vasopressin
deficiencies are complete, the patients are at great risk of
life-threatening hyponatremia. In particular some patients
who develop adipsic diabetes insipidus following surgery
to aneurysms of the anterior communicating artery show
significant defects of cognitive function, including shortterm memory loss. They are also unable to manage their
fluid intake without assistance (McKenna and Thompson,
1998; Smith et al., 2002).
The adipsogenic disorders are supposed to be based
upon an osmoreceptor dysfunction and often associated
with a defective osmoregulated vasopressin secretion and
diabetes insipidus. Patients are at risk for de- and overhydration (Verdin et al., 1985; Ball et al., 1997). The
patients usually have structural hypothalamic abnormalities such as germinoma or other tumors such as gliomas
(Zazognik et al., 1974; Hammond et al., 1986). In addition, vascular abnormalities, granulomatous diseases,
trauma, hydrocephalus, congenital malformations, histiocytosis, microcephaly and ventricular cysts have been
found. Surgery or irradiation may also cause this disorder
(Hammond et al., 1986; Ball et al., 1997). In one case a

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pseudotumor cerebri and an empty sella turcica were


found. Pseudotumor cerebri was diagnosed on the basis
of a high intracranial pressure, normal CSF composition,
signs of intracranial hypertension and normal radiographic
studies. Deficiency of vasopressin secretion was presumed
to result from neurohypophysial suppression (Verdin
et al., 1985).
A number of children with a number of hypothalamic
dysfunctions, including hypodipsia, are described in
Chapter 32.1. The case of a 9-year-old boy may serve as
a first example. In him, the onset of obesity was accompanied by decreased activity, episodes of lethargy,
increased perspiration, mood changes, wide temperature
oscillations, hypernatremic crises, high prolactin levels,
an inability to excrete a water load and hypothyroidism.
A follow-up study after 4 years could not identify any
demonstrable hypothalamic structural lesion. The patient
had a loss of thirst, there was no diabetes insipidus, and
no explanation for the strong hypothalamic abnormalities
could be offered (Hayek and Peake, 1982). In one case
of a 2-year-old child who lacked thirst perception and
suffered from polyphagia, obesity and inadequate temperature regulation, autopsy was performed and revealed
inflammation of the hypothalamic nuclei (Travis et al.,
1967). The possibility that inflammatory or autoimmune
processes in the hypothalamus are the cause of this condition should thus be further investigated. In two unrelated
boys of 13 and 18 years of age, a hypothalamic syndrome
has been described consisting of early puberty dysfunction associated with aggressive behavior (Dunger et al.,
1985). The pathogenetic mechanism of this syndrome has
not yet been clarified. An absence of thirst has also been
reported in Kallmann syndrome (see Chapter 24.3),
together with hypernatremia and an elevated osmotic
threshold for vasopressin release. The fact that some
patients with Kallmann syndrome have osmoreceptor
dysfunction and abnormal thirst regulation indicates
that there is more extensive hypothalamic involvement in
this disorder than previously appreciated (Hochberg
et al., 1982). In various reported cases of hypodipsic
hypernatremia, associated defects in antidiuretic function
occurred. In several patients a deficiency of vasopressin
was demonstrated with osmotic but not with nonosmotic
stimuli, indicating that the osmoreceptors for thirst and
vasopressin occupy overlapping areas in the anterior
hypothalamus (Hammond et al., 1986). In addition, a
unique patient has been described who had hypernatremia
and hypodipsia without any defect in the osmoregulation
of vasopressin secretion. This indicates that the neuronal
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pathways that mediate osmoregulation of thirst and vasopressin secretion in humans are so discrete that they can
be affected separately. Development was delayed in this
child and optic atrophy and intracerebral calcifications
were found, as, e.g. in the case of a congenital cytomegalovirus infection (Hammond et al., 1986). In one
patient with defective hypothalamic osmoreceptors a
normal posterior pituitary bright spot was seen on MR
images (Chiumello et al., 1989), which also indicates
different locations for the two functions.
Treatment consists of attempting to prevent chronic
fluid deficit, e.g. by adopting a regime of regular water
intake based on changes in body weight (Hammond et
al., 1986). The hypertonic saline test with measurements
of plasma osmolality and vasopressin is useful for distinguishing partial diabetes insipidus from psychogenic
polydipsia and for the diagnosis of complex disorders of
osmoreceptor and posterior pituitary function (Mohn et
al., 1998).
22.4. Nocturnal diuresis
Children with nocturnal enuresis, defined by persistent
bed-wetting for at least 3 nights a week after the 5th year
of age (Mller et al., 2002b), fail to wake in response to
the need to void. Nocturnal diuresis or nightly bed-wetting
in children older than 7 years affects about 10%. From
this age onward there is a spontaneous cure rate of about
15%/year, which means that few children remain affected
after the age of 16 years. The problem may lie in the
arousal mechanism and/or in the amount of urine
produced at night. Vasopressin is involved in both antidiuresis and arousal. Different subgroups of nocturnal
enuresis with probably different etiologies are distinguished (Lckgren et al., 1999). For a long time now,
DDAVP has been advertised as a treatment for nocturnal
diuresis (Klauber, 1989; Janknegt and Smans, 1990;
Nevus et al., 2002). The vasopressin analogue was
claimed to lead to total or almost total dryness in approximately two-thirds of the enuretics (Hunsballe et al.,
1998). DDAVP has no major effects on sleep in enuretic
children as such, but does delay bladder emptying
(Nevus et al., 2002). The possibility of permanent effects
of peptides on brain development (Swaab et al., 1988)
has, however, never been considered in these young children, although central effects of this compound are very
probable (Mller et al., 2002b). In spite of the fact that
DDAVP is generally used, the scientific basis for the use

of DDAVP in children with nocturnal diuresis is considered by some to be rather narrow (De Jong and Van der
Heyden, 1991) and, when the recommended dose of
DDAVP is exceeded, coupled with high fluid intake, it
is even liable to cause hyponatremia and seizures (Davis
et al., 1992). Hyponatremia resulting in delirium, seizures
and/or coma may occur in children and occasionally in
adults who are given DDAVP for nocturnal diuresis
(Chan, 1997; Donoghue et al., 1998; Chapter 22.6). In
addition to DDAVP, alarms are used and behavioral
therapy is given (Lckgren et al., 1999). Interestingly,
some cases of primary nocturnal enuresis and nephrogenic diabetes insipidus have been found to be caused
by mutations in the aquaporin-2 gene which cause this
protein to be inactive. Although one would expect
DDAVP to be inactive, treatment with DDAVP resolves
primary nocturnal enuresis completely. DDAVP consequently does not act exclusively through alteration of the
renal concentrating ability but also seems to act by central
targets. There are families with primary nocturnal diuresis
that have a disease locus at chromosome 12q13-21 around
the aquaporin-2 gene locus (Radetti et al., 2001).
However, since no mutation in the aquaporin-2 coding
sequence has been found, this gene is excluded as a candidate for autosomal dominant nocturnal enuresis in these
families.
In a significant proportion of patients with nocturnal
enuresis, the normal diurnal rhythm in plasma vasopressin
and urine output is reported to be absent (Nrgaard et
al., 1985; Rittig et al., 1989). However, a later study has
shown that such an abolished circadian rhythm is only
present in the subgroup of DDAVP-responding diuretics
with considerable polyuria and poorly concentrated urine
at night (Hunsballe et al., 1998). There is a subgroup
of children who respond to high (but not to normal)
doses of DDAVP (Nevus et al., 1999a). Various relevant
differences between DDAVP responders and nonresponders have been reported. Nonresponders have a smaller
spontaneous bladder capacity, and responders produce
less-concentrated urine (Nevus et al., 1999a).
Enuretic children responding to DDAVP treatment
have more rapid eye movement sleep than therapy-resistant children (Nevus et al., 2002). The favorable response
of nonresponders to anticholinergic medication supports
the hypothesis that these children had nocturnal bladder
instability (Nevus et al., 1999b). In addition, responders
have a lower nocturnal aquaporin-2 excretion than nonresponders, while plasma vasopressin levels and osmolality
were similar. DDAVP treatment is proposed to increase

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aquaporin-2 secretion in the responders, thus reducing


nocturnal water loss (Radetti et al., 2001).
With the lack of normal, diurnal vasopressin rhythms
in some cases of nocturnal enuresis and the presence
of a normal melatonin rhythm (Kirchlechner et al.,
2001), one may wonder whether immaturity of the
retinohypothalamic tract innervating the SON, or of
the suprachiasmatic nucleus (SCN) efferents close to the
SON and possibly innervating its dendrites (Dai et al.,
1998a; see Chapter 4), may contribute to a subgroup of
patients with this disorder. The other possibility, i.e. that
the SCN itself is a relatively late-maturing structure
(Swaab et al., 1991, 1994), is less likely, because in children with nocturnal enuresis the melatonin rhythm as
measured by 6-hydroxy-melatonin sulfate excretion in the
urine is normal (Kirchlechner et al., 2001). Alternatively,
Hunsballe et al. (1998) and Jonat et al. (1999) propose
that nocturnal pituitary vasopressin failure is not the sole
mechanism of nocturnal polyuria in enuretics persisting
into adulthood, although they also mention that this group
of older enuretics, even in adulthood, fail to establish
normal rhythms in urine output. A normal day-to-night
variation in urine output may account for the poor efficacy of DDAVP in the nonresponders according to these
authors.
However, another study has shown that enuretic children needed plasma vasopressin levels that are 23 times
higher in order to maintain osmolality. These data point
to a defect at the level of the vasopressin receptor or at
the level of the signal transduction pathway (Eggert et
al., 1999). Devitt et al. (1999) have shown that enuretic
children that have either very low or very high plasma
vasopressin levels are unresponsive to DDAVP. The children with very high plasma vasopressin levels are
probably children with a nephrogenic diabetes insipidus
based on an aquaporin-2 defect, since there is linkage to
chromosome 12q. This diagnosis has been questioned
since it was discovered that nocturnal enuresis responds
to DDAVP. However, a case report has been published
on a boy with a nephrogenic diabetes insipidus based
upon a molecular-genetically confirmed mutation of the
vasopressin V2 receptor gene on chromosome q28. This
boy has nocturnal enuresis and DDAVP does not affect
urine osmolality. Although the daily intranasal application of DDAVP does not further reduce urine output, it
dramatically decreases the frequency of bed-wetting. It
has therefore been hypothesized that the target for this
DDAVP effect may be the vasopressin V1b receptor,
influencing the central regulation of bladder control.

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In a 67-year-old patient with ShyDrager syndrome


(multisystem atrophy), nocturnal polyuria was observed,
associated with an abnormal circadian rhythm of vasopressin. The patients plasma vasopressin levels were
higher during the day than during the night (Ozawa et
al., 1993), indicating that a disorder of the SCN was later
indeed confirmed in this disease (Ozawa et al., 1998). In
order to determine whether the nocturnal decrease in vasopressin secretion into plasma found in this patient with
multisystem atrophy was a usual finding in this disorder,
Ozawa et al. (1999) determined plasma vasopressin levels
in 13 of such patients. The vasopressin levels showed
considerable variations, but were indeed lowest during
the night.
DDAVP can be effective (Mathias et al., 1986). In
patients with other causes of autonomic failure nocturnal
polyuria and overnight weight loss may also be found.
The possible mechanism for diuresis and natriuresis
induced by recumbency is not known, but may include
resistance to mineralocorticoids, inappropriate secretion
of vasopressin, increased renal perfusion from a rise in
blood pressure, and release of atrial natriuretic peptide.
DDAVP reduces nocturnal polyuria, diminishes overnight
weight loss and raises supine blood pressure (Mathias et
al., 1986). In geriatric patients the diurnal rhythm of
water excretion disappears or is reversed (Minamisawa,
1980; Chapter 4.3), and nocturia is frequent in the elderly
(Kallas et al., 1999). After a complete examination has
ruled out the most common organic and behavioral causes
of nocturia in the elderly, DDAVP may be given and
decrease night-time diuresis. Elderly patients who are
treated with DDAVP should be monitored periodically
for the development of hyponatremia and fluid overload
(Kallas et al., 1999; Weiss and Blaivas, 2000). It should
be noted that familial hypothalamic diabetes may be
mistaken for enuresis nocturna (Hansen et al., 1997).
22.5. Vasopressin hypersecretion in diabetes mellitus
Diabetes mellitus is associated with polyuria and polydipsia. In patients with diabetic ketoacidosis, plasma
osmolality and vasopressin levels are increased, circulating volume is decreased and urinary excretion of the
aquaporin-2 water channel is increased (Kusaka et al.,
2002). Polyuria persists despite markedly elevated levels
of vasopressin, due to the osmotic effect of hyperglycemia
and altered osmoregulation of vasopressin secretion and
thirst. Polyuria is classically said to be due to the osmotic
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diuresis caused by glucosuria. However, when hyperglycemia is improved by i.v. infusion of insulin and fluid,
plasma vasopressin levels decrease promptly, within 6 h,
although plasma osmolality is still high. This indicates
that both osmotic and nonosmotic stimuli are involved in
the hypersecretion of vasopressin. The nonosmotic control
of vasopressin may contribute to circulating homeostasis,
protecting against severe blood volume depletion in
diabetic patients suffering from hyperglycemia and dehydration, and in patients with diabetic coma (Walsh et al.,
1979; Ishikawa et al., 1990; Fujisawa et al., 1996). On
the other hand, vasopressin may play a critical role in
diabetic hyperfiltration and albuminuria induced by
diabetes mellitus. Vasopressin elevation is considered to
be an additional risk factor for diabetic nephropathy
(Bardoux et al., 1999). Attenuated thirst and drinking
response may be important factors in the development of
the hypernatremic dehydration, which is characteristic
of this condition (McKenna and Thompson, 1998).
Subnormal osmoregulated thirst sensation and fluid intake
could contribute to the development of hypernatremia
characteristic of hyperosmolar coma. These patients
respond to water deprivation with exaggerated secretion
of vasopressin, blunted thirst sensation and attenuated
drinking during rehydration. Reduced thirst and drinking
in association with exaggerated vasopressin release has
also been reported in aging. Therefore a premature
aging of the osmoreceptor has been proposed to exist
in those subjects who are at risk of hyperosmolar coma
(McKenna et al., 1998). The MRI signal intensity of the
posterior lobe in patients with uncontrolled non-insulindependent diabetes mellitus is lower than in healthy
controls. This is thought to be due to a decreased vasopressin content of the posterior lobe, due to persistent
hypersecretion, which accompanies the elevation of
plasma vasopressin levels. The normal hyperintense signal
reappears after diabetic control within 12 months
(Fujisawa et al., 1996; Fig. 22.8). Plasma vasopressin and
urinary excretion of aquaporin-2 are decreased to normal
levels promptly in days (Kusaka et al., 2002). During the
acute phase of ketoacidosis, cerebral complications may
develop. A lethal outcome has been reported in 6070%
of the cases and 15% survive with severe neurological
disorders. Neuroendocrine consequences are rare but
have been described. A 5-year-old child survived an
intracerebral crisis following ketoacidosis with visual
impairment due to a vascular occipital lesion. Two to
four months after the initial episode, a hypothalamopituitary disorder developed, consisting of growth hormone,

Fig. 22.8. A. The hyperintense signal in the posterior lobe is absent at


the first MRI examination of a patient with uncontrolled diabetes
mellitus. The signal-intensity ratio of the posterior lobe to the pons is
1.07. B. The hyperintense signal appears after diabetic control (arrow).
The signal intensity ratio of the posterior lobe to the pons is 1.54. (From
Fujisawa et al., 1996, Fig. 2 with permission.)

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ACTH, TSH deficiencies and central precocious puberty.


MR images showed no visible lesion in the hypothalamopituitary region (Tubiana-Rufi et al., 1992).
Both vasopressin and oxytocin are released from the
neurohypophysis in hypoglycemia. Serotonergic 5-HT3
receptors at least partly mediate the vasopressin response,
but not the oxytocin release to hypoglycemia (Volpi
et al., 1998).
It has been hypothesized that type 2 diabetes mellitus
is due to damage of the ventromedial nucleus or to a
defect of insulin or insulin receptors in the brain (Das,
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147

and adrenal function are normal. Plasma osmolality is


below the osmotic threshold for thirst, and drinking
is minimal. In fact, the threshold for thirst seems to be
reset to protect the lower plasma osmolality. In contrast
to the situation in nephrogenic diabetes insipidus (Chapter
22.2) total and apical membrane expression of aquaporin2 is increased (Deen et al., 2000; Ishikawa, 2000) and
this water channel is excreted in higher amounts in the
urine in cases of inappropriate secretion of vasopressin
with hyponatremia, also after acute water load (Saito
et al., 1998; 2000a; Deen et al., 2000; Ishikawa, 2000).
In this syndrome the hydro-osmotic action of vasopressin
is exaggerated more than expected from the plasma
vasopressin levels, with nonsuppressible but normal vasopressin levels, in spite of the hypo-osmotic condition
(Saito et al., 2001).
The syndrome was first described following exogenously administered pitressin (Goldstein et al., 1983;
McKenna and Thompson, 1998) and may also be due to
excessive vasopressin release from the posterior pituitary,
despite hypo-osmolality (Ishikawa et al., 1996). It should
be noted here that, in cases of nonosmotic baroreceptormediated stimulation of vasopressin release, as in the
case of pulmonary hypertension or liver cirrhosis, there
is a decrease in effective blood volume or arterial
underfilling. Therefore the enhanced vasopressin release
(Panayotacopoulou et al., 2002), lower plasma sodium
and osmolity, e.g. in congestive heart failure (Szatalowicz
et al., 1981; Rondeau et al., 1982), cannot be considered
to be inappropriate but rather as an appropriate reaction to a hemodynamic stimulus. The same holds true
for the increased excretion of aquaporin-2, indicating
increased vasopressin release in cardiac failure and liver
cirrhosis (Cadnapaphornchai and Schrier, 2000; Schrier
et al., 2001). It is thus better to exclude the diagnosis of
inappropriate secretion of antidiuretic hormone in these
conditions (Kovacs and Robertson, 1992). Also the
release of vasopressin in children with severe head injury
appeared to be appropriate in response to hypovolemia
and/or sodium administration (Simma et al., 2001).
The inappropriate vasopressin syndrome may be due
to ectopic production of vasopressin by extrahypophysial
neoplasms, e.g. by a bronchus carcinoma (Table 22.1).
Such paraneoplastic symptoms are found, in particular,
in head and neck malignancies. Most tumors of this kind
are squamous carcinomas with lower numbers of olfactory
neuroblastomas or esthesioneuroblastoma, small cell
neuroendocrine carcinomas, adenoid cystic carcinomas
and undifferentiated carcinomas (Ferlito et al., 1997;

22.6. Inappropriate secretion of vasopressin


(a) Syndrome of inappropriate secretion of antidiuretic
hormone (SchwartzBartter syndrome)
The syndrome of inappropriate secretion of antidiuretic
hormone (SchwartzBartter syndrome) is characterized
by high vasopressin levels that are nonsuppressible by
acute water load, renal sodium loss (high urine sodium
concentrations of more than 40 mmol/l), hypotonic hyponatremia (serum sodium level less than 134 mmol/l),
and by urine that is relatively or absolutely hyperosmolar
to serum. The clinical features may include confusion,
muscle cramps, seizures, fatigue, loss of appetite, nausea,
vomiting, some clouding of consciousness and coma
(Kovacs and Robertson, 1992; Saito, 2001; Milionis et al.,
2002). Electrophysiological evidence indicates that
hypoosmolality promotes epileptiform activity by
strengthening both the excitatory synaptic communication
in the neocortex and the field effects among the entire cortical population (Andrew, 1991). In 61% of patients with
central pontine myelinolysis on which autopsy was performed, hyponatremia was found (Brisman and Chutorian,
1970; Burcar et al., 1977; Apple et al., 1978; Hirshberg
and Ben-Yehuda, 1997). Indeed, rapid correction of
hyponatremia may lead to central pontine and extrapontine myelinolysis, for which alcoholism and malnutrition
are risk factors (Chan, 1997). The pathogenetic mechanism involved in this relation-ship is unknown. When
postoperative hyponatremic encephalopathy develops,
menstruant women are 25 times more likely to die or have
permanent brain damage than men or postmenopausal
women (Ayus et al., 1992).
In inappropriate vasopressin secretion, urine osmolality
is usually greater than 300 mosmol/kg, edema-forming
states or volume depletion are absent, while renal function
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TABLE 22.1.
Etiology of the syndrome of inappropriate secretion of vasopressin. In most patients the defect in urinary dilution is caused by ectopic
production, exogenous administration, or osmotically inappropriate neurohypophyseal secretion of vasopressin.
Congenital
Eutopic
Malformations
Acquired
Ectopic
Neoplasm
Drugs
Eutopic
Neoplasm
Drugs
Head trauma
Infections
Pulmonary
Neurologic
Metabolic

Agenesis corpus callosum, cleft lip and palate, other midline effects

Carcinoma of bronchus, duodenum, pancreas, prostate, ovary, bladder; thymoma, mesothelioma, sarcoma
Vasopressin, pitressin or DDAVP, oxytocin
Carcinoma of bronchus
Vincristine, carbamazepine, nicotine, phenothiazine, cyclophosphamide, tricyclic antidepressants, monoamine oxidase
inhibitors, serotonin reuptake inhibitors
Closed, penetrating
Bacterial or viral pneumonia, abscess of lung or brain, tuberculosis of lung or brain, aspergilloma, encephalitis, bacterial
or viral meningitis
Asthma, pneumothorax, positive-pressure respirator
GuillainBarr, multiple sclerosis, delirium tremens, psychosis, amyotrophic lateral sclerosis, hydrocephalus,
cerebrovascular occlusion or hemorrhage, cavernous sinus thrombosis
Acute porphyria

From Robertson, 2001, p. 688.

Mller et al., 2000b). Such tumors may also be the reason


for the high (830%) incidence of this syndrome
following neck dissection (Zacay et al., 2002). Other
neoplasmas that may produce ectopic vasopressin are, e.g.
oat cell or adenocarcinomas of the lung, lymphomas,
leukemia, Hodgkins disease, mesotheliomas, Ewing
sarcomas and esthesioneuroblastomas (Kovacs and
Robertson, 1992; Horvath et al., 1997). Moreover, brain
tumors, both primary brain tumors and metastases
(Kovacs, 1984), including a case of craniopharyngioma,
a hypothalamic glioma (Brisman and Chutorian, 1970)
and a ganglioma of the neurohypophysis, which produced
vasopressin and caused inappropriate vasopressin secretion (Fehn et al., 1998), have been described. A case of
Ratkes cleft cyst was accompanied by this syndrome
(Iwai et al., 2000).
Other diseases which may be accompanied by increased
vasopressin release include head injuries in which IL-6
may be the mediator through which the vasopressin secretion is stimulated (Gionis et al., 2003). The syndrome
is also associated with fractures in the frontotemperal
region extending to the base of the skull (Twijnstra
and Minderhoud, 1980), pneumonia, exacerbations of
multiple sclerosis, brain infarction, hematoma, traumata,
subarachnoid hemorrhage, subdural hematoma, stroke,
polyneuritis, asthma, hepatorenal syndrome (Mather

et al., 1981; Kovacs and Robertson, 1992; Pasqualetti


et al., 1998) and a case of Wernickes encephalopathy
(Haak et al., 1990; Gonzalez-Portillo et al., 1998). In
addition, a case of anterior hypothalamic infarction that
had alternating inappropriate vasopressin secretion and
diabetes insipidus has been described (Rudelli and Deck,
1979). Moreover, inappropriate antidiuretic hormone
excretion has been described in a few patients with
Whipples disease, caused by the gram-positive bacterium
Tropheryma whippelii. Evidence of hypothalamic involvement, including contrast enhancement in the mamillary
bodies, was found by CT and MRI. The patient experienced changes in sleep pattern, memory loss and other
neurological symptoms (Marinella an Chey, 1997). In
addition, this syndrome was found to accompany central
nervous system infections such as meningitis (tuberculosus, or a fungal infection such as coccidioidomycosis),
encephalitis, brain abscess and malaria (Haak et al.,
1990; Webb et al., 2002). Since interleukin-6 was found
to cause a strong elevation of plasma vasopressin levels
(Mastorakos et al., 1994), this cytokine may be one of
the mediators causing the syndrome of inappropriate vasopressin secretion during active infections or inflammatory
diseases. Hypothyroidism may lead to inappropriate vasopressin secretion according to some authors (Hanna and
Scanlon, 1977), but may be due to a direct action of

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thyroid hormones on the kidney (Sahun et al., 2001) and


should be excluded from this diagnosis by others. The
same goes for renal and adrenal insufficiency (Kovacs and
Robertson, 1992).
Inappropriate vasopressin secretion has also been
described in hydrocephalus, cerebellar and cerebral
atrophy, delirium tremens, GuillainBarr syndrome,
myocardial infarction and after medicines, e.g. following
administration of vasopressin, or of oxytocin when given
in large quantities for the induction or augmentation of
labor or following excessive self-administration via a
nasal spray by nursing mothers. The syndrome of inappropriate vasopressin secretion has been found in patients
using psychotropic drugs (Spigset and Hedenmalm, 1995)
such as chlorpropamide, carbamazepine, antipsychotics,
antidepressants, nonsteroidal antiinflammatory drugs,
acetylcholine esterase inhibitors, vincristine, vinblastine,
dopaminergic drugs, chlorothiazide, nicotine, phenothiazides, cyclophosphamide, morphine or barbiturates
(Pessin, 1972; Hamilton, 1978; Spigset and Hedenmalm,
1995; Chan, 1997; Horvath et al., 1997; Goldman, 1999),
after taking ecstacy (Henry et al., 1998) and in a case
of Wernickes encephalopathy (Haak et al., 1990).
The syndrome is also found in schizophrenic patients
(Goldman et al., 1997). In fact, polydypsia would be
present in some 20% of the chronic psychiatric inpatients
and hyponatremia in more than 10% (DeLeon, 2003). In
some of these cases, but certainly not in all, this may be
due to antipsychotic drugs (Hirshberg and Ben-Yehuda,
1997; see Chapter 27.1). In one patient with schizophrenia, hyponatremia disappeared after recovery from
psychosis by electroconvulsive therapy (Suzuki et al.,
1992), indicating that SchwartzBartter syndrome may be
due to the disease process.
The treatment of inappropriate vasopressin secretion
consists of fluid restriction, urea, furosemide, or a mineral
corticoid (Ishikawa et al., 1996; Decaux, 2001; Wong et
al., 2003). In addition, effective treatment has been
described with demeclocycline, a nonpeptide V2 vasopressin receptor antagonist or diphenylhydantoin (Kamoi
et al., 1999; Decaux, 2001; Paranjape and Thibonnier,
2001). No evidence has been found to support fluidrestriction therapy in patients with the syndrome of
inappropriate secretion of vasopressin in meningitis
(Mller et al., 2001).
A subset of psychiatric patients have a version of
altered antidiuretic hormone activity known as reset
osmostat, in which urine osmolality and sodium excretion can be suppressed, and hence appear normal, if

149

plasma osmolality is sufficiently diminished. This holds


true for enhanced vasopressin action on the kidney by
neuroleptics, but to a similar degree also for all schizophrenics or acute psychosis that enhances vasopressin
secretion as in a subset of polydipsic schizophrenic
patients who become water-intoxicated. To exclude this
variant the patient should be given an oral waterload.
Although urine osmolality and sodium concentration in
these patients are low, it is typical for reset osmostat to
be considerably higher than what one would be likely
to see with normal antidiuretic function (Goldman,
1999). Reset osmostat has also been described in a
number of patients with central nervous system midline
defects, including one with a chromosome 13 anomaly
(Gupta et al., 2000). The inappropriate vasopressin
secretion reported in acute intermittent porphyria is
thought to be due to damage to the SON and PVN
(Chapter 28.3). An unusual case of inappropriate antidiuresis in the absence of excess vasopressin due to a
nonfunctional pituitary macroadenoma has been reported
(Hung et al., 2000).
(b) Cerebral/central salt wasting
Inappropriate secretion of vasopressin is differentiated
from cerebral/central salt wasting caused by excessive
renal sodium loss which leads to a decrease in extracellular fluid volume (Kamoi et al., 1999). Also in this
syndrome, vasopressin levels are increased, despite hypoosmolality. It has been proposed that inappropriate
natriuresis is caused by natriuretic hormones such as atrial
natriuretic peptide (ANP) or by an alteration of the neural
input to the kidney (Ishikawa et al., 1996). Since mineralocorticoids might improve hyponatremia dramatically,
a disorder of the reninaldosterone system may be
involved. Hyponatremia accompanied by renal sodium
loss and volume depletion has been reported in patients
with primary cerebral tumors, carcinomatous meningitis,
subarachnoidal hemorrhage, head trauma and after
intracranial surgery or pituitary surgery. The volume
condition, which is different from the inappropriate vasopressin secretion syndrome has to be determined by
physical investigation and hematocrit (Ishikawa et al.,
1996). The treatment consists of sodium and water
replacement and a mineralocorticoid (Ishikawa et al.,
1996). It has been proposed that damage to the lamina
terminalis (Chapter 30.5) important for the interaction
between osmoreceptors and the SON and PVN may be
the cause of this disorder (Kamoi et al., 1999).
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(c) Other causes of hyponatremia


There may be various causes of hyponatremia (Robertson,
2001). Idiopathic inappropriate secretion of vasopressin
is frequently found among elderly hospitalized patients
(Goldstein et al., 1983; Chan, 1997; Miller, 1997). In
elderly people with the syndrome of inappropriate antidiuretic hormone secretion, 42% were found to be
stuporous and 10% had seizures. Sensory impairment was
mainly found in patients with sodium levels below 110
mmol/l The majority, i.e. 60% of cases, was idiopathic,
while the main causes identified were pneumonia and
medication (Hirshberg and Ben-Yehuda, 1997). It should
be mentioned that the reduced renal concentrating ability
also contributes to enhanced vasopressin secretion in
elderly people (see Chapter 8.3).
Severe hyponatremia may also occur in some patients
with Addisons disease or untreated hypopituitarism
with hypocortisolism and hypothyroidism. They have
inappropriately high vasopressin levels in relation to the
low plasma osmolality. In addition, hyponatremia not
infrequently occurs in elderly patients with secondary
adrenal insufficiency. The hyponatremia in patients with
adrenal insufficiency can be cured by corticosteroids or
corticosteroids combined with mineralocorticoids. These
hormones suppress vasopressin secretion and normalize
the elevated aquaporin-2 excretion (Ahmed et al., 1967;
Salomez-Granier et al., 1983; Oelkers, 1989; Hanna and
Scanlon, 1997; Iwasaki et al., 1997, 2001; Yatagai et al.,
2003). The synthesis of vasopressin seems thus under the
inhibitory control of adrenal corticosteroids (Ahmed et
al., 1967). And indeed, in the hypothalamus of patients
who had received corticosteroid treatment we not only
found a decreased number of CRH-expressing neurons in
the paraventricular nucleus, but also a lower vasopressin
staining in the supraoptic and paraventricular nucleus
(Erkut et al., 1998).
Hyponatremia is well recognized in primary hypothyroidism. Some 75% of the hypothyroid patients have
raised plasma vasopressin levels, which do not suppress
normally after water ingestion. The high plasma vasopressin levels in hypothyroid patients may be due to a
nonosmotic stimulus, presumably hypovolemia, resulting
in urine concentration, even when plasma osmolality is
high. Thyroid replacement will restore sodium concentrations to normal in most patients. However, in refractory or symptomatic cases, moderate fluid restriction may
enhance recovery (Hanna and Scanlon, 1997).

Hyponatremia is also found in gastrointestinal bleeding,


leading to hypovolemia with nonosmotic stimulation of
vasopressin and renal failure, partly because of the
decreased clearance of vasopressin (Cadnapaphornchai
and Schrier, 2000).
22.7. Wolframs syndrome
(a) Clinical symptoms
Wolframs syndrome (DIDMOAD: Diabetes Insipidus,
Diabetes Mellitus, Optic Atrophy and Deafness; OMIM
222300) was first described by Wolfram and Wagener
in 1938, although the association between optic atrophy
and diabetes mellitus was already known in 1858 by
the work of Albrecht von Graefe, a German ophthalmologist (Khardori et al., 1983). It is a disorder involving
the presence of vasopressin-sensitive diabetes insipidus,
juvenile-onset, insulin-dependent diabetes mellitus, slowly
progressive atrophy of the optic nerve and perceptive
hearing loss due to degeneration of the cochlear nuclei
(Khardori et al., 1983; Mtanda et al., 1986; Rando et al.,
1992); but only in 13% of cases are all four components
present (Gunn et al., 1976). Juvenile diabetes mellitus
and atrophy of the optic nerves, chiasm and tracts are the
symptoms that occur most frequently in Wolframs
syndrome (Scolding, 1996). Diabetes mellitus manifests
at a median age of 6 years, followed by optic atrophy
at 11 years. Diabetes insipidus occurs in 73% of cases,
but Gunn et al. (1976) gives much lower figures, while
nephrogenic diabetes insipidus was excluded, (Thompson
et al., 1989); deafness occurs in 62% of cases within the
second decade and renal tract abnormalities in 58% of
cases within the third decade, followed by neurological
complications in 62% of cases in the fourth decade
(Barrett et al., 1995; Barrett and Bundey, 1997; Dean
et al., 2000; Fuqua, 2000). Apart from these features, the
clinical picture is highly variable and may include
anosmia, degeneration and gliosis of olfactory bulbs and
tracts, ataxia, vertigo, dysarthria, dysphagia, nystagmus,
mental retardation, diffuse cortical atrophy, psychiatric
disorders and seizures (Marquardt and Loriaux. 1974;
Carson et al., 1977; Cremers et al., 1977; Shannon et al.,
1999; Dean et al., 2002, unpubl. res.). In addition, a focus
of MRI signal change in the right substantia nigra was
observed in a 12-year old Wolfram patient (Galluzzi
et al., 1999).

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Endocrine abnormalities may include growth retardation,


hypothyroidism, hypogonadism, amenorrhea, gynecomastia and testicular atrophy (Marquardt and Loriaux,
1974; Rando et al., 1992; Kinsley et al., 1995; Collier et
al., 1996; Barrett and Bundey, 1997). Sexual maturation
appears to be delayed in some cases. Frequent mention was
made of menstrual disorders, sometimes leading to amenorrhea. Defective fertility may occur in patients of both
sexes (Editorial, 1986; Thompson et al., 1989; Barrett et
al., 1995; Kinsley et al., 1995). According to Khardori et
al. (1983) there would be no adrenal atrophy in Wolframs
syndrome, but Marquardt and Loriaux (1974) found a
blunted cortisol response to pyrogen infusion, although
they responded normally to metyrapone and ACTH. The
hypothalamopituitary adrenal axis in Wolframs syndrome
thus needs further investigation. The course and management of the diabetes mellitus is different from that of
patients with classic type I diabetes (Kinsley et al., 1995).
Optic atrophy is probably not secondary to retinal
pathology, but part of a generalized process of neurodegeneration (Mtanda et al., 1986). Dilatation of the
efferent urinary tract, i.e. hydronephrosis, hydroureter and
atonic bladder, may also be present in Wolframs
syndrome (Cremers et al., 1977). The urinary tract abnormalities were presumed to be secondary to polyuria (Wit
et al., 1986), but degeneration of the nerves innervating
the bladder is a more likely explanation (Thompson
et al., 1989). Sixty percent of the Wolfram syndrome
patients die at age 35 (Kinsley et al., 1995) from neurological disorders and urinary tract infections.

151

mutations were found in a cohort of 19 Wolfram patients


by Hardy et al. (1999). The patients described by Rtig
et al. (1993) had pigmented retinopathy and thus probably KearsSayre syndrome (Dean et al., 2002, unpubl.
res.). The patient with mitochondrial mutations described
by Pilz et al. (1994) probably suffered from Lebers hereditary optic neuropathy (Dean et al., 2002, unpubl. res.).
The later finding that WFS1 protein (see below) is not
located on mitochondria also argues against the idea that
Wolframs syndrome would be a mitochondria-mediated
disorder (Takeda et al., 2001). Mitochondrial abnormality
may, however, be present in a minority of the Wolfram
patients (Barrett et al., 1995; Scolding et al., 1996; Rigoli
et al., 1998), be a polymorphism rather than a pathogenic
point mutation (Jackson et al., 1994), and thus a risk
factor for the disease (Hofmann et al., 1997). Barrientos
(1996a, b) suggested an opposite relationship, i.e. that
the chromosomal defect on chromosome 4p16.1 might
predispose to mitochondrial DNA deletions. This possibility remains an interesting point for future research, the
more so since a Wolfram patient has been described
with mitochondria that was morphologically abnormal
and showed a deficient glutamate metabolism (Bundey
et al., 1992).
A novel gene (WFS1) encoding a putative transmembrane protein was found on chromosome 4p16.1 (Inoue
et al., 1998). In the same year another group found the
same gene on chromosome 4p, which they called
wolframin. Wolframin codes for an 890-amino acids transmembrane protein and carries various loss-of-function
mutations in 90% of Wolfram patients (Strom et al., 1998;
Khanim et al., 2001). Mutation screening in Wolfram
families showed a series of different mutations including
stop, frameshift, deletion, nonsense and missense mutations, multiple polymorphisms and insertion mutations,
most of them located in exon 8. At present little is known
about the intracellular location of the protein or its
physiological functions (Gerbitz, 1999; Khanim et al.,
2001; Dean et al., 2002; Domnech et al., 2002). The
intracellular localization of the WFS1 protein is primarily
in the endoplasmic reticulum, suggesting a role in, e.g.
membrane trafficking or protein processing. It was
suggested that the WFS1 protein was important for the
survival of islet -cells. Indeed, missense mutations have
been found in the WFS1 gene in type 1 diabetes,
suggesting that this gene may play a role in
the development of this type of diabetes (Awata et al.,
2000). Noninactivating mutations in WFS1 do not lead

(b) Molecular genetics, differential diagnosis and


psychiatric symptoms
Wolframs syndrome is an autosomal-recessive, neurodegenerative disease, generally located on chromosome
4p16.1 (Cremers et al., 1977; Polymeropoulos et al., 1994;
Kinsley et al., 1995; Barrientos et al., 1996a, b; Hofmann
et al., 1997). However, some Wolfram patients have
linkage to chromosome 4q22-24 (El-Shanti et al., 2000).
In addition, mutations and multiple deletions of mitochondrial deoxyribonucleic acid (DNA) have been
claimed to be present in Wolfram syndrome patients,
leading to a respiratory chain defect (Rtig et al., 1993;
Hofmann et al., 1997). However, Seyrantepe et al.
(1996) found no deletion in mitochondrial DNA of nine
Wolfram patients, and neither did we in our patients (Dean
et al., 2002, unpubl. res.). No pathogenetic mitochondrial

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to Wolframs syndrome, but to low-frequency, sensorineural hearing impairment (Cryns et al., 2002; Lesperance
et al., 2003).
A new phenotypic variant has been described with
absent diabetes insipidus, presence of peptic ulcer disease
and bleeding tendency secondary to a platelet aggregation
defect. It also turned out to be a genotypic variant with
linkage to a second Wolfram syndrome locus (WFS2) on
chromosome 4q22-24 (Ajlouni et al., 2002).
The exact prevalence of Wolframs syndrome is
unknown, but probably between 1 in 100,000 (Rando et
al., 1992) and 1 in 770.000 (Barrett et al., 1995). A large
proportion of the individuals who are homozygous for
the condition suffer severe psychiatric symptoms that lead
to suicide attempts or psychiatric hospitalization (Swift
et al., 1991; Barrett et al., 1995). Of the homozygous
Wolfram syndrome patients, 60% experienced episodes
of severe depression, psychosis or organic brain
syndrome, as well as impulsive verbal and physical
aggression, and 25% had a severe mental illness (Swift
et al., 1991). Heterozygous carrier frequency is between
1 in 100 (Polymeropoulos et al., 1994) and 1 in 354

(Barrett et al., 1995). It is therefore of great interest that


there is some evidence that the heterozygous carriers of
the gene for Wolframs syndrome may have a predisposition for significant psychiatric illness that is some 26
times larger than that of noncarriers. Wolframs syndrome
was claimed to account for about 8% of all psychiatric
hospitalizations or suicides in the USA. The most prominent psychiatric manifestations are supposed to be
depression, violent or aggressive behavior, and organic
brain syndrome (Swift et al., 1990; Owen, 1998; Swift
et al., 1998). A subsequent study did not, however,
confirm those high frequencies of psychiatric illness in
heterozygous carriers (Barrett et al., 1995). A number of
linkage studies have provided evidence for the existence
of a bipolar susceptibility gene on chromosome 4p16.
However, so far no evidence has been found that polymorphisms in the Wolfram gene play an important role
in determining the susceptibility to affective illness or
schizophrenia (Evans et al., 2000b; Middle et al., 2000;
Khanim et al., 2001; Torres et al., 2001). Preliminary
evidence suggests a role for the WFS1 gene in the pathophysiology of impulsive suicide (Sequeira et al., 2003).

Fig. 22.9. Paraffin sections through the paraventricular nucleus of a Wolframs syndrome patient 94-133. (A) With the antibody III-D-7 that recognizes processed vasopressin, no immunoreactivity is found. (B) No immunoreactivity is present either with the antibody PS41 predominantly
recognizing the processed form of neurophysin (NP), but (C) many positive cells are stained with the antibody Boris Y-2, recognizing the
glycopeptide part of the VP precursor. These data indicate a processing disorder. Bar: 25 m. (From Gabrels et al., 1998a, Fig. 1 with permission.)

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not to involve an osmoreceptor defect (Thompson et al.,


1989). Older publications reported no abnormalities in
the hypothalamus of Wolfram patients (Cremers et al.,
1977; Khardori et al., 1983; Mtanda et al., 1986). While
Karp et al. (1978) had already pointed to loss of neurons
and accumulation of iron and calcium in hypothalamic
nuclei, the phenomena were not reported by others. The
SON and PVN are affected (see below), there is not only
atrophy of the optic nerve, optic chiasm and optic tracts,
but also demyelination and degeneration of the brainstem
and cerebellum (Carson et al., 1977; Scolding et al.,
1996). Degeneration has also been reported of the
olfactory bulbs and tracts, as well as loss of neurons in
the lateral geniculate nucleus, atrophy of the superior
colliculus, pons, medullary reticular activating system,
loss of fibers of the cochlear nerve, loss of neurons in
the cochlear nuclei and inferior colliculus, substantia
nigra, superior and inferior olives and cerebellum.
Swollen and dystrophic axons were found in the pons,
fornix, hippocampus and the deep cerebral white matter.

The prediction that 25% of all patients hospitalized for


depression are Wolfram heterozygotes (Swift and Swift,
2000) can now be tested by mutation screening.
(c) The hypothalamoneurohypophysial system
The differential diagnosis includes olivopontocerebellar
atrophy, multisystem atrophy, congenital rubella syndrome, Lebers hereditary optic atrophy, KearnsSayre
syndrome, and thiamine-responsive anemia with diabetes
mellitus and deafness. The association of diabetes mellitus
with optic atrophy also occurs in Friedreichs ataxia,
Refsums disease, Alstrms syndrome and Lawrence
Moon/BardetBiedl syndrome (Chapter 23.3; Dean et al.,
2002, unpubl. res.). Deafness and diabetes also occur in
the 3243 mitochondrial DNA mutation (Barrett and
Bundey, 1997).
The use of three dynamic stimuli, i.e. an osmotic stimulus, hypoglycemia and a baroregulator stimulus, showed
the diabetes insipidus to be of hypothalamic origin and

Fig. 22.10. Quantification of the total number of vasopressinergic neurons as stained by the anti-glycopeptide antibody Boris-Y-2 and compared
with antivasopressin of controls as stained by Truus 18-9-85 (see Swaab et al., 1995a) showed a normal total number of vasopressin neurons
in the PVN of the Wolframs syndrome patient 94-133, and a modest decrease in the number of neurons staining for oxytocin (OXT). (From
J.S. Purba and D.F. Swaab, unpubl. observations.)

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Fig. 22.11. (a) A control case, (95-33, with very long postmortem delay of 6 days stained with antibody 748 (anti-growth hormone releasing
hormone (GHRH)) in the infundibular nucleus. (b) The same case as (a), shown at lower magnification. (c) A Wolfram case, 94-133, with a postmortem delay of 6 days. (d) The same case as (a), shown at lower magnification. Note the lower number of neurons expressing GHRH in this
case of Wolframs syndrome. In another case of Wolframs syndrome (95-68), no GHRH staining at all was found in the infundibular nucleus.
Scale bar = 50 m. (From A. Salehi and D.F. Swaab, unpublished results.)

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The latter changes were sufficient to cause a changed


MRI signal intensity on MR images of the area around
the ventricles (Shannon et al., 1999). MRI can also show
atrophy of the optic nerves, hypothalamus, including the
unusually wide third ventricle, brainstem, cerebellum and
cerebellar hemispheres (Scolding et al., 1996; Gens et
al., 1997; Dean et al., 2003, in prep.). The posterior lobe
of the pituitary is largely absent (Carson et al., 1977).
The absence of a high-intensity MRI signal in the region
of the posterior pituitary that normally gives rise to a
posterior lobe bright spot is in agreement with the degeneration of the hypothalamoneurohypophysial system, but
has also been described with various other causes of
hypothalamic diabetes insipidus (Rando et al., 1992; Dean
et al., 2002, unpubl. res.; see Chapter 22.2). We performed
immunocytochemistry in three cases of Wolframs
syndrome (Dean et al., unpubl. res.). In the two Wolfram
patients with diabetes insipidus (94-133 and 96-46) we
found that the SON contained hardly any neurosecretory
neurons, using thionine staining, and no neurons that
stained processed vasopressin. There was, moreover, a
strong gliosis present in the SON as stained by GFAP.
The PVN did not contain processed vasopressin or neurophysin-expressing neurons either (Fig. 22.9). However,
using a potent antibody against the vasopressin precursor
(antiglycopeptide 22-39 Boris Y-2; Friedmann et al.,
1994), a normal number of vasopressinergic neurons was
present in the PVN (Figs. 22.9, 22.10), although the cells
were clearly too small (Fig. 22.9). No vasopressinergic
neurons were found in the SON with Boris Y-2. Only a
partial loss of oxytocin neurons was found in the PVN.
In one Wolfram patient, who had a mild form of diabetes
insipidus (95-68), there was only a partial absence of
processed vasopressin, while no gliosis was present in
the SON of this patient. It seems thus that in these patients
with diabetes insipidus, there is no global loss of vasopressin neurons in the PVN as has been presumed

155

(Thompson et al., 1989), while neuronal loss seems to


take place in the SON. Degeneration was thus more severe
in the SON than in the PVN, in contrast with the report
by Carson et al. (1977). On the other hand, Shannon et
al. (1999) found severe loss of the magnocellular neurons
in the SON and PVN and no immunoreactivity for vasopressin in a female Wolfram patient of 38 years of age.
The conclusion of our own observations on three cases
was that the vasopressin neurons were present in the PVN
in these Wolframs syndrome cases, but did not produce
processed vasopressin, possibly due to a deficiency in
processing of the precursor with later superadded neuronal
loss. In the two Wolfram patients who did not have vasopressin staining, there was indeed also an absence of
protein convertase (PC)-2 and the molecular chaperone
7B2, strongly suggesting the presence of a processing
disturbance of the vasopressin precursor (Gabrels et al.,
1998a; Dean et al., unpubl. res.). The anterior commissure showed gliosis, loss of axons and scattered mineral
concretions.
In addition, in two Wolfram cases (94-133 and 95-68),
no or only a few growth-hormone-releasing hormone
(GHRH)-expressing neurons were observed in the
infundibular nucleus (A. Salehi, unpublished results; Fig.
22.11). Indeed, one case of a Wolframs syndrome patient
has been described with a disturbance in the growth
hormone axis (Hofmann, 1997). Growth hormone
responded normally to AVP and insulin but also failed
to respond to an infusion of pseudomonas polysaccharide
complex (Marquardt and Loriaux, 1974). This neuroendocrine axis should thus be studied further in Wolframs
syndrome. The determinations of 1-44 GHRH in venous
plasma of Wolfram patients as an indicator of hypothalamic GHRH release may be an interesting procedure for
estimating the central disturbance of this neuroendocrine
axis (Kimber et al., 1997).

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)


The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved

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CHAPTER 23

Eating disorders (Fig. 23A)

Oh Lord, make my words sweet and appetizing. Tomorrow


I may have to eat them (Prof. Head, 1959, cited by G.W.
Bruyn, 1997).

Obesity is one of the most pressing health problems in


the Western world. It is, among other things, responsible
for 6575% of essential hypertension, diabetes mellitus
and cardiovascular problems (Hall et al., 2001). This
epidemic is in need of therapeutics, but only limited
progress has been made as far as the pharmacotherapy
of this condition is concerned (Van der Ploeg, 2000;
Clapham et al., 2001). The etiologies of eating disorders
such as anorexia nervosa, bulimia nervosa (Chapter 23.2)
and obesity are poorly understood. Inherited vulnerabilities, cultural pressures and adverse individual and family
experiences are presumed to have a part in the pathogenetic mechanisms (Walsh and Devlin, 1998; Polivy and
Herman, 2002), while biological factors have only
recently become the subject of studies (Fig. 23.1).
Some clinical observations illustrate the importance
of hypothalamic mechanisms for governing satiety and
hunger (Lustig et al., 1999). Lesions in the ventromedial
hypothalamic area cause increased appetite (Chapter
26.3) and obesity (Fig. 19.13), whereas lesions in the
lateral hypothalamic area (LHA) may cause anorexia
(Chapter 14).
Uncommon, intractable hypothalamic obesity syndrome
occurs after cranial insults. It is often coupled with other
hypothalamopituitary disturbances that may exacerbate
the obesity, such as growth hormone deficiency or
hypothyroidism, but the obesity remains after hormone
replacement. Neurocystiscerosis in the anterior hypothalamus, an infection caused by the presence of Taenia larvae, was accompanied by obesitas and hyperphagia (Lino
et al., 2000). Satiation produces significant decreases in
bloodflow in the hypothalamus of obese women (Gautier
et al., 2001). Using a new temporal clustering technique
for focal MRI (fMRI), Liu et al. (2000) observed two
eating-related peaks in neural activity at two different

Fig. 23A. Museo del Prado, Madrid. JuanCarro de Miranda, Eugenia


Martinez Vallejo, La Monstrua Desnuda, 1680 (Catalogue no. 2800)
Sanz Vega 3079.

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Fig. 23.1. Central and peripheral pathways involved in the regulation of food intake and energy stores. Leptin is secreted by adipose tissue and
circulates to the brain, where it crosses the bloodbrain barrier to reach the arcuate nucleus (ARC) within the hypothalamus. Here, a cascade is
initiated that ultimately regulates feeding behavior, various endocrine systems and other functions. Leptin directly affects neurons (so-called firstorder neurons), in which either the anorexigenic peptides pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)
or the orexigenic peptides neuropeptide-Y (NPY) and agouti-related protein (AGRP) are colocalized. The POMCCART- and NPYAGRPcontaining neurons, which are regulated in an opposing manner by leptin, project further to other brain centers. These include the ventro- and
dorsomedial hypothalamus (VMH, DMH), which also express NPY, the paraventricular nucleus (PVN) and the lateral hypothalamic area (LHA),
which express the neuropeptides orexin (ORX) and melanin-concentrating hormone (MCH). The LHA and other brain areas communicate with
the cerebral cortex, where feeding behavior is finally coordinated. During and after a meal, various signals are generated in the periphery, which
include taste signals from the oral cavity, gastric distention and humoral signals (e.g. cholecystokinin) from secretory cells of the gastrointestinal
tract. These afferent signals are transmitted mainly by the vagus nerve, but also by the sympathetic nervous system to the hindbrain, particularly
the nucleus of the solitary tract (NTS). This brain region communicates with higher brain areas such as the hypothalamus and the cerebral cortex.
(From Chiesi et al., 2001, Fig. 1 with permission.)

times with distinct localization, i.e. in the upper-anterior


and medial region of the hypothalamus. However, these
areas cannot be linked at present to the microscopic or
chemical anatomy of the hypothalamus, although there

was a dynamic interaction between these fMRI responses


and plasma insulin levels.
Eating disorders may accompany many diseases.
Progressive wasting is a common occurrence in many

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types of cancer, acquired-immunodeficiency syndrome


(AIDS) and other infectious diseases, cardiovascular
disease and rheumatoid arthritis. The cachexia-anorexia
syndrome is one of the main factors that lead to death
and is thought to be due to cytokine stimulation of anorexigenic neuropeptides in the hypothalamus (Inui, 1999;
Plata-Salamn, 2000). Some 50% of the patients with
hypothalamic amenorrhea (Chapter 24.1a) have an eating
disorder (Perkins et al., 2001). Eating disorders, either
leading to obesity or to underweight, are associated with
a number of genetic and epigenetic factors (Chapter 23d,
e) and frequently occur in adults with an intellectual
disability (Gravestock, 2000; Chapters 26.5, 23.1, 23.3).
In addition, cultural influences are considered by some
authors to be of crucial importance, as illustrated by
historical and cultural differences (Bemporad, 1997).
Although a large number of brain areas other than the
hypothalamus form a complex network reacting to hunger
and satiety (Del Parigi et al., 2002), these areas will not
be systematically dealt with in this monograph. Indeed,
hunger in normal volunteers is associated with an
increased cerebral blood flow not only in the hypothalamus, but also in the insular cortex, orbitofrontal cortex,
cingulate cortex and parahippocampal and hippocampal
formation, thalamus, caudate, precuneus, putamen and
cerebellum. In addition, satiation was associated with
changes in blood flow in the ventromedial prefrontal
cortex, dorsolateral prefrontal cortex, thalamus, amygdala,
cingulate cortex, insular cortex, parahippocampal gyrus,
temporal cortex, cerebellum and inferior parietal lobule
(Rolls, 1984; Tataranni et al., 1999; Gautier et al., 2001).
The larger number of brain structures involved in eating
disorders in adolescence may be associated with an
elevated risk of developing a broad range of physical
and mental health problems. Adolescents with eating
disorders run a substantially elevated risk of anxiety disorders, cardiovascular symptoms, chronic fatigue, chronic
pain, depressive disorders, limitations in activities due to
poor health, infectious diseases, insomnia, neurological
symptoms and suicide attempts (Johnson et al., 2002).
An interesting example of a nonhypothalamic eating
disorder is the Gourmand syndrome, characterized by
a preoccupation with food and a preference for fine eating,
generally due to lesions involving the right anterior
cerebral hemisphere (Regard and Landis, 1997).
It should be noted that central neural mechanisms and
autonomic system function occur in parallel. Sympathetic
nervous system activation has a general inhibitory effect
on gastrointestinal function, reducing intestinal motility

159

and gastric emptying. It also plays a major role in the


control of lipolysis in adipose tissue, both directly and
due to effects on pancreatic hormone secretion (Snitker
et al., 2000). Animal experiments using immunocytochemistry denervations and retrograde transsynaptic
tracers have demonstrated parasympathetic and sympathetic control of, e.g. the pancreas by the paraventricular
nucleus (PVN) and other hypothalamic centers involved
in the regulation of food intake (Buijs et al., 2001). Diet
is a potent regulator of adaptive thermogenesis. Starvation
can decrease resting metabolic rate by 40%, while feeding
acutely increases metabolic rate. Activation of the satiety
systems decrease food intake and increase sympathetic
nervous system outflow, leading to catabolic effects,
whereas activation of the hunger systems increases food
intake and parasympathetic nervous outflow, leading to
anabolic effects (Nonogaki, 1999). Depression of the
sympathetic and parasympathetic system is associated
with increasing percentages of body fat (Peterson et al.,
1988). Recent animal experimental work has revealed that
the autonomic innervations of fat tissue consist not only
of the sympathetic system, known for its catabolic effect,
but also of a parasympathetic anabolic input. In addition,
the observed somatotopic organization of the subcutaneous versus intraabdominal fat has provided an excellent
explanation for the dissociation in distribution of these
two fat compartments, e.g. in the metabolic syndrome, in
Cushings syndrome and in AIDS lipodystrophy (Kreier
et al., 2002).
An important matter is eating, because it brings together
those that are apart.
Talmoed Bawli

(a) Hypothalamic nuclei involved


Classically, lesions in the ventromedial nucleus (VMN;
Chapter 26.3) are thought to cause avaricious appetite
(Haugh and Markesbery, 1983), whereas lesions in the
LHA (Chapter 14) are thought to cause anorexia (Chapter
14). However, lesions that are precisely restricted to the
rat VMN do not cause hypothalamic obesity, and it has
been proposed that the observed obesity is largely due to
damage of the nearby aminergic medial forebrain bundle,
rather than to a particular nucleus such as the VMN itself
(Gold 1973; Chapter 9). On the other hand, for the
feeding-suppressing action of histamine, the VMN
appears to be the most important site of action (Brown
et al., 2001). Moreover, the presence of hypocretin
(orexin) neurons in the lateral hypothalamus, and in
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particular in the perifornical region, has brought this structure back into focus with regard to eating regulation
(Sakurai et al., 1998; Chapter 14). Recent neurobiological research has revealed a great number of different
hypothalamic neuronal systems, such as neuropeptide-Y
(NPY), and fibers innervating the hypothalamus such as
the aminergic systems, which are involved in the physiology and pathology of food intake. This points to
extensive circuits and networks involved in eating
behavior, rather than one particular nucleus, such as the
VMN or LHA, as the responsible center (Flynn et al.,
1988; Kalra et al., 1999; Chapter 26.3; Fig. 23.1).
One of the most potent stimulants of food intake, NPY,
a 36-amino acid member of the pancreatic polypeptide
family, is produced in the infundibular nucleus (= arcuate
nucleus in rodents; see Chapter 11). The letter Y refers
to two tyrosine residues, which occur at both ends of the
molecule (Tomaszuk et al., 1996). In the human hypothalamus, moderate amounts of NPY messenger RNA
(mRNA) were found not only in the infundibular nucleus
but also in the PVN (Jacques et al., 1996). Injections of
NPY directly into the PVN elicit a dose-dependent
increase in feeding (Stanley et al., 1984). Animal experimental evidence clearly shows that upregulation
of NPY and increased receptor availability underlie hyperphagia (Kalra et al., 1999). It is proposed that there
is altered processing of NPY in mice with the recessive
anorexia mutation (anx), which causes decreased
food intake and starvation, which lead to death at 22 days
after birth (Broberger et al., 1997). For other feeding
regulating peptides in the infundibular nucleus, see
Chapter 23c.
The highest concentration of NPY in the human hypothalamus is found in the infundibular nucleus and in the
VMN (Corder et al., 1990). NPY specifically enables the
ingestion of carbohydrates and would have little or no
impact on the consumption of fat or protein (Leibowitz,
1992). NPY neurons project to the rat PVN on galanin
neurons (Horvath et al., 1996) and corticotropin-releasing
hormone (CRH) neurons (Li et al., 2000), which are both
involved in the regulation of ingestive behavior. In addition, NPY fibers innervate thyrotropin-releasing hormone
(TRH) neurons (Mihaly et al., 2000). In the monkey PVN,
NPY-containing terminals are found on cocaine- and
amphetamine-regulated transcript (CART)-producing
neurons (see below) (Dall Vechia et al., 2000).
The PVN is a major appetite-regulating center in which
oxytocin, CRH and galanin neurons, and NPY, noradrenaline, dopamine and serotonin terminals meet. It is,

moreover, presumed that NPY serves as a messenger


between the neuronal processes that regulate reproduction and those that maintain energy homeostasis, and may
thus be a key molecule in the nutritional infertility seen
in anorexia (Kalra and Kalra, 1996; see Chapter 23.2).
In addition, NPY is one of the strongest genetic factors
identified that affect serum cholesterol levels (Uusitupa
et al., 1998). Not only the PVN but also the perifornical
area is a major focus of NPY effects on feeding behavior
(Stanley et al., 1993). The activity of NPY and its receptors fluctuate over the course of the day (Leibowitz, 1992).
It has been hypothesized that a defective inhibition of the
NPY neuron that colocalizes agouti-related protein
(AGRP) (see below) would result in reduced energy
expenditure, disturbances of glucose and lipid metabolism, and obesity (Morton and Schwartz, 2001). Our
research showed the opposite. The infundibular NPY
content is decreased in PraderWilli patients and nonsyndromal obesity (Goldstone et al., 2002; Fig. 23.8).
Surprisingly, the absence of NPY in mice fails to alter
their feeding pattern or body weight. Because a deficiency
of even a single component of the pathway that limits
food intake (such as leptin or the melanocortin (MC)-4
receptor; see above) can result in obesity, it has been
suggested that anorexigenic signals are more redundant
than those limiting food intake, and that NPY is not the
only factor responsible for normal feeding and leptin
response (Woods and Stock, 1996; Shimada et al., 1998;
see below). NPY effects are mediated by a family of
receptor subtypes Y1-5 and there is strong evidence
for the occurrence of additional receptor subtypes.
Inactivation of the Y2 receptor in mice caused increased
body weight, food intake, fat deposition and an attenuated response to leptin (Naveilhan et al., 1999). The Y4
and Y5 receptors have been cloned and expressed. The
Y5 receptor has been suggested to be the Y1-like receptor
in feeding (Gerald et al., 1996; Balasubramaniam, 1997).
However, Y5 receptor knock-out mice developed only
mild late-onset obesity, so it does not seem to be the
most critical feeding receptor in mice (Marsh et al., 1998).
The Y5 receptor has also been designated as Y2b, and
the confusion increased with the concurrent publication
of a different Y receptor that was also called Y5. Y5
mRNA levels are high in the human hypothalamus, while
conventional radio ligand techniques do not detect Y5like binding sites (Statnick et al., 1998). Following the
International Union of Pharmacology (IUPHAR) recommendations, the Y receptor that has been referred to as
both Y5 and Y2b has been designated Y6. The message

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for Y6 is present in the human brain and absent in rat


tissue. However, the human Y6 gene appears to contain
a frame-shift mutation followed by a stop codon, truncating the receptor at the sixth transmembrane domain,
probably rendering the receptor inactive in all primates
tested so far (Burkhoff et al., 1998). Throughout the
human hypothalamus, 25 times more Y1 binding sites
than Y2 binding sites were found. The number of binding
sites was moderate to low. This is rather surprising, as
the hypothalamus is highly enriched in both NPY cell
bodies and fibers. Perhaps other receptor subtypes will
ultimately appear to be present in higher amounts (Jacques
et al., 1997). Dumont et al. (1998, 2000) found a relative paucity of both Y1 and Y5 receptors in the human
brain, except for the dentate gyrus of the hippocampus
and the bed nucleus of the stria terminalis, where significant amounts of Y1-like and Y2-like receptors were
observed. Moderate levels of Y2/Y5 binding sites were
reported in the human PVN and dorsomedial nucleus
(Dumont et al., 2000). The NPY-Y5 receptor gene was
found to be expressed in the infundibular nucleus, PVN,
VMN and posterior hypothalamus (Jacques et al., 1998).
The suprachiasmatic nucleus (SCN; see Chapter 4) is
responsible for the circadian pattern in feeding behavior
(Bernardis and Bellinger, 1996). Animal experiments
indicate that the neurons of the SCN are involved in the
circadian control of the autonomous nervous system and
thus in the circadian regulation of glucose metabolism.
The SCN may exert these functions by influencing the
function of the PVN and dorsomedial nucleus (DMN;
Nagai et al., 1996) and other hypothalamic nuclei that
project to the parasympathetic dorsal motor nucleus of
the vagus or the sympathetic preganglionic spinal cord
neurons that innervate, e.g. the pancreas (Buijs et al.,
2001). The nucleus basalis of Meynert (NBM) contains
feeding cells, and stimulation of this area can mimic the
reward value of food (Rolls, 1984).

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(Satoh et al., 1997), possibly by decreasing the production of NPY in the arcuate nucleus (Stephens et al., 1995),
although activation of the alternative pathways should
also be considered (Eriksson et al., 1996). Plasma leptin
levels are significantly higher in obese subjects and
PraderWilli patients. These elevations are proportional
to the increased body-mass index (Carlson et al., 1999),
suggesting that some obese humans are resistant to leptin.
Either leptin deficiency or leptin resistance can cause
severe obesity in mice (Schwartz and Seely, 1997). Leptin
crosses the bloodbrain barrier by a saturable, receptormediated transport system (Couce et al., 1997). However,
it should be noted that the arcuate nucleus is presumed
to be situated outside the bloodbrain barrier. In the
arcuate nucleus of the rat, leptin binding increases twofold
after a 2-day fast (Baskin et al., 1999). Cerebrospinal
fluid (CSF) leptin concentrations in children reflect
plasma leptin concentrations, including the rise in leptin
levels during the advent of sexual dimorphism at puberty.
Only free leptin is detectable in CSF (Landt et al., 2000).
Arcuate nucleus NPY neurons and pro-opiomelanocortin
(POMC) neurons are principal sites of leptin-receptor
expression. Leptin increases the electrical activity of the
anorexic POMC neurons, while melanocortin has an
autoinhibitory effect on this circuit (Cowley et al., 2001).
In addition, leptin may not only act on the arcuate nucleus.
In obese rats the strongest leptin response was found in
the PVN (Woods and Stock, 1996). Electrophysiological
studies on rat PVN slices suggest that leptin acts as a
satiety signal to inhibit feeding as a result of its ability
to influence the excitability of PVN neurons (Smith
et al., 1998). Leptin activates CART neurons, which
mostly also contain POMC. Elmquist et al. (1997) found
activation as a result of leptin administration not only in
the PVN, but also in the VMN, DMN and ventral
premamillary nuclei. Leptin may also act via the tuberomamillary histaminergic neurons on feeding behavior
(Yoshimatsu et al., 1999). Experiments in rat indicate
that leptin decreases food intake induced by melaninconcentrating hormone (MCH), galanin or NPY (Sahu,
1998), suggesting that modulation of the postsynaptic
actions of these peptides is one of the mechanisms of
action of leptin. The circadian fluctuations in leptin
(Mantzoros, 2000) indicate a role of the suprachiasmatic
nucleus.
The possibility that leptin is produced not only by fat
cells, but also in the brain, should certainly not be
excluded (Reichlin, 1999). Leptin concentrations in the
internal jugular vein are significantly higher than arterial

(b) Leptin
Leptin (from the Greek word leptos = thin), a satiety
factor that is produced by fat cells, has a potent influence on central mechanisms of food intake and is an
essential chain in circuits that act as an adipostat. Leptin
is the product of the LEP gene (Zhang et al., 1994; Halaas
et al., 1995; Clapham et al., 2001). It informs the brain
about the size of the body fat depots by receptors that
are present in the arcuate nucleus. It reduces food intake
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levels in lean females and in obese (but not in lean) men


(Wiesner et al., 1999). Indeed, leptin mRNA was found
to be present in the rat hypothalamus and other brain
regions. Since leptin mRNA expression in the brain is
suppressed by fasting, a role for brain leptin in the central
regulation of appetite is suggested (Morash et al., 1999).
The leptin receptor occurs in at least five forms as a
result of alternative splicing. It is the long form that is
the most important for the regulation of the energy balance
(Clapham et al., 2001). In the rat brain the leptin receptor
is located in the arcuate nucleus, PVN, VMN and lateral
hypothalamic area. In addition, the olfactory bulb,
neocortex, cerebellar cortex, dorsal raphe nucleus, inferior olive, nucleus of the solitary tract, and the dorsal
motor nucleus of the vagus nerve also show immunoreactivity. Western blotting yields the expected 120-kDa
major band (Shioda et al., 1998). An immunocytochemical study of the human hypothalamus has shown
leptin-receptor staining in a number of human hypothalamic nuclei, i.e. the arcuate nucleus, SCN, mamillary
nucleus, PVN, DMN, supraoptic nucleus (SON), posterior nucleus, and the NBM. Moreover, the leptin-receptor
is found in extrahypothalamic sites such as the inferior
olivary nucleus and cerebellar Purkinje cells (Couce et
al., 1997; Burguera et al., 2000), as well as in the choroid
plexus, ependymal lining and small vessels wall. It was
hypothesized that leptin may cross the bloodbrain barrier
in this way (Couce et al., 1997). Indeed, high-affinity
transport systems mediating leptin uptake were found in
the rat hypothalamus and across the bloodCSF barrier.
High-affinity binding of leptin was also detected in the
choroid plexus. In contrast, low-affinity carriers for leptin
were found at the bloodbrain barrier outside the hypothalamus (Zlokovic et al., 2000). The gene for the leptin
receptor is mutated in fatty (fa/fa) rats and diabetic (db/db)
mice (Clapham et al., 2001).
The hormonal message of plasma leptin is transduced
by the NPY neurons of the arcuate nucleus, e.g. to CRH,
TRH and luteinizing hormone-releasing hormone (LHRH)
neurons, as shown in animal experiments. The latter
finding is a possible basis for coupling of the energy imbalance with menstrual irregularity and infertility (Costa
et al., 1997b; Gehlert and Heiman, 1997; see Chapter
23.2). Indeed, low leptin synthesis appeared to be associated with amenorrhea in underweight females. Apparently
a critical leptin level is needed, not only to trigger the
menarche (Matkovic et al., 1997), but also to maintain
menstruation (Kpp et al., 1997). Moreover, a rise of
endogenous circulating leptin concentrations precedes the

onset of puberty in humans (Mantzoros et al., 1997).


Information about the energy balance that is fed back to
the TRH and CRH neurons of the PVN determines consequent effects in thermogenesis and stress reactions.
Very high serum leptin levels beyond the expected
levels for body mass index are found in idiopathic
intracranial hypertension, a neurological disorder mainly
affecting obese females, and after hypothalamic surgery,
i.e. after craniopharyngeal removal (Lampl et al., 2002).
(c) Neuropeptides and hormones involved
The effects of leptin (Chapter 23b) and NPY (see Chapter
23a; Table 23.1) on appetite have been discussed previously. The peptide alpha-melanotropin (-MSH) is a
POMC-derived peptide (Fig. 23.2) that is produced in the
infundibular nucleus (Mihaly et al., 2000) and inhibits
feeding behavior by acting on the MC-4 receptor.
Opiates such as dynorphin and endorphin stimulate
food intake (Williams et al., 1991; Rohner-Jeanrenaud,
1995; Bernardis and Bellinger, 1996; Tritos et al., 1998b;
Lustig et al., 1999; Taylor, 1999; Stving et al., 2002).
A mouse knock-out for POMC developed hyperphagia
and obesity, defective adrenal development and altered
pigmentation (Barsh, 1999; Yaswen et al., 1999).
Moreover, MSH/ACTH 4-10, the core sequence of
all melanocortins, administrated intranasally to human
subjects, reduces body fat, plasma leptin and insulin levels
(Fehm et al., 2001). It may be of relevance to weight
changes after the age of 50 years that the POMC gene
expression is decreased in the infundibular nucleus of postmenopausal women (Abel and Rance, 1999). Inactivation
of this receptor by gene targeting results in mice that
develop a maturity onset obesity syndrome associated
with hyperphagia, hyperinsulinemia and hyperglycemia.
This syndrome recapitulates several of the characteristic
features of the agouti obesity syndrome as discussed
below (Huszar et al., 1997). In humans, mutations of the
G-protein-coupled MC-4 receptor gene are the cause of
obesity in some 5% of the subjects. Mutation carriers
have severe obesity, increased lean mass, increased linear
growth, hyperphagia, and severe hyperinsulinaemia.
Homozygotes are more affected than heterozygotes. The
major phenotype of MC4R mutations is binge-eating
(Vaisse et al., 1998; Yeo et al., 1998; Gu et al., 1999;
Hinney et al., 1999; Jacobson et al., 2002; Branson et al.,
2003; Farooqi et al., 2003). Multiple molecular mechanisms are involved in the disruption of MC4 receptor

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TABLE 23.1
Food consumption-regulating neuroactive compounds in the hypothalamus.
Localization cell bodies

Effect on food consumption

Alpha melanotropin (-MSH)


Agouti-related protein (AGRP)
Cocaine and amphetamine-regulated
transcript (CART)
Corticotropin (CRH), Urocortin
Dopamine
Dynorphin
Endorphins
Galanin
Ghrelin
Growth hormone releasing hormone (GHRH)
Histamine
Hypocretin 1 and 2 (or orexin A and B)
Leptin
Melanin-concentrating hormone (MCH)

Infundibular nucleus (Fig. 23.2)


Infundibular nucleus; coexpression in NPY neurons
Infundibular nucleus and many other hypothalamic
nuclei
Paraventricular nucleus
Ventral tegmentum
Tuberal and caudal hypothalamus (Fig. 31.2)
Infundibular nucleus
Many hypothalamic nuclei
Arcuate nucleus
Infundibular nucleus
Tuberomamillary nucleus
Lateral hypothalamus and perifornical area
Fat tissue
Lateral, posterior hypothalamus and a number
of other hypothalamic areas
Locus coeruleus
Infundibular nucleus
Paraventricular nucleus
Raphe nuclei
Periventricular nucleus

Noradrenaline
Neuropeptide-Y (NPY)
Oxytocin
Serotonin (5-HT)
Somatostatin

Active compound

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NPY neurons (Mihaly et al., 2000). Fasting increases


AGRP mRNA (Hahn et al., 1998a) and overexpression
of AGRP leads to obesity (Rossi et al., 1998b). In addition, agouti-related peptides, when administered centrally,
induce hyperphagia (Rossi et al., 1998b). In PraderWilli
syndrome (PWS) (Chapter 23.1) and nonsyndromic obese
patients, we did not find a significant change in AGRP
staining in the infundibular nucleus (Goldstone et al.,
2002, see Chapter 23.2; Fig. 23.8). Three single nucleotide
polymorphisms (SNPs) have been identified in the coding
region of the human AGRP. Two of these SNPs were
associated with susceptibility for anorexia nervosa (Vink
et al., 2001b).
Hypocretins 1 and 2, also known as orexins A and B,
a pair of hypothalamic peptides, also act on G-proteincoupled orexin 1 and 2 receptors (Kunii et al., 1999). The
peptides were called hypocretins because they were
produced in the hypothalamus and resembled the secretin
neuropeptides that help regulate gut function (Samson and
Resch, 2000). The word orexis means appetite. Orexin
A and B cell bodies are located in and around the lateral
and posterior hypothalamus and in the perifornical area
(Peyron et al., 2000; Chapter 14). These peptides stimulate food consumption and influence metabolic rate and

function by mutations, such as impaired cell surface


expression on reduced binding of the ligand (Yeo et al.,
2003). Injection of an MC-4 receptor agonist inhibits and
injection of an MC-4 receptor antagonist stimulates
feeding when injected directly into the rat PVN, where
the expression of this receptor is very high (Giraudo et
al., 1998). Observations in rat indicate that the satiety
effect of leptin is mediated by stimulation of the hypothalamic POMC system.
Agouti regulates hair color and body weight and acts
as a high-affinity, natural antagonist of the MC-1, MC-3
and MC-4 receptors (Rossi et al., 1998b). Mutations in
the agouti coat color gene cause obesity in mice (Fan et
al., 1997; Huszar et al., 1997; Schith et al., 1997; Barsh,
1999; Nagle et al., 1999). Mutations within the mahogany
locus suppress obesity of the agouti-lethal yellow mutant
mouse, but do not suppress the obese phenotype of the
MC-4 receptor null allele. The mahogany gene is
expressed in the ventromedial nucleus and mahogany can
suppress diet-induced obesity. The amino acid sequence
of mahogany protein suggests that it is a large, single
transmembrane-domain receptor-like molecule with a
short cytoplasmatic tail. There is an AGRP that is an
endogenous MC receptor antagonist that coexpresses in
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Fig. 23.2. The protein sequence of the pro-opiomelanocortin (POMC)-derived peptides is shown to illustrate the composition of the single peptides,
their position within the precursor POMC and their endoproteolytic cleavage. The first residues containing the signal peptide were given negative
numbers. Residues in dark gray represent the paired basic sites that serve as targets for PC1 and PC2; black arrows indicate preferential cleavage
by PC1; white arrows indicate preferential cleavage by PC2. The interaction of each peptide with the two sets of receptors and the functional roles,
where known, are shown. Note the exclusive binding of the MC2-R by corticotropin (ACTH) and the restricted affinity of gamma-melanotropin
(-MSH) to the MC3-R. Because the physiological role of -MSH is not clear, the affinities to the different MC receptors are not included.
Residues in light gray represent the binding cores of each peptide. MCR, melanocortin receptor; PC, prohormone convertase. (From Krude and
Grters, 2000, Fig. 1 with permission.)

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arousal. Prepro-orexin mRNA is upregulated after fasting


(Sakurai et al., 1998) and genetic ablation of orexin
neurons in mice results in obesity (Hara et al., 2001),
orexin may act as MC-4 receptor agonists and may also
be involved in autonomic and neuroendocrine regulation
(Samson and Resch, 2000). Recently it was found that a
mutation in the hypocretin (orexin) receptor 2 gene or a
disappearance of the hypocretin system is responsible for
narcolepsia (Lin et al., 1999; Peyron et al., 2000; Samson
and Resch, 2000; Hara et al., 2001; Chapter 28.4). It is
interesting though that narcolepsy patients have serum
levels of leptin that are more than 50% reduced, pointing
to the presence of an alteration in the regulation of food
intake and metabolism in this disorder (Schuld et al.,
2000).
Yet another factor that influences eating behavior is
galanin. It stimulates food consumption, preferentially
increasing the ingestion of fat and leaving the uptake of
carbohydrate and protein unaffected (Leibowitz, 1992;
Akabayashi et al., 1994). Galanin is overexpressed in the
PVN and median eminence of the obese Zucker rat (Beck
et al., 1993), which has no functional leptin receptor. This
peptide is present in the arcuate nucleus, SCN, sexually
dimorphic nucleus, PVN and tuberomamillary (TMN)
and supramamillary nuclei. In the human SON and SCN,
as well as in the PVN, galanin is colocalized with vasopressin, oxytocin or tyrosine hydroxylase (Gai et al.,
1990). From experimental studies in rat, it appears that
only the anterior parvocellular, galanin-containing PVN
neurons are involved in the metabolic and behavioral
processes of fat metabolism and ingestion (Wang et al.,
1998). In early postnatally overfed rats, excess weight
and hyperinsulinemia have been observed, accompanied
by an increased number of galanin-positive neurons in
the PVN at weaning. The galanin neurons in the PVN
may thus be involved where perinatal overfeeding is a
risk factor for excess weight and diabetes during life
(Plagemann et al., 1999).
Oxytocin release accompanies treatments known to
inhibit food intake (Verbalis et al., 1995), and oxytocin
neurons of the PVN are considered to be satiety cells (see
Chapter 23.1), probably acting by their projections to the
brainstem nuclei (Buijs et al., 1983). The increased oxytocinergic activity observed during depression might
therefore be related to the decreased food uptake in this
condition (Purba et al., 1996; Chapter 26.4), and the
decreased number of oxytocin neurons in the PVN of
PraderWilli patients may be responsible for their insatiable hunger (Swaab et al., 1995a; Chapter 23.1). On the

165

other hand, the satiety effects of oxytocin are not without


controversy. One research group has shown that long-term
oxytocin subcutaneous treatment may result in increased
food intake and weight gain, a mechanism that is suggested
to be of possible physiological importance in lactationinduced hyperphagia (Bjrkstrand and Uvns-Moberg,
1996; Uvns-Moberg et al., 1998). In fact, oxytocin may
either increase or decrease food intake, depending on the
rat strain studied (Uvns-Moberg et al., 1996).
Endogenous corticosteroids play a pivotal role in
visceral adipose tissue deposition. Subjects with abdominal obesity are characterized by hyperactivity of the
hypothalamopituitaryadrenal (HPA) axis, which leads
to functional hypercortisolism (Pasquali and Vicennati,
2000a, b). Glucocorticoids stimulate NPY and inhibit
CRH, and this combination promotes food consumption
and therefore weight gain, e.g. in Cushings syndrome or
treatment with corticosteroids (Schwartz and Seely,
1977). However, the reversibility of the HPA axis changes
with weight loss, suggesting that these changes are consequences of rather than the cause of an expanding
intraabdominal fat deposit (Kopelman, 1999), and autonomic innervation of the adrenal and adipous tissue may
play a crucial role (Buijs and Kalsbeek, 2001). CRH and
urocortin inhibit food intake and are therefore considered
to be responsible for at least some of the changes in
eating behavior in stress and depression (Holsboer et al.,
1992; Raadsheer et al., 1995; Bradbury et al., 2000; see
Chapter 26.4). Judging by the data from transgenic
mice, the CRH receptor-1 does not, however, seem to
play a critical role in the basal regulation of ingestive
behavior (Mller et al., 2000a). The observation that CRH
in human CSF diminishes after feeding has been interpreted as not supporting the hypothesis that CRH is a
central satiety factor in human (Kasckow et al., 2001a).
However, CRH levels in CSF do not seem to reflect
hypothalamic CRH production (see Chapter 26.4d),
while some studies indicate that plasma and salivary
cortisol levels are diminished in severely obese patients
(Putignana et al., 2001). Others claim that basal cortisol
levels are normal in obese women. However, different
HPA-activity changes were observed in obese women in
relation to abdominal versus subcutaneous fat distribution.
A recently discovered satiety factor is the peptide
CART, which is produced in the DMN, SON and PVN,
posterior hypothalamus, premamillary nucleus, TMN,
infundibular nucleus, LHA, bed nucleus of the stria terminalis, amygdala, thalamus and cortex in the human brain
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(Hurd and Fagergren, 2000; Elias et al., 2001). In humans,


CART contains 116 amino acid residues. CART mRNA
is upregulated by leptin and the expressed CART is a
potent anorectic peptide that overrides the feeding
response induced by NPY (Thim et al., 1998). The
CART/POMC neurons innervate sympathetic preganglionic neurons in the spinal cord that may contribute to
the increased thermogenesis and energy expenditure and
the increased body weight that are observed after leptin
administration (Elias et al., 1998). CART administration
intracerebroventricularly (ICV) inhibits food intake,
induces the expression of c-Fos in the PVN and causes
a transient rise in plasma oxytocin levels in rat (Vrang
et al., 2000). This suggests that CART might act through
the oxytocinergic system to bring about its inhibitory
effects on feeding behavior. Oxytocin cells of the PVN
are considered to be satiety neurons (Swaab et al., 1995a).
Interestingly, preliminary observations by our group indicate that there is a tendency toward a reduction in CART
cell number in the infundibular nucleus in PWS (F.
Goezinne et al., unpubl. results).
MCH is produced in the LHA, perifornical area, tuberomamillary nucleus, posterior nucleus and zona incerta
(Pelletier et al., 1987; Bresson et al., 1989; Mouri et al.,
1993; Qu et al., 1996; Saito et al., 2000b; see Chapter
14). MCH is overexpressed in the hypothalamus of obese
mice and during fasting. ICV injection of MCH in rat
increases food consumption (Qu et al., 1996). Mice deficient for MCH have reduced body weight due to
hypophagia and an inappropriately increased metabolic
rate, despite the reduced amounts of leptin and POMC
mRNA in their arcuate nucleus (Shimada et al., 1998).
MCH is the cognate ligand for the orphan G-proteincoupled receptor SCL-1, which is expressed in the rat
ventromedial and dorsomedial nuclei (Chambers et al.,
1999; Saito et al., 1999). Apart from its role in feeding,
the MCH receptor may be involved in the regulation of
the HPA axis in stress, olfaction and anxiety (Saito et
al., 2000). There are at present two G-protein-coupled
receptors known for MCH (Sailer et al., 2001). MCHbinding sites are present in the human hypothalamus and
other brain areas (Sone et al., 2000). Neurotensin,
bombesin and glucagon-like peptide inhibit food intake,
and somatostatin increases feeding, while octreotide, a
long-acting somatostatin receptor agonist, promotes
weight loss, possibly by suppressing excessive insulin
secretion. Growth hormone-releasing hormone (GHRH)
stimulates feeding (Leibowitz, 1992). Ghrelin is an
endogenous growth hormone-release-stimulating peptide

that is produced in the rat arcuate nucleus. Ghre comes


from the Indo-European root for the word grow. It also
increases feeding in rats and stimulates NPY and AGRP
neurons (Nakazato et al., 2001; Lu et al., 2002). It is a
peptide of 28 amino acids, which acts through the endogenous ligand for the growth hormone secretagogue receptor
(Lu et al., 2002) and antagonizes leptin action through
the activation of the NPY/Y1 receptor pathway (Shintani
et al., 2001). Recently a mutation was found in the
preproghrelin sequence that corresponds to the last amino
acid in the mature ghrelin product in heterozygous obese
subjects, showing that the ghrelin gene could play a role
in the etiology of obesity (Lustig et al., 1999; Ukkola et
al., 2001). PWS patients have markedly elevated plasma
ghrelin levels, which may contribute to the severe hyperphagia and obesity associated with this syndrome
(Cummings et al., 2002; Chapter 23.1). In addition,
increased fasting ghrelin plasma levels are found in
patients with bulimia nervosa (Tanaka et al., 2002).
Ghrelin causes a hypothalamic release of GHRH,
CRH, arginine vasopressin (AVP), and NPY (Wren et
al., 2002).
Injection of serotonin (5-HT) suppresses carbohydrate
intake, with little or no change in protein and fat in freely
moving animals (Bernardis and Bellinger, 1996); but, in
the rat, serotonergic control of feeding behavior has been
designated both as suppressant and stimulant. A serotonergic disorder has been presumed in anorexia and
bulimia nervosa (Walsh and Devlin, 1998). Dopamine
and noradrenaline inhibit food intake and the VMNlesion syndrome may be partly if not completely due to
interruption of the aminergic innervation of the hypothalamus (see Chapters 9, 26.3; Bernardis and Bellinger,
1996). In genetically obese mice, there are hypothalamic
noradrenergic receptor changes and an increased noradrenergic activity is presumed (Boundy et al., 2000).
Histamine, derived from the TMN (Chapter 13),
suppresses feeding (Brown et al., 2001).
Moreover, a number of substances from the periphery
affect the balance of nutrient and energy homeostasis,
such as cholecystokinin (CCK) from the gastrointestinal
tract (Hopkins and Williams, 1997). Corticosteroids,
aldosterone, estrogens and the nutrients glucose, fatty
acids and amino acids, also affect the energy homeostasis
(Williams et al., 1991; Leibowitz, 1992; for leptin, see
Chapter 23b). In addition, sex hormones and sex
hormone-binding globulin may play a role in obesity and
may explain the increased abdominal obesity in
menopause-induced estrogen deficiency (Tchernof and

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Desprs, 2000). The anorectic action of estrogens in rat


is mediated by the central estrogen receptor- (Liang et
al., 2002). Insulin receptors are present in the human
hypothalamus (Hopkins and Williams, 1997). Mice with
neuron-specific disruption of the insulin receptor gene
show increased food intake and a diet-sensitive obesity,
with increases in body fat and plasma leptin levels
(Brning et al., 2000). In patients with suprasellar lesions,
documented pituitary, hypothalamic lesions, and profound
obesity, T3 supplementation weight loss was promoted
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humans than in mice. Treatment of this 9-year-old child


with recombinant leptin led to sustained reduction in
weight, predominantly as a result of a loss of fat. This
therapeutic response confirms the importance of leptin in
the regulation of body weight in humans and establishes
an important role for this hormone in the regulation of
appetite (Farooqi et al., 1999). Polymorphisms in the leptin receptor gene are associated with levels of abdominal
fat in postmenopausal overweight women (Wouters et al.,
2001). Another genetic defect was found in a woman with
extreme childhood obesity, abnormal glucose homeostasis, hypogonadotropic hypogonadism, hypocortisolism
and elevated plasma proinsulin and POMC concentrations,
but a very low insulin level. This disorder seems to be
based upon a mutation in the prohormone processing
endopeptidase, prohormone convertase 1 (PC1) (Jackson
et al., 1997). Severe early-onset obesity, adrenal insufficiency and red hair pigmentation were found to be caused
by POMC mutations (Krude et al., 1998; Krude and
Grters, 2000). The patients had severe early-onset obesity and red hair pigmentation due to mutations truncating the POMC molecule and leading to the complete lack
of ACTH and -MSH (Krude and Grters, 2000; MacNeil
et al., 2002). However, a cryptic trinucleotide repeat polymorphism in exon 3 of POMC that was associated with
elevated leptin levels, appeared not to be associated with
obesity (Rosmond et al., 2002). Mutations in the MC-4
receptor gene (MC4R) seem to be a common cause of
monogenic human obesity. Up to 46% of severely obese
humans have defects of the MC-4 receptor gene. Affected
individuals have hyperphagia in childhood, which loses
its intensity later in life. These individuals of normal
height, present with binge-eating as the major phenotype
characteristic. Some patients had cyclothymia or bipolar
affective disorder (Cone, 1999; Mergen et al., 2001;
Kobayashi et al., 2002; Branson et al., 2003; Farooqi et
al., 2003). A patient with both extreme obesity and bulimia
nervosa has been described, who has a haploinsufficiency
mutation in the MC-4 receptor (Hebebrand et al., 2002).
A SNP in the AGRP, a natural MC-4 receptor agonist, is
thought to increase the risk of developing anorexia nervosa (Vink et al., 2001b). In one patient with both extreme
obesity and bulimia nervosa, a haplo-insufficiency mutation was found in the MC-4 receptor (Hebebrand et al.,
2002). A novel MC-3 receptor mutation has been observed
in an obese girl and her father (Lee et al., 2002). However,
MC-3 receptor variantss are common and generally considered not to explain human morbid obesity (SchalinJntti et al., 2003). In a number of obese subjects a

(d) Molecular genetic factors involved in obesity


Human obesity certainly has an important inherited component. In fact, studies in twins, adoptees and families
indicate that 80% of the variance in body-mass index is
attributable to genetic factors (Rosenbaum et al., 1997).
The obesity gene map 2000 reports on the presence of
47 human cases of obesity caused by single-gene mutation in six different genes, including SIM1, a critical transcription factor for the formation of the SON and PVN
in mice. In addition, 24 Mendelian disorders exhibiting
obesity as one of their clinical manifestations have now
been mapped (Prusse et al., 2001), yet the genetic factors responsible for most obesity in the general population have remained elusive so far. As far as the single-gene
mutations are concerned, obese subjects with a mutation
in the gene that encodes for leptin (Montague et al., 1997;
Strbel et al., 1998) or for the leptin receptor (Clment
et al., 1998) have been described. The missense leptin
mutation described by Strbel et al. (1998) is associated
not only with morbid obesity but also with hypogonadism
and primary amenorrhea. The male patient never enters
the stage of puberty. The mutation described by Clment
et al. (1998) results in a truncated leptin receptor, lacking both the transmembrane and the intracellular domains.
In addition to their early-onset morbid obesity and lack
of pubertal development, patients who are homozygous
for this mutation also have reduced secretion of growth
hormone, growth retardation and central hypothyroidism.
The observations in subjects with mutations in the leptin
receptor and leptin itself suggest that leptin not only controls body mass but is also a necessary signal for the initiation of puberty in humans. However, since in a child
with congenital leptin deficiency there was no evidence
of substantial impairment in basal or total energy expenditure, and her body temperature was normal, leptin may
be less central to the regulation of energy expenditure in
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mutation in the preproghrelin gene was found that corresponds to the last amino acid of ghrelin (Ukkola et al.,
2001), but so far there is no good evidence that sequence
variants in the coding region of the ghrelin gene influence body weight (Hinney et al., 2002). However, growth
hormone secretogogues such as ghrelin may be important
for feeding. When the expression of the receptor for this
compound in the arcuate nucleus was blocked, the rats
had lower body weight and less adipose tissue than controls (Shuto et al., 2002). A glucocorticoid receptor polymorphism is associated with obesity and dysregulation of
the HPA axis (Rosmond et al., 2000). A patient with a
mutation in the transcription factor steroidogenic factor 1
had a complete sex reversal and developed obesity in late
adolescence (Ozisik et al., 2002).
PWS, which is characterized by obesity, hypotonia,
mental retardation and hypogonadism, is discussed in
Chapter 23.1. PraderWilli patients usually have a de
novo, paternally derived, deletion of the chromosome
region 15q11-13. In contrast, Angelmans syndrome is
generally due to a maternally derived deletion of the chromosome 15q11-13 region. Its clinical features comprise
severe mental retardation, postnatal microcephaly, macrostomia and prograthia, absence of speech and a happy
disposition. A group of patients has been reported who
lack most of these features, but present with obesity,
muscular hypotonia and mild retardation, i.e. features that
are also seen in PWS. The Angelman patients had an
apparently normal chromosome 15 of biparental inheritance but possibly an incomplete imprinting defect or
cellular mosaicism. For other eating disorders, such as
BardetBiedl syndrome, see Chapter 23.3.

and some authors propose that cultural factors are of great


importance (Bemporad, 1997). Moreover, morbid obesity
has been reported following encephalitis lethargica infection and other viral neurological infections (Nagashima
et al., 1992; Chapter 20.2). Animal models with human
adenovirus-induced adiposity also suggest the possibility
of viral involvement (Dhurandhar et al., 2000). In addition, Langerhans cell histiocytosis (Chapter 21.3) and
ventromedial hypothalamic lesions (Chapter 26.3) may
be accompanied by adipositas. Autoantibodies against MSH, ACTH, and LHRH have been found in anorexia
and bulimia nervosa (Fetissov et al., 2002). Both conventional and newer antipsychotics are associated with weight
gain. Among the newer agents, clozapine appears to have
the largest potential to induce weight gain, and ziprasidone the smallest (Allison et al., 1999).
Progressive wasting as found in cancer is considered
to be due to a disruption of the physiological mechanisms
controling energy intake. Cancer anorexia is multifactorial and may involve most of the neuronal signaling pathways modulating energy intake. Factors probably involved
are cytokines, such as tumor necrosis factor , interleukins-1 and -6, interferon-, leukemia inhibitory factor
and ciliary neurotrophic factor. They are proposed to
stimulate anorexigenic neuropeptides such as CRH in the
hypothalamus, and to inhibit neuropeptides of the orexogenic network such as NPY, galanin and opioids, and
hormones such as leptin. In addition, neurotransmitters
such as serotonin and dopamine are presumed to be
involved (Inui, 1999; Laviano et al., 2002). Animal experiments have shown that cachexia induced by lipopolysaccharide administration and by tumor growth is ameliorated
by central MC4-R blockade (Marks et al., 2001).

(e) Epigenetic factors in obesity and anorexia cachexia


In addition to the genetic factors, epigenetic factors seem
to be involved in obesity as well. People exposed to
famine, during the first half of pregnancy, in the Dutch
hunger winter of 19441945, displayed significantly
higher obesity rates. Exposure to famine during the last
trimester of pregnancy and the first months of life,
however, resulted in significantly lower obesity rates
(Ravelli et al., 1976). A syndrome of intractable weight
gain may result from hypothalamic damage following
radiation for a brain tumor in children (Lustig et al.,
2003). A wide range of childhood aversions is associated
with elevated risk of developing eating disorders during
adolescence or early adulthood (Johnson et al., 2002a, b)

23.1. PraderWilli syndrome (PWS; MIM no.


176270, Fig. 23A)
(a) Symptoms and molecular genetics
In 1956, Prader, Labhart and Willi described a syndrome
in children characterized by grossly diminished fetal
activity and hypotonia in infancy, mental retardation
(mean IQ of 65) or learning disability, feeding problems
in infancy, and later insatiable hunger and gross obesity
(Fig. 23.3), hypogonadism and hypogenitalism. Unilateral
or bilateral cryptorchism is found in 80100% of male
PraderWilli patients. Additional features are a variety
of minor malformations, including a small forehead,

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almond-shaped eyes, triangular mouth, small hands and


feet, short height, decreased pigmentation of skin
and hair, which is probably of neural crest origin, and
ophthalmic disorders. PWS is the most frequent form of
human syndromal obesity (Apkarian et al., 1989; Smeets
et al., 1992; Mller, 1997; Butler et al., 1998; Eiholzer
et al., 2000). In the USA, PWS is also known as the H3O
syndrome, after the four essential features: hypotonia,
hypomentia, hypogonadism and obesity. The glucose
tolerance test result is often abnormal (Tolis et al., 1974).
Diagnostic criteria for PWS have been developed by
consensus and two scoring systems have been provided:
one for children aged between 0 and 36 months, and
another for children from 3 years onwards, into adulthood
(Holm et al., 1993).
The majority of PWS cases are sporadic, but familial
cases have been reported (McEntagart et al., 2000). In
70% of the patients a de novo deletion of the paternally
inherited chromosome 15q11-13 is present. About 28%
of PWS cases are due to maternal uniparental disomy,
that would result in a slightly milder phenotype with better
cognitive functions. Paternal deletion and maternal
uniparental disomy are functionally similar as they both
result in the absence of a paternal contribution to the
genome in the 15q11-13 region. A third, and the
most severe, phenotype with a high incidence of congenital heart disease are the patients with maternal uniparental
disomy 15 with mosaic trisomy 15 (Olander et al.,
2000). A few PWS cases with mosaicism for the deletion have been reported (Golden et al., 1999), but definite
evidence has not yet been found (Nicholls, 2000).
Less than 2% of the cases have an abnormality in the
imprinting process, which causes nonexpression of the
paternal genes in the PWS-critical region (ASHG/ACMG
Report, 1996; Brndum-Nielsen, 1997). In a 3-yearold, a cryptic interstitial duplication of the entire
PraderWilli/Angelman critical region was found. It was
of maternal origin. The phenotype included developmental mental delay, speech problems and seizures
(Thomas et al., 1999). Duplication, triplication and tetrasomy of the 15q11-q13 region has been reported with
varying degrees of clinical manifestation (Butler et al.,
2002). In a clinically atypical PWS patient, a rare,
balanced de novo translocation has been observed
(Conroy et al., 1997) and several cases with phenotype
overlapping with the PWS phenotype had maternal
uniparental disomy 14. Some PWS candidate genes have
been identified. The SNRPN (small nucleoriboproteinassociated polypeptide N) gene is probably part of the

169

putative imprinting center that regulates the expression


of several genes in PWS transcriptional domain (Martin
et al., 1998a). An intact genomic region and/or transcription of SNRPN exons 2 and 3 seem to play a pivotal
role in the manifestations of the clinical phenotype in
PWS (Kuslich et al., 1999). However, other human cases
tend to exclude SNRPN as the causative gene for PWS
genotype (Conroy et al., 1997). In addition, the human
necdin gene, NDN, which is maternally imprinted and
located in PWS chromosomal region, was considered to
be a candidate gene (Jay et al., 1997). Although at first
necdin-deficient mice did not develop the hypogonadism,
infertility or obesity characteristics of PWS (Tsai et al.,
1999), later on Necdin mouse mutants were developed
that showed hypothalamic and behavioral alterations
reminiscent of the human PWS, including a reduction of
90% in oxytocin neurons and of 25% in LHRH-producing
neurons, increased skin-scraping activity (Muscatelli et
al., 2000), and a deficiency of respiratory drive (Ren
et al., 2003). Others claim that the imprinted genes
ZNF-127 and -127 AS may be associated with some of
the PWS features (Jong et al., 1999). In addition, there
is a small evolutionarily conserved RNA resembling C/D
box, small-nucleolar RNA, which is transcribed from
PWCR1, a novel imprinted gene in the PWS deletion
region, which is highly expressed in brain (De los Santos
et al., 2000).
PWS occurs in 1 of every 10,00025,000 births.
Epidemiologic studies have shown an increased incidence
of paternal preconceptional employment in hydrocarbonexposed occupations (gasoline/petrol) (Cassidy et al.,
1989; kefeldt, 1995; Martin et al., 1998a). The exact
causes of mental retardation, behavioral problems such
as fits of temper, depression and sudden aggression in
PWS children are not known, but the major symptoms
of this syndrome are seen as the result of hypothalamic
disturbances (Swaab, 1997). This fits in with the experimental data of Keverne et al. (1996), who showed that
cells that carry only paternal genes accumulate in clusters scattered through the hypothalamus, septum, preoptic
area and amygdala, while cells that carry only maternal
genes accumulate in the cortex and striatum. Misrouting
of retinal ganglion fibers at the optic chiasm a finding
previously only reported in forms of albinism was
claimed to be present in PWS (Creel et al., 1986) but
could not be confirmed in a later study (Apkarian et al.,
1989). The original observation does not, therefore,
appear to give a clue for changes in brain development
(see Chapter 18.5).
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Fig. 23.3. Characteristic pattern of obesity in a patient with PraderWilli syndrome. (From Kaplan et al., 1991, Fig. 1 with permission.)

(b) Hypothalamic abnormalities


Dysfunction of various hypothalamic systems, neuroendocrine and nonneuroendocrine, may be the basis of a
number of symptoms in PWS. Severe fetal hypotonia is
often already noticed by the mother during pregnancy;

the baby does not seem to move much. Apart from the
babys underactivity, its position in the uterus at the onset
of labor is often abnormal (either a transverse, face or
breech presentation). These abnormal presentations result
in a high percentage of assisted deliveries. In addition,
the percentage of asphyctic infants is at least 8 times

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higher than in the general population. It has often been


presumed that the fetal position is caused by hypotonia,
the child being too weak to move itself in the correct
position. However, there are other congenital disorders
in the hypothalamus and pituitary in which hypotonia
is not reported which are also accompanied by abnormal
presentation of the fetus at birth, such as anencephaly
and septo-optic dysplasia (De Morsier syndrome) (see
Chapters 8.1, 18.3b). The way the hypothalamus is
involved in fetal hypotonia is not known at present. The
timing of the moment of birth is often also abnormal; too
high a percentage of children with PWS are born either
prematurely or too late (Wharton and Bresman, 1989),
an abnormality also found in anencephaly (Chapter 18.1).
An abnormality of the hypothalamus, which plays a
central role in the childs timing of its own birth, may
explain these phenomena (see Chapter 8.1).
Abnormal function of nerve cells in the hypothalamus
containing LHRH is thought to be responsible for
decreased levels of sex hormones, resulting in cryptorchism in boys, hypoplastic external genitalia in children
of both sexes and delayed or incomplete pubertal
development, as well as decreased sexual behavior and
insufficient growth during puberty, resulting in short
stature (Hamilton et al., 1972; Wannarachue et al., 1975;
Cassidy et al., 1997; Mller, 1997; Burman et al., 2001).
It should be noted though that there is a considerable
degree of variation in the function of the hypothalamopituitarygonadal axis in PWS and also hypergonadotropic
hypogonadism secondary to cryptorchism has been
described (Tolis et al., 1974; Mller, 1997). Serum testosterone levels are uniformly low in male PWS, whereas
serum estradiol, LH and follicle-stimulating hormone
(FSH) levels in females are usually low, which is consistent with hypogonadotropic hypogonadism. The onset of
menstruation is often late in girls, if it occurs at all (Mller,
1997). It is not yet known whether the proposed abnormality in LHRH production is due to absence of the LHRH
neurons, or due to an abnormal location, or to a deficiency
in LHRH production or perhaps to the production of an
abnormal form of the hormone. Gonadal function may also
be normal in a small number of patients (Rubin and
Cassidy, 1988; Cassidy et al., 1997, Mller, 1997; Martin
et al., 1998a). In some rare cases, precocious puberty has
been observed, once even in combination with empty
sella syndrome. In 5% of cases, empty sella syndrome is
accompanied by hyperfunction of the pituitary (Linneman
et al., 1999). It is generally assumed that PWS patients are
infertile. However, one woman with PWS was reported to

171

have given birth to a healthy baby girl, presumably related


to the treatment with a serotonin reuptake inhibitor
(kefeldt et al., 1999). In addition it was reported (Schulze
et al., 2001) that a 32-year-old woman with PWS had given
birth to a girl with Angelmans syndrome, due to a
maternal deletion on chromosome 15q11-13. Treatment of
hypothalamopituitarygonadal failure in PWS remains
a controversial issue. More recently, sex hormone
replacement therapy is given. This encourages the development of secondary sexual characteristics and potentially
improves bone mineral content and density. Given the
reports of pregnancy in a few PWS cases, care-givers
should, however, be aware of the possible need for
contraceptives. If aggressiveness in male PWS patients
during testosterone substitution increases, the substitution
should be stopped (Burman et al., 2001).
Short stature and delayed skeletal maturation are the
most frequent features of PWS, probably partly due to
hypogonadism (see above) and partly to a growth
hormone (GH) deficiency, and are seen in 90% of the
PWS patients (Angulo et al., 1996). Some PWS patients
have abnormally low spontaneous nocturnal GH and
insulin-like growth factor-I (IGF-1) serum levels and
blunted GH responses to pharmacological stimuli and to
GHRH, suggesting that hypothalamic dysfunction of this
axis may be a factor in the short stature (Costeff et al.,
1990; Cappa et al., 1993; 1998; Angulo et al., 1996;
Grosso et al., 1998; Eiholzer et al., 2000). In addition,
insulin-like growth factor (IGF) binding protein-3 levels
are low in PWS as compared to healthy obese children
(Eiholzer et al., 1998). GH deficiency is independent of
weight status (Thacker et al., 1998). The possibility that
short stature is due to a deficit at or above the level of
the pituitary is reinforced by the fact that GH treatment
stimulates body growth in PWS patients. In addition,
weight gain decreased and IGF-I (somatomedin C) and
insulin levels increased after GH treatment (Lee et al.,
1987; Angulo et al., 1991; Eiholzer et al., 1997; Hauffa,
1997; Lindgren et al., 1997b, 1998, 1999; Lindgren and
Ritzn, 1999; Myers et al., 1999; 2000; Lee, 2000). GH
therapy during a period of up to 4 years continued to give
beneficial effects on body composition and growth
velocity. Prior improvements in strength and agility were
sustained (Carrel et al., 2002). Interestingly, GH treatment
appeared to have psychological and behavioral benefits
also. Parents reported that the children were more alert,
had a more stable temperament, were more interested
in other children and were easier to handle than before
treatment (Lindgren et al., 1997b). However, the only
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difference in cognition or behavior reported in a recent


study was an increase in hyperactivity after growth
hormone intervention. In GH-deficient PWS children, the
overall mean height SD and weight SD changed from
2.2 to 0.8 and from 3.5 to 2.4, respectively, in a period
of 2 years of treatment (Angulo et al., 1996). The
determination of GH levels, either spontaneous nocturnal
ones or after stimulation tests (Grosso et al., 1998), in
venous plasma as an indicator of hypothalamic GHRH
release is used (Kimber et al., 1997). GHRH that is
produced in the arcuate nucleus (Ciofi et al., 1990; Fig.
23.4) was expected to be affected in PWS. However,
observations in postmortem material from our group have
shown that the number of GHRH-expressing neurons in
this nucleus is not decreased in PWS, and increased to
the same degree as it is in controls, due to chronic illness,
so there is no evidence that the GH deficiency in PWS
results from reduced GHRH cell number (Goldstone et
al., 2003).
The hypothalamopituitaryadrenal and thyroid axes
remain largely intact in PWS, and prolactin and cortisol
levels are generally normal (Tolis et al., 1974;
Wannarachue et al., 1975; Mller, 1997; Grosso et al.,
1998; lAllemand et al., 2002). Dehydroepiandtosterone
(DHEA), DHEA-S and androstenedione levels are elevated (Burman et al., 2001; lAllemand et al., 2002).
Premature adrenarche, characterized by growth of axillary hair and pubic hair is frequently observed in PWS
(Linnemann et al., 1999; Burman et al., 2001). One patient
has been reported with the rare combination of PWS and
congenital hypothyroidism caused by an ectopic sublingual thyroid gland. Although early initiation of thyroid
replacement therapy took place, she continued to suffer
from hypotonia and developmental delay, after which
PWS was discovered (Sher et al., 2002).
The observation of an aberrant control of body temperature in PWS is also interpreted as a hypothalamic
disturbance (Vela-Bueno et al., 1984). It should be
noted, however, that thermoregulatory disturbances are
not specific for this syndrome and may occur in any
neurodevelopmentally handicapped person (Williams
et al., 1994).
The abnormal ventilatory control during wakefulness
and sleep in patients with PWS may, apart from being
linked to sleep apnea, also be related to a hypothalamic
disorder, since this brain area modulates both hypercapnic
and hypoxic ventilatory responses (Menendez, 1999).
Leptin is a satiety factor that is produced by fat cells
and acts on the infundibular nucleus and other hypothal-

amic areas in order to inhibit food intake (see Chapter


23b) and was, therefore, presumed to be involved in
obesity in PWS. Plasma leptin levels are increased in
PWS, but this was generally in relation to the increased
body-mass index (Carlson et al., 1999). It was therefore
thought to be improbable that an explanation for the
increased food intake and obesity could be presented on
the basis of a disturbance in the leptin gene (Wallace et
al., 1999). However, subtle differences may be present
in leptin. The normal sex difference females have higher
leptin levels than males is not present in PWS, and it
is remarkable that the differences between obese and
nonobese PWS subjects are small and insignificant. In
fact, plasma leptin levels in nonobese male PraderWilli
subjects were nearly 5 times higher than in nonobese
control males (Butler et al., 1998). While a difference in
the hypothalamic response to leptin could not be excluded
on the basis of the study by Lindgren et al. (1997a), our
finding that there is less NPY in the infundibular nucleus
in PWS patients (see below) seems to exclude a gross
disturbance of the leptinleptin receptorNPY interaction
(Goldstone et al., 2002).
Leptin is presumed to inhibit NPY production in the
infundibular nucleus (see Chapter 23b). In order to see
whether an increased activity of NPY neurons in the
infundibular nucleus might explain the eating disorder in
PWS patients, we determined the amount of NPY in the
infundibular nucleus immunocytochemically, and NPY
mRNA, by means of an image-analysis system, in PWS
cases, nonsyndromic obese patients and controls. The
infundibular nucleus contains NPY cell bodies and an
extremely dense network of NPY fibers that generally do
not extend to the most ventral part of the median
eminence, which contains the portal capillaries. This indicates that most of the NPY fibers have central projections.
NPY immunoreactivity and mRNA are decreased in PWS
patients, to the same degree as in the other obese patients
(Figs. 23.5, 23.6, 23.8). NPY immunocytochemistry and
mRNA increases with longer disease duration (Goldstone
et al., 2002; Fig. 23.6). Apparently the insatiable hunger
in PWS is not due to increased NPY expression, as these
neurons show a normal reaction to the obese state and
disease duration of these patients. No increase was found
in the AGRP staining or mRNA in the infundibular
nucleus of PWS patients either (Fig. 23.7, 23.8). This
peptide, too, is upregulated with disease duration
(Goldstone et al., 2002; Fig. 23.7). AGRP is another
peptide that stimulates feeding and is colocalized with
NPY, but not with POMC (Figs. 11.3, 11.4). The

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Fig. 23.4. Growth hormone-releasing hormone (GHRH)-immunoreactive neurons in the infundibular nucleus of 3 controls (left column) and 3
PraderWilli syndrome (PWS) patients (right column). The top row shows the cases with the highest number of GHRH-immunoreactive neurons,
the middle row shows cases with the highest number of GHRH-immunoreactive neurons, the middle row shows cases with a median GHRH neuron
number and the last row represents the cases with the lowest GHRH-neuron number: (a) control case 96-030, (b) PWS case 43830, (c) control
case 85-124, (d) PWS case 96-000, (e) control case 80-271 and (f) PWS case 97-049. Scale bar 50 m. Note that there is a great variability in
number of GHRH neurons, both within the control group and in the PWS patient group. Although the PWS patients generally tended to have
fewer GHRH neurons and their staining tended to be less intense, this appeared to be due to differences in disease duration and not to PWS per
se. (cf. Goldstone et al., 2003, preparation by U. Unmehopa.)

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Fig. 23.5. Hypothalamic neuropeptide-Y (NPY) in human illness and obesity. NPY immunocytochemistry (ICC) staining in the infundibular nucleus
of control, PraderWilli syndrome (PWS) and non-PWS adults, with sudden death, premorbid illness duration of less than 2 wk and more than 6
wk. Note that NPY ICC staining increases with longer periods of illness, but that each illness duration levels are lower in both PWS and nonPWS obese subjects, compared with controls. Bar 50 m. (From Goldstone et al., 2002, Fig. 4 with permission.)

Fig. 23.6. Hypothalamic neuropeptide-Y (NPY) mRNA in human illness and obesity. Representative autoradiographs of NPY in-situ hybridization
in the infundibular nucleus of control, PWS, and non-PWS obese adults, with sudden death, premorbid illness duration of less than 2 wk or more
than 5 wk. Note that NPY mRNA expression increases with longer periods of illness, but that at each illness duration levels are lower in PWS
or non-PWS obese subjects, compared with controls. 3V, third ventricle. (From Goldstone et al., 2002, Fig. 5 with permission.)

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Fig. 23.7. Hypothalamic agouti-related protein (AGRP) peptide in human illness and obesity. Representative autoradiographs of AGRP ICC staining
in the infundibular nucleus of control, PWS, and non-PWS obese adults, with sudden death, premorbid illness duration of less than 2 wk or more
than 5 wk. Note that AGRP ICC staining increases with longer periods of illness, and that levels are not increased in PWS or non-PWS obese
subjects, compared with controls. Bar 50 m. (From Goldstone et al., 2002, Fig. 6 with permission.)

peptide are increased to a level reported to stimulate


appetite and food intake (Cummings et al., 2002; Del
Parigi et al., 2002; Haqq et al., 2003). The possibility
that this peptide also has a source in the human brain
should be investigated.
The birth weight of PWS children is often too low, but
from age two onwards these children tend to grow fatter
than other children. Appetite control is exacerbated when
there is more severe mental retardation. The obesity may
be caused by an increased drive to eat as well as by an
impaired mechanism of satiation. Both functions are
controlled by the hypothalamus. Animal experiments have
shown that the parvocellular oxytocin neurons of the
hypothalamic PVN are crucial for the regulation of food
intake. Oxytocin release accompanied various treatments
that inhibit food intake (Verbalis et al., 1995). In the rat,
the oxytocin neurons of the PVN project to brainstem
nuclei, for example the nucleus of the solitary tract and
the dorsal motor nucleus of the nervus vagus (Buijs et
al., 1983; De Vries and Buijs, 1983; Voorn and Buijs,
1983). These connections are held responsible for the
satiety effects of oxytocin (Verbalis et al., 1995). Small

decreased NPY and AGRP content of the hypothalamus


indicates that the transport of information between the fat
cells and the infundibular nucleus to the PVN by the NPY
neurons will be largely intact, including leptin and leptin
receptors, and that abnormalities have to be searched for
in other peptide systems of the arcuate nucleus or in the
area of termination of the NPY fibers, such as the PVN
(Goldstone et al., 2002). Seemingly in contrast to our
data, kefeldt et al. (2001) reported that the NPY content
of CSF in PraderWilli children with a mean age of 8
years was higher. However, in two PWS infants of 6 and
8 months, we did not find the reduction in NPY either
(Goldstone et al., 2002). The developmental state may
thus be of crucial importance in these hypothalamic
peptide changes. Preliminary results from our group indicate that there is a reduction of CART-containing neurons
in the infundibular nucleus of PWS patients (F. Goezinne
et al., unpubl. observ.). Since CART inhibits feeding, this
observation has to be followed up.
A new putative factor involved in obesity in PWS is
ghrelin. This peptide is an orexigenic circulating hormone
implicated in meal-time hunger. The plasma levels of this
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Fig. 23.8. Hypothalamic neuropeptide-Y (NPY) is decreased and agoutirelated peptide (AGRP) is not increased in obesity. (A) NPY ICC
staining volume, (B) NPY mRNA expression by ISH; and (C) AGRP
ICC staining volumes, in the infundibular nucleus/median eminence
(INF/ME), in control, PraderWilli syndrome (PWS) and non-PWS
obese subjects. + represents females,  hypogonadal females (postmenopausal or PWS),  intact males,  hypogonadal males (castrated
controls or PWS). Dashed line represents median for each group. Note
that, in obese subjects (PWS and non-PWS) compared with controls,
there is a significant reduction in NPY ICC staining and mRNA, but
no difference in AGRP ICC staining, when adjusting for significant
covariates. P-values: a Mann-Whitney test; b adjusting for differences in
premorbid illness duration by ANCOVA; cadjusting for differences in
premorbid illness duration and storage time by ANCOVA. (From
Goldstone et al., 2002, Fig. 2 with permission.)

lesions in the rat PVN cause overeating and obesity


(Leibowitz et al., 1981), suggesting that the PVN usually
has an inhibitory effect on eating and body weight. In
addition, stimulation of the medial parvocellular subdivision of the rat PVN elicits significant increases in gastric
acid secretion (Rogers and Hermann, 1986). Central
administration of oxytocin or oxytocin agonists inhibits
food intake and gastric motility in rat, whereas these
effects are prevented by an oxytocin receptor antagonist
(Rogers and Hermann, 1986; Arletti et al., 1989; Benelli
et al., 1991; Olson et al., 1991a, b). In a patient whose
PVN was bilaterally destroyed by a hypothalamic astrocytoma, obesity and hyperphagia were indeed reported
(Haugh and Markesbery, 1983). It should be noted,
however, that in this patient one side of the VMN was
also affected.
We have investigated whether a disorder of the PVN,
or, more particularly, of its putative satiety neurons the
oxytocin neurons might be the basis of the insatiable
hunger and obesity in PWS. Apart from gross obesity,
oxytocin neurons are also thought to be crucial for various
aspects of sexual behavior, including sexual arousal,
orgasm, sexual satiety and other aspects of sociosexual
interaction (Hughes et al., 1987; Murphy et al., 1987;
Argiolas, 1992; Arletti et al., 1992; Carter, 1992; Chapters
8f, 8g). The thionine-stained volume of the PVN appeared
to be 28% smaller in PWS patients and the total cell
number of the PVN is 38% lower than in controls (Swaab
et al., 1995a). Following immunocytochemistry, the
immunoreactivities for oxytocin and vasopressin are
decreased in PWS patients (Fig. 23.9), although the variation within the groups is high. A large and highly
significant decrease (42%) in the number of oxytocinexpressing neurons was found in all five PWS patients
(Fig. 23.10). The volume of the PVN containing the OXTexpressing neurons is 54% lower in PWS. The number
of vasopressin-expressing neurons in the PVN did not
change significantly (Fig. 23.9). The finding that volume
and total cell number and oxytocin cell number was so
much lower in PWS patients points to a developmental
hypothalamic disorder, and agrees with the hypothesis
that oxytocin neurons of the PVN may be good candidates for a physiological role as satiety neurons in
ingestive behavior, also in the human brain (Swaab et al.,
1995a). In addition, it seems worthwhile to investigate
whether it is possible to curb childrens appetites by
administration of oxytocin. It should be noted, though,
that the recent observation that oxytocin levels in CSF
of five PWS patients were just significantly elevated

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Fig. 23.9. In thionine-stained sections of the paraventricular nucleus (PVN), no qualitative differences were observed between controls (no. 81255;
A) and PWS patients (no. 43830; B). The staining of oxytocin (OXT) (C, D) and vasopressin (AVP) (E, F) was generally lower in PWS patients
(no. 43830; D, F) than in controls (no. 81255; C, E). G, H, Two PWS patients (no. 1 and 4) had intense and weak OXT staining (no. 93056; G)
and only negligible AVP staining (no. 93056; H) in the PVN. Bar 50 m. (From Swaab et al., 1995a, Fig. 1, with permission.)

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Fig. 23.10. Number of oxytocin-expressing (OXT) (left panel) and vasopressin-expressing (AVP) (right panel) neurons in the PVN of 27 controls
and 5 PraderWilli syndrome (PWS) patients. The values of the PWS patients are delineated by a minimum convex polygon. Note that the oxytocin
neuron number of these patients is about half of that of the controls (left panel), which is not the case for vasopressin (right panel). (From Swaab
et al., 1995a, Fig. 2 with permission.)

seems to be at odds with our observation in the PVN,


although it is of course possible that different subpopulations of oxytocin neurons in the PVN, with different
projection sites, react in a different way to the disease
process (Martin et al., 1998b). Clearly oxytocin should
be studied in more PWS patients, both in postmortem
hypothalamic material and in CSF.
It should be mentioned that, in two of seven of our
PWS patients, vasopressin neurons stained only weakly
(Swaab et al., 1995a) or not at all (Gabrels et al., 1994),
depending on the antibody used. In these two PWS
patients there was no staining with antibodies against 7B2,
a neuroendocrine chaperone preventing premature activation of the enzyme prohormone convertase (PC)2. Since
the precursor of vasopressin was present in these two
PWS patients (Fig. 23.11) and no PC 2 activity was found
in the SON and PVN, a processing enzyme disturbance
is presumed that also affects the 7B2 gene from the
paternal allele (Gabrels et al., 1994, 1997). The finding
that vasopressin expression is occasionally diminished in
PWS patients agrees with the demonstration of Miller et
al. (1996) that MRI shows a complete absence of the
posterior pituitary bright spot in 20% of these patients,

indicating a disturbed function of the hypothalamohypophysial system as found in patients with hypothalamic
diabetes insipidus (see Chapter 22.2). Whether a vasopressin defect is indeed present in those PraderWilli
patients that lack the posterior pituitary bright spot in
MRI should be proved by further observations.
The extensive calcifications found in the brain and
spinal cord of a 16-year-old boy with PWS are most probably an incidental finding not directly related to the
syndrome (Reske-Nielsen and Lund, 1992). In conclusion, so far hypothalamic research has revealed an intact
NPY/AGRP system in PWS syndrome that is inhibited
in a normal way by obesity, but the number of oxytocinexpressing neurons in the PVN is clearly diminished.
(c) Behavioral disorders
Behavioral problems are a frequent occurrence in PWS
(Curfs et al., 1991). Symptoms of mood disorder and
anxiety laminate the picture of PWS. They can, at least
partly, also be considered to be hypothalamic symptoms
(Chapter 26.4). In addition, temper tantrums and compulsive behavior such as skin-picking may be present (Martin

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Fig. 23.11. Paraffin sections of the supraoptic nucleus (SON) from PraderWilli syndrome patient 93-056 shows no immunoreactivity with antibody III-D-7 recognizing processed vasopressin (A), but very intense immunoreactivity with antibody PS41 recognizing neurophysin predominantly
in its processed form (B), and very intense immunoreactivity with antibody Boris Y-2 recognizing the glycopeptide part of the vasopressin precursor
(C). These data indicate a processing disorder. Bar 25 m. (From Gabrels et al., 1998b, Fig. 1 with permission.)

patients show hypersomnolence and little or no sleep


apnea, but REM-related oxygen desaturation is quite
common. In addition, abnormal REM sleep cycles, sleeponset REM periods and fragmented REM sleep with
multiple, brief REM periods are present (Kaplan et al.,
1991; Hertz et al., 1993; Clift et al., 1994; Richdale et
al., 1999; Manni et al., 2001). It is hypothesized that the
abnormal sleep findings in this syndrome are related to
a disturbance of the posterior hypothalamus (Hertz et al.,
1993; Manni et al., 2001). Clift et al. (1994) presume
that sleep apnea is also of some importance. An alternative explanation would be disturbed circadian functioning
(Vela-Bueno et al., 1984).

et al., 1998a; Holland et al., 2003). Moreover, psychosis


and bipolar illness have been reported in PWS cases, but
it is not clear whether they are more prevalent in PWS
than in the general population (Clarke, 1993; Clarke et
al., 1995; Descheemaeker et al., 2002). It is postulated
that in PWS an abnormal pattern in expression of a sexspecific imprinted gene on chromosome 15, such as in
maternal uniparental disomy, is associated with psychotic
illness in early adult life (Boer et al., 2002). Patients with
PWS may be especially vulnerable to the development
of cycloid psychosis that reacts favorably to lithium
(Verhoeven et al., 1998; Descheemaeker et al., 2002).
PWS is, moreover, associated with high rates of ritualistic behaviors, such as the need to ask or tell something,
insistence on routines, hoarding and ordering objects and
repetitive actions and speech (Clarke et al., 2002). In relation to the behavioral disturbances, the increased
concentrations of dopamine, 5-HT and metabolites may
be of relevance (kefeldt et al., 1998).
Another symptom that is present in 90% of the PWS
patients and may originate in the hypothalamus is the
excessive day-time hypersomnolence, accompanied by
snoring and early waking (Richdale et al., 1999). PWS

(d) Comorbidity
One case of KleineLevin syndrome has been described
in a boy with PWS (Gau et al., 1996). KleineLevin
syndrome is characterized by episodes of hypersomnia
and hyperphagia and considered to be a hypothalamic
syndrome (see Chapter 28.1). The small hypothalamus
observed in this patient with MRI (Gau et al., 1996)
supports the idea that this brain area is strongly affected.
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A case of multiple endocrine neoplasia (MEN) type 1


was found to be accompanied by PWS. MEN-1 (MIM
no. 131100) is a syndrome characterized by hyperplastic
or neoplastic disorder of endocrine organs. More than
90% of the affected subjects manifest hyperparathyroidism. Pituitary tumors and pancreatic endocrine tumors
are seen in 50% of the patients. Mutations of the MEN1
gene on chromosome 11q13 have been identified in most
of the affected subjects (Nakajima et al., 1999).
Four patients suffering from both PWS and Klinefelter
syndrome (47,XXY; see Chapter 24.4) have been
described. In the most recent case both parents contributed
to the chromosomal abnormalities, supporting the possibility of a coincidental association (Geffroy et al., 1998).
Symptoms characteristic of PWS have also been
described in a woman with a duplicated X chromosome,
random X-inactivation pattern and negative molecular
genetic studies for PWS (Monaghan et al., 1998). There
are also other observations indicating that on the proximal
long arm of the X-chromosome a gene or genes are located
that in case of malfunction result in obesity, mental retardation and small hands and feet (Tmer et al., 1998).
In addition, PWS patients with trisomy-X syndrome and
with XYY syndrome have been described (Honma et al.,
1999; Stalker et al., 2003).

23.2. Anorexia nervosa and bulimia nervosa


(Fig. 23B)
Anorexia nervosa is among the most disabling and lethal
of psychiatric disorders (Walsh and Devlin, 1998).

Anorexia nervosa was first described by Lasgue (1873)


and Sir William Gull (1873) (for references see Li Parry
Jones et al., 1994). The prevalence of eating disorders
among young females is about 0.3% for anorexia nervosa
and about 1% for bulimia nervosa (Hoek et al., 1995).
In fact, 93% of anorexia nervosa cases and 75% of bulimia
nervosa cases are found in women, an example of a clear
sex difference in psychiatric diseases (Chapter 1, Table
1.1). They are relatively rare disorders, with an incidence
rate of 0.8/10,000 for anorexia nervosa and 1.2/10,000
for bulimia nervosa. Comorbid psychiatric conditions
such as affective disorders, anxiety disorders, substance
abuse and personality disorders are frequently present
(Halmi, 2002). Cultural pressures are presumed by some
authors to play a role in the prevalence of these disorders, as indicated by cultural and historical differences in
prevalence (Bemporad, 1997; Walsh and Devlin, 1998).
Obstetric complications are mentioned as risk factors for
anorexia nervosa (Verdoux and Sutter, 2002). This
concerns in particular very early birth and birth traumas.

Fig. 23B. Alberto Giacometti (19011966) Piazza, 19471948 (cast 19481949). Bronze, 21  62.5  42.8 cm. Peggy Guggenheim Collection,
Venice (The Soloman R. Cuggenheim Foundation, New York); photograph by David Heald. Photograph 2003 The Solomon R. Cuggenheim
Foundation, with permission.

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The incidence of bulimia nervosa is lowest in rural areas


and highest in large cities (0.7/10,000 and 3.8/10,000
women per year, respectively). However, the epidemiological comparisons between different periods are full of
pitfalls (Wakeling, 1996). No ruralurban differences
were found for anorexia nervosa (Hoek et al., 1995).
There is no indication of a secular increase in the incidence of anorexia nervosa (Fombonne, 1995), but the
incidence of bulimia nervosa tends to increase (Hoek et
al., 1995). The incidence of mortality among anorexia
nervosa patients is generally said to range between 5 and
20%. However, in a long-term survival study in Rochester
(New York), anorexia nervosa patients did not differ from
controls. So the overall mortality was not increased
(Korndrfer et al., 2003). On average, less than one-half
of the anorexia patients recover, whereas one-third
improved. Twenty percent remain chronically ill (Barry
and Klawans, 1976; Ratnasuriya et al., 1991; Licinio et
al., 1996; Steinhausen, 2002). Suicide attempts are
frequent (27.8% of the women), often serious, and
multiple. Women who attempted suicide had higher
severity of depressive and general symptoms and more
impulse-disordered conducts.
Evidence is emerging that both anorexia and bulimia
nervosa are familial and that clustering in families may
arise partly from genetic transmission of risk (Kaye et
al., 1999; Strober et al., 2000; Wade et al., 2000;
Brambilla, 2001). Twin studies in bulimia indicate
substantial genetic variance (44%) and do not support a
strong role for shared environmental effects (Rowe et al.,
2002). A single patient with extreme obesity and bulimia
nervosa had a haplotype-insufficiency mutation in the
MC-4 receptor (Hebebrand et al., 2002) and significant
linkage was found on chromosome 10 in families with
bulimia nervosa (Bulik et al., 2003). SNPs in the AGRP
gene were found to be associated with an increased
susceptibility for anorexia nervosa and are presumed to
be caused by a defective suppression of the MC-4
receptor, leading to a decreased feeding signal (Vink et
al., 2001b). One patient has been described with both
bulimia nervosa and extreme obesity, and a haploinsufficiency mutation in the MC-4 receptor (Hebebrand et al.,
2002). Allele 13 of the polymorphic microsatellite marker
D11S911 is significantly overrepresented in the anorexia
nervosa population, and the UCP2/UCP3 genes on chromosome 11q13 are thought to play a role in the control
of energy expenditure and thermogenesis (Campbell et
al., 1999). Modest evidence for linkage of anorexia
nervosa with chromosome 4 and better evidence with

181

linkage with chromosome 1p was obtained (Grice et al.,


2002). Candidate genes for anorexia nervosa in the
1p3336 linkage region are the serotonin 1D and delta
opioid receptor loci (Bergen et al., 2003). In addition, a
5-HT2A promotor polymorphism has been reported in
anorexia nervosa (Sorbi, 1998), but a combined analysis
of 316 trios from six European centers did not reveal any
evidence for a significant role of the 5-HT2A gene in
anorexia nervosa (Gorwood et al., 2002). The frequency
with which the H (high) allele of the enzyme catecholO-methyltransferase occurs is significantly higher in
anorexia nervosa patients than in those not affected.
Individuals that are homozygous for the H allele run a
two-fold increased risk of developing anorexia nervosa
(Frish et al., 2001). Anorexia nervosa was found to be
associated with a polymorphism in the novel norepinephrine transporter gene promotor polymorphic region
(Urwin et al., 2002). Also variability in the estrogen
receptor- may contribute to the genetic susceptibility to
anorexia nervosa. An association was found between the
heterozygous genotype of the G1082A polymorphism and
anorexia nervosa (Eastwood et al., 2002). Genetic factors
also substantially contribute to the comorbidity between
anorexia nervosa and major depression (Wade et al.,
2000). Patients with congenital adrenal hyperplasia
compound heterozygotes for mutations/deletions of the
CYP21A2 gene may be at risk for anorexia nervosa
(Brand et al., 2000). Alterations in transmitters as biological factors involved in the pathogenesis of anorexia and
bulimia have been proposed repeatedly. Especially noradrenaline and 5-HT levels are lower in bulimia
(Brambilla, 2001). Moreover, 5-HT transporter availability is impaired in the hypothalamus (Tauscher et al.,
2001). Concerning the latter, studies show that postsynaptic hypothalamic-pituitary serotonergic pathways
are altered in anorexia, and that many differences tend
to persist despite a weight increase. After recovery,
anorexics still have increased levels of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of
serotonin. This suggests the existence of brain-related
serotonergic activation in the brain (Brewerton and
Jimerson, 1996; Kaye et al., 1998). In addition, increased
activity of the dopaminergic system in anorexia nervosa
has been hypothesized (Barry and Klawans, 1976).
Anorexia patients are more likely to be born in March
to June; a seasonal effect that may, e.g. be due to viral
factors (Waller et al., 2002). In 74% of anorexia and
bulimia patients, autoantibodies against -MSH, ACTH
and LHRH are found. It is not clear how they are involved
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in the pathogenesis of these disorders (Fetissov et al.,


2002).
Sociocultural factors (e.g. media and peer influences),
family factors (e.g. enmeshment and criticism, negative
affect, low self-esteem and body dissatisfaction) are often
mentioned as causal factors in eating disorders (Polivy
and Herman, 2002), although hard evidence for such
factors is lacking. In the lay press it is often stated that
anorexia nervosa is caused by the visually ideal body
image as perceived by girls watching extremely thin
fashion models. There has been a recent study on the
impact on eating behaviors and attitudes following
prolonged introduction of television among media-naive,
ethnic adolescent Fijian girls. Key indicators of disordered eating were significantly more prevalent following
exposure, and narrative data revealed the subjects interest
in weight loss as a means of modeling themselves after
television characters. This indeed suggests a negative
impact of television on disordered eating attitudes and
behaviors in a media-naive population (Becker et al.,
2002). However, clinical diagnoses were not sought in
this study, so that we do not know whether the introduction of television may indeed have induced anorexia
or bulimia nervosa in this population.
On the other hand, a study of six blind patients
has been published: the patients developed anorexia
nervosa but had been blind since infancy, which
suggests that eating disorders can develop independently
of cultural conceptions of feminine appearance (Sharp,
1993).
. . . It is not known whether minor cytologic changes occur
in any part of the hypothalamus to correspond with these
functional disturbances.
(Sheehan and Kovacs, 1982)
The well-known anorexia nervosa of girls seems to me on
careful observation to be a melancholia occurring where
sexuality is underdeveloped.
(Sigmund Freud in The Origin of Psychoanalyisis:
Letters to Wilhelm Fleiss, 1959)

(a) Symptoms
Anorexia nervosa is characterized by a series of hypothalamic symptoms (for review see Kaplan and Garfinkel,
1988), of which it is often not yet clear whether they are
related and primarily due to a hypothalamic process, or
state-related and secondary to the cachectic process (Kaye

et al., 1998; Stving et al., 2001). Depressed affect and


disturbance of body image have been reported prior to
the onset of anorexia in a 14-year-old girl (Morgan
and Lacey, 1996), which argues against the idea that
these symptoms are secondary to the cachectic process.
The same holds true for amenorrhea (see ii, below).
Many of these symptoms also occur in bulimia. In fact,
the two disorders are closely related: some 15% of the
patients with anorexia nervosa develop bulimia nervosa
(Ratnasuriya et al., 1991). The fact that third ventricle
enlargement in anorexia nervosa is greater than that of
the lateral ventricles supports the idea of hypothalamic
involvement (Golden et al., 1996). The putative hypothalamic symptoms include:
iiv(i) Eating disturbances and weight loss. Neuroimaging
shows morphological and functional alterations that
are at least partly reversible after weight gain. The
reversible shrinkage of the brain (pseudoatrophy)
also affects the pituitary gland. PET reveals caudate
hyperactivity. It is tempting, but purely speculative,
to relate the increased caudate dopamine activity to
the well-known increased body activity of these
patients (Barry and Klawans, 1976). Several mild,
rightleft asymmetries have been reported in
bulimia nervosa (Herholz, 1996). Body image
distortion is a core symptom and often persistent,
and it continues to pose a threat of relapse, even
after weight recovery. Images of their own body
induce an activation of the right amygdala and other
components of the fear network, as shown by
fMRI (Seeger et al., 2002).
iv(ii) Altered levels of steroid hormones, i.e. reduced
plasma concentrations of estradiol are found not
only in anorexia but also in bulimia nervosa. In
addition, secondary amenorrhea, decrease in libido,
and loss of secondary sexual characteristics are
observed (Kaplan and Garfinkel, 1988; Raboch
and Faltus, 1991; Monteleone et al., 1999; 2001;
Cotrufo et al., 2000; Stving et al., 2001). Primary
amenorrhea occurs in only 411% of cases (White
et al., 1993). In about 20% of cases, amenorrhea
takes place before a great deal of weight loss occurs.
Menstrual irregularities and amenorrhea also
occur in a high proportion (more than 30%) in
patients with a normal weight bulimia syndrome
(Ramacciotti et al., 1997). A strong association has
been found between bulimia and polycystic ovary

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syndrome (Chapter 24.1d): ultrasonography indicates that some 75% of patients with bulimia have
polycystic ovaries. Changes in bulimic eating may
mirror changes in ovarian morphology. The two
conditions may be linked by changes in peripheral
insulin sensitivity (Morgan et al., 2002). Even
in the absence of overt menstrual disturbances,
altered LH secretion elicited by LHRH stimulation
is found, with a more severe impairment in purging
than in nonpurging normal-weight bulimia
(Ramacciotti et al., 1998). Thus amenorrhea cannot
be adequately explained solely on the basis of
weight loss, which seems to be in favor of a primary
hypothalamic process. Low levels of gonadotropins
are generally reported and are possibly related
to the low leptin levels (see point xi, below). Both
bulimic and anorexia nervosa patients who are
underweight demonstrate an ACTH secretion
pattern that resembles that of prepubertal girls.
In this light it is interesting that anorexia and
cachexia go together with signs of hyperactivity in
the subregion of the hypothalamic infundibular
nucleus, i.e. the subventricular nucleus, probably
due to a lack of inhibitory feedback action of
sex hormones on this nucleus (see Chapter 11;
Hart, 1971). From a follow-up of anorexia nervosa
women, it appeared that they had only one-third
of the expected fertility, that the rate of prematurity
among their offspring was twice as high, and
that perinatal mortality was 6 times higher than
expected. So far no explanation has been given
for these reproductive disorders (Brinch et al.,
1988). There is also a relationship between the
phase of the menstrual cycle and bulimia symptoms.
The symptoms are exacerbated in both the midlateral and premenstrual phases (Lester et al., 2003)
indicating a role for steroid hormones.
Testosterone plasma levels are reported to be
increased in women with bulimia nervosa in one
study, and a positive correlation is found between
testosterone plasma levels and aggressiveness in
patients but not in controls (Cotrufo et al., 2000).
In another study, testosterone levels were decreased
in anorexia and unchanged in bulimia. Neuroactive
steroids such as 3,5-tetrahydroprogesterone,
DHEA and DHEAS exhibited increased plasma
levels in that study, both in anorexia and bulimia
(Monteleone et al., 2001).

183

(iii) The HPA axis is generally found to be hyperactive


in anorexia and bulimia (Licinio et al., 1996;
Monteleone et al., 1999; Cotrufo et al., 2000;
Neudeck et al., 2001). Although cortisol secretion
is not found to be markedly higher in anorexia
nervosa patients than in matched controls, and no
relationship has been found with cognitive functions
in a later study (Seed et al., 2002), various other
studies, with both plasma and salivary hormone
assays, have shown that there is an overdrive of the
HPA axis (Putignano et al., 2001). Bingeing and
vomiting in bulimic patients was associated with
modest increases in cortisol secretion (Weltzin
et al., 1991; Galderisi et al., 2003) and increased
DHEA(S) levels (Galderisi et al., 2003), while
normal-weight bulimic women showed normal
circadian ACTH and cortisol variations and levels
(Vescovi et al., 1996). A recent study showed that
elevated cortisol secretion followed exacerbation of
bulimic symptoms (Lester et al., 2003). Anorexia
and bulimia nervosa patients often have a marked
hypercortisolism but normal plasma ACTH. When
CRH was given, hypercortisolism was associated
with a marked reduction in plasma ACTH as a
response to the elevated levels of cortisol. When
these patients were studied shortly after their body
weight had been restored, hypercortisolism had
disappeared, but the abnormal response to CRH
remained unchanged. On the other hand, at least 6
months after the loss of weight had been corrected,
their responses returned to normal. These observations suggest that hypercortisolism in anorexia
reflects a defect at or above the level of the
hypothalamus (Gold et al., 1986). In addition,
CSF levels of CRH of anorexia patients are elevated
(Hotta et al., 1986; Kaye, 1996), which may also
reflect a change in extrahypothalamic rather than in
hypothalamic function (see Chapter 26.4). It should
be noted that CRH administration to experimental
animals may produce many of the symptoms
of anorexia nervosa, such as hypothalamic hypogonadism, decreased sexual activity, decreased
feeding behavior, hyperactivity and depression
(Holsboer et al., 1992; Kaye, 1996; Licinio et al.,
1996; see Chapter 26.4).
It has been hypothesized that self-starvation
through physical activity would activate the HPA
axis. Stimulated CRH activity would subsequently

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1
activate the reward system consisting of dopaminer2
gic neurons in the ventral tegmentum, whose
3
terminals are located in the nucleus accumbens.
4
Cortisol would enhance the reward by stimulating the
5
release of dopamine in this nucleus. Self-starvation
6
would thus be rewarding (Bergh and Sdersten,
7
1996; Wheatland, 2002). Evidence for such a vicious
8
circle as the pathogenic mechanism of anorexia
9
nervosa, however, has yet to be collected.
101 ii(iv) The hypothalamopituitarythyroid axis is hypo1
active in anorexic patients (Leslie et al., 1978).
2
The alterations fit into the euthyroid sick syndrome
3
(see Chapter 8.6). Thyroid volume is markedly
4
reduced in anorexia nervosa. Thyroid atrophy could,
5
hypothetically, be involved in a vicious circle main6
taining anorectic or depressive symptomatology
7
(Stving et al., 2001). The TSH response in anorexic
8
patients is often low or delayed. Following weight
9
recovery, TRH responses often continue to be
201
abnormal. The thyrotropin (TSH) response to TRH
1
of bulimic patients is blunted. In normal-weight
2
bulimic patients, T4, T3 and TSH levels are also
3
lower, as is the response to TRH (Kiyohara et al.,
4
1988; Schreiber et al., 1991b). These observations
5
contradict the idea that thyroid axis hypoactivity is
6
a result of malnutrition and support the idea of a
7
primary hypothalamic process.
8
iii(v) Basal GH levels are elevated in anorexia and IGF9
I levels are lower, probably due to the state of
301
malnutrition. GH response to GHRH, however, was
1
normal, indicating a disturbance at the hypothalamic
2
level in anorexia and bulimia. A hypothalamic
3
subsensitivity of postsynaptic D-2 receptors and a
4
presynaptic dopamine hypersecretion has been
5
proposed (Casanueva et al., 1987; Brambilla et al.,
6
2001; Stving et al., 2001) but not proven. The
7
enhanced growth hormone secretion in anorexic
8
patients is the result of an increased frequency of
9
secretory pulses superimposed on an enhanced tonic
401
secretion. These changes suggest the presence of
1
both an increased number of GHRH discharges and
2
a decreased somatostatin tone (Scacchi et al., 1997;
3
Stving et al., 2001). Indeed, the GHRH secreto4
gogue ghrelin was found to be elevated, both in the
5
anorexia nervosa, binge eating/purging-type and in
6
bulimia nervosa purging-type patients. Vomiting
7
may have a strong effect on this gastric peptide.
8
Since this gastric hormone is also an efficient
911

orexigenic factor, the increase of ghrelin levels


could be considered an adaptive mechanism,
promoting energy intake and fat stores (Tanaka et
al.,2003; Tolle et al., 2003). Bingeing and vomiting
in bulimic patients was associated with reduced GH
secretion (Weltzin et al., 1991).
ii(vi) Bingeing and vomiting in bulimic patients is accompanied by moderate prolactin increases according
to some authors (Weltzin et al., 1991), and with
reduced plasma prolactin concentrations according
to others (Monteleone et al., 1999; Cotrufo et al.,
2000). More attention should be paid to their
possibly altered circadian rhythms (see ix).
i(vii) Neurohypophysial disorders are present in anorexia
nervosa. A syndrome of partial diabetes insipidus
has been reported and vasopressin seems to be
secreted erratically, independent of plasma sodium
levels (Gold et al., 1983). The response to hypertonic saline is abnormal. The hyperintense MRI
signal in the posterior part of the pituitary was
reported not to be abnormal (Herholz, 1996).
However, an anorexia patient with high serum
vasopressin levels and an absence of the posterior
pituitary bright spot on MRI has also been described,
indicating increased release of vasopressin (Sato
et al., 1993). In addition, anorexic patients are
not able to excrete a large volume of water (Russell
et al., 1966), indicating hypersecretion of vasopressin. Moreover, hypersecretion of vasopressin
and reduction of oxytocin have been reported in
CSF of underweight anorexics (Demitrack et al.,
1989). The elevation of CSF vasopressin was
confirmed in women who had recovered from
anorexia nervosa/bulimia nervosa. In patients
recovered from bulimia nervosa, elevated CSF
vasopressin may be related to having a life-long
history of major depression (Frank et al., 2000).
There is impairment of the oxytocin response to
challenging stimuli, such as oestrogens and insulin
in underweight anorectic women. After complete
weight recovery, the oxytocin response, too, was
regained. This neuroendocrine abnormality thus
seems to be associated with starvation and/or weight
loss. The reduced CSF levels of oxytocin in
anorexics (Demitrack et al., 1989) were not
expected, because of the feeding behavior inhibiting
effect of this peptide (Swaab et al., 1995a).
Although a later study showed increased CSF

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oxytocin levels, they may be related to the use of


birth control pills and not to the eating disorder in
some bulimia patients (Frank et al., 2000).
(viii) The basal temperature is unusually reduced, and
the temperature regulation in heat and cold is
disturbed. Heat and cold intolerance have, however,
also been found due to weight loss (Vela-Bueno
et al., 1984);
ii(ix) In anorexia, circadian variation of blood pressure
is absent. This reverts to normal after refeeding
(Awazu et al., 2000). In anorectic patients, not only
were leptin levels low; their relative diurnal variation was strikingly reduced in one study (Stving
et al., 2001), or qualitatively altered (Herpertz
et al., 1998); while, in another study (Herpertz et
al., 2000), diurnal secretion patterns were found to
be preserved, even in the severe state of emaciation. Also, the levels of plasma cortisol often show
a loss of the normal diurnal rhythm (Hotta et al.,
1986; Herpertz et al., 1998), pointing to a disorder
in the circadian timing system. However, others
reported that the circadian variations in cortisol
remained the same despite an increase in the mean
levels of cortisol (Balligand et al., 1998). Hypercortisolism in underweight anorexics reflects
hypersecretion of hypothalamic CRH rather than
primary glucocorticoid resistance (Kling et al.,
1993). Hypercortisolism is presumed to cause a loss
of circadian rhythms (Awazu et al., 2000). Our
observation that corticosteroid treatment of patients
for different reasons decreases vasopressin mRNA
in the SCN (Liu et al., 2003, submitted) agrees with
this idea. In a subsample of bulimia patients who
experienced reversed symptoms such as hypersomnia and hyperphagia when they were depressed,
low plasma cortisol levels were observed. These
lower levels may, however, have been due to circadian phase alterations (Levitan et al., 1997).
Prolactin, ACTH, -endorphin and melatonin circadian rhythms are also disturbed in anorexia and
bulimia nervosa according to some studies (Ferrari
et al., 1990; Kaye, 1996; Pacchierotti et al., 2001)
and the circadian rhythm of leptin is completely
abolished (Balligand et al., 1998). Bulimic women
have blunted nocturnal prolactin patterns (Weltzin
et al., 1991). Other studies report that the circadian
rhythm of melatonin was unaltered in bulimia and
anorexia (Brown, 1992), and that the nocturnal

185

Fig. 23.12. Seasonal variation in binge eating, purging and feeling worst
among 31 bulimic and 31 comparison subjects. Binge eating (a), purging
(b), and feeling worst (c) were determined according to the modified
seasonal pattern assessment questionnaire. Number of dark hours was
defined as 24 h minus the average photoperiod for each month.
(a) A significant group effect (F = 103.99, df = 1, 60, p < 0.001), month
effect (F = 9.91, df = 11, 50, p < 0.001) and group by month interaction (F = 7.06, df = 11, 50, p < 0.001) were found. The correlation
between number of dark hours and likelihood of binge eating was
significant (r = 0.97, df = 12, p < 0.001).
(b) A significant group effect (F = 83.77, df = 1, 60, p < 0.001), month
effect (F = 3.99, df = 11, 50, p < 0.001) and group by month interaction (F = 2.76, df = 11, 50, p < 0.007) were found. The correlation
between number of dark hours and likelihood of purging was significant (r = 0.94, df = 12, p < 0.001).
(c) A significant group effect (F = 6.46, df = 1, 60, p < 0.02) and group
by month interaction (F = 2.50, df = 11, 50, p < 0.02) were found.
The correlation between number of dark hours and likelihood of
feeling worst was significant (r = 0.92, df = 12, p < 0.001). (Blouin
et al., 1992, Fig. 1 with permission.)

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1
secretion of melatonin was significantly greater in
2
anorectics (Arendt et al., 1992; Luboshitzky et al.,
3
2001), or even that there was an enhanced circa4
dian rhythm of melatonin in anorexia nervosa with
5
higher diurnal and nocturnal plasma melatonin
6
levels (Tortosa et al., 1989). That the night levels
7
of serum melatonin in patients with anorexia are
8
increased was confirmed by Manz et al. (1990).
9
Since, a significant decrease in melatonin secretion
101
has been found, coexisting with depression in
1
patients with eating disorders, which may at least
2
partly explain the variable results in the literature
3
on this topic (Kennedy et al., 1990; Brown, 1992).
4
A clear seasonal pattern has been reported in the
5
signs and symptoms of bulimia nervosa. Bingeing
6
behavior and mood disorders were found to be
7
closely associated with the photoperiod in that the
8
symptoms are the most severe in winter and the
9
least severe in summer (Blouin et al., 1992; Fig.
201
23.12). Such seasonal changes are not present in
1
anorexia nervosa (Lam et al., 1996a). In bulimic
2
patients with worsening of mood and eating symp3
toms in winter, bright white light therapy was effec4
tive for both symptoms (Lam et al., 1994), an
5
important observation that has so far not gained
6
much following. However, it should be noted that
7
Pasternak and Zimmerman (2002) did not find
8
higher rates of bulimia in winter in an outpatient
9
psychiatric practice in the USA.
301 iii(x) Various peptides that are involved in the regulation
1
of food intake (Chapters 11, 23c) show alterations.
2
Reduced CSF -endorphin levels have been found.
3
This peptide stimulates feeding behavior (Kaye,
4
1996). Plasma -endorphin concentrations were sig5
nificantly higher in bulimic than in control subjects
6
at all time points (Vescovi et al., 1996). Since nalox7
one has some effects in the treatment of anorexia
8
(Moore et al., 1981), the opiate system, too, should
9
have research attention. It is not remarkable that ele401
vated CSF levels of NPY have been found in anorec1
tics (Krysiak et al., 1999), since this peptide is
2
upregulated by lower levels of leptin (see Chapter
3
23b) (Kaye, 1996; Krysiak et al., 1999). Galanin is
4
an orexigenic peptide that stimulates appetite and
5
fat consumption. The galanin level in the CSF of
6
recovered anorexia nervosa patients is lower than
7
that of controls, and may thus play a role in food
8
restriction and fat avoidance (Frank et al., 2001).
911
Leptin is a satiety factor that is produced by fat

cells. The protein is encoded by the LEP gene and


acts on the arcuate nucleus and other hypothalamic
areas to reduce food intake (see Chapter 23b). Both
serum and CSF leptin levels are lower in anorexia
nervosa patients but appropriate to body-weight
decrease. However, altered transport of leptin over
the bloodbrain barrier is presumed. Weight gain in
anorexia patients leads to steep increases in leptin
plasma levels. Low leptin levels are also associated
with amenorrhea. A critical leptin level seems to be
needed to maintain menstruation (Grinspoon et al.,
1996; Hebebrand et al., 1997; Kpp et al., 1997;
Balligand et al., 1998; Herpertz et al., 1998; Stving
et al., 1998; Mantzoros, 2000). Recently, increased
fasting plasma levels of ghrelin have been reported
in patients with bulimia nervosa; this peptide stimulates eating (Tanaka et al., 2002).
ii(xi) Using single photon emission computed tomography
(SPECT), a reduced hypothalamic and thalamic
5-HT transporter availability was found in bulimia
nervosa. The impaired 5-HT transporter availability
was more pronounced with longer duration of the
illness (Tauscher et al., 2001). The association with
the presence of 5-HT2A promotor polymorphism
in anorexia (Sorbi et al., 1998) may be related to
such alterations. Because elevated concentrations
of 5-HIAA were found in the CSF of anorexia
and bulimia nervosa patients after recovery, altered
5-HT metabolism is proposed to be a trade-related
characteristic (Kaye et al., 1998) and may be the
basis of the therapeutic effects of SSRIs.
i(xii) One of the most paradoxical features of anorexia
nervosa is that, during periods of extreme caloric
restriction and weight loss, the majority of patients
display abnormally high levels of physical activity.
Interestingly, in many kinds of animals, heightened
locomotion is a behavioral marker of sensitivity to
stress (Davis et al., 1999b).
(xiii) Whether the elevated pain threshold in anorexia nervosa, bulimia nervosa and binge-eating disorder
(Raymond et al., 1999; see Chapter 23.3) is based
upon a hypothalamic pain mechanism (Chapter 31)
remains to be investigated.
(b) Hypothalamic tumors mimicking anorexia nervosa
The possibility that anorexia and bulimia may primarily
be a hypothalamic disease is reinforced by a number of

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case histories of patients who were, after they had been


diagnosed to suffer from anorexia and sometimes
subjected to psychotherapy, at autopsy, found to have a
tumor in the hypothalamus. These cases not only include
a number of children that had atypical anorexia, but also
adults with a typical diagnosis of anorexia nervosa.
In cases of anorexia it may be difficult to differentiate
between psychogenic and organic causes. Psychological disturbances without neurological manifestations
may be due to occult intracranial tumors masquerading
as anorexia nervosa (DeVile et al., 1995). In a neonate,
an obstinate anorexia and a subsequent failure to gain
weight had been present since birth. At autopsy, at 6
months of age, an astrocytoma, probably originating from
the meninges and occupying the third ventricle, was
found. The tumor was not sharply demarcated from the
hypothalamic regions and was continuous with the
meninges (Kagan, 1958). A 10-year-old child with a diagnosis of major depression and atypical anorexia nervosa
was found to have a teratoma in the hypothalamic region
(Chipkevitch and Fernandes, 1993). DeVile et al. (1995)
describes three boys with tumors affecting the hypothalamus and invading the brainstem, causing psychological
dysfunction and anorectic symptoms without initial neurological signs. The CT scans of all three patients were
normal. The children suffered from, respectively, a craniopharyngioma, a disseminating pineal germinoma, and a
low-grade astrocytoma. A 13-year-old girl with anorexia
nervosa was found to have an infiltrating tumor in the
left hypothalamic area. The symptoms abated after the
tumor was irradiated (Weller and Weller, 1982).
In various adult patients who had been diagnosed to
suffer from anorexia nervosa, it also turned out to be a
tumor that appeared to be the cause. A 22-year-old girl
with a psychiatrists diagnosis of anorexia nervosa
suddenly lost consciousness, had an epileptic fit and died
in coma. She had been obsessed by her weight. Her condition deteriorated after learning that her father suffered
from an inoperable carcinoma. She probably also suffered
from diabetes insipidus and had developed pneumonia.
In retrospect, she suffered from hypopituitarism. She
had a hypothalamic tumor, atypical pinealoma (no tumor
cells were found in the pineal gland), seminoma, dysgerminoma or atypical teratoma (Clinicopathological
Conference, 1973).
Another case was that of a 62-year-old woman who
became extremely cachectic and refused to eat. According
to a psychiatrist she had anorexia nervosa. At autopsy,
her brain revealed a cystic lesion on the wall of the

187

third ventricle at the level of the infundibulum, which


was bordered medially by normal ependymal and subependymal tissue. The cyst had caused a decrease in
hypothalamic substance. The lateral hypothalamic nuclei
showed paucity of neurons (White and Hain, 1959).
A 22-year-old woman with anorexia nervosa first went
through a phase of nonspecific and inconsistent signs and
symptoms such as sleep disturbances and increased fluid
intake. The psychodynamic features were the most
striking, but the characteristics of the ventromedial hypothalamic syndrome complicated the psychiatric picture;
she had urges to kill people and induced vomiting whenever she overate. Eventually the intractable headaches and
loss of visual fields pointed to a hypothalamic tumor. The
craniopharyngioma was removed (Climo, 1982).
Yet another case report concerns a 25-year-old woman
with a history of secondary amenorrhea and weight loss.
Her father had died six months earlier, after which she
had begun to lose weight. A diagnosis of anorexia nervosa
was made. She suffered from sudden losses of consciousness, with low blood sugar levels and died 2 weeks later
from an infection. The hypothalamus contained a small,
0.5-cm-diameter, circumscript astrocytoma immediately
posterior to the optic chiasm and to the right of the tuber
cinereum (Lewin et al., 1972).
Although these case histories show that all the signs
and symptoms of anorexia nervosa can be found in
patients with a hypothalamic tumor, including the characteristic that the psychodynamic features are the most
outstanding, it should be noted that these are rare cases
and that the majority of the hypothalamic tumors are not
associated with symptoms of anorexia nervosa.
(c) Association with other disorders
Comorbidity between eating disorders and other psychiatric diseases is common, e.g. with depression, anxiety
disorders, oppositional defiant disorder and substance
abuse (Rowe et al., 2002). Bulimia has been found to be
associated with Parkinsons disease (Rosenberg et al.,
1977). Bulimia disappeared in these Parkinson patients
following L-DOPA treatment. This indicates that a
disorder of the dopaminergic system might be a basis for
the change in appetite in bulimia (Rosenberg et al., 1977),
but no direct data on this possibility are available. The
presence of bulimia in Parkinson patients may also fit in
with the idea that oxytocin neurons of the paraventricular nucleus are satiety cells (Swaab et al., 1995a),
because their number decreases in Parkinsons disease
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(Purba et al., 1994). Bulimia may also be present in


borderline personality disorder. In addition, a greater lifetime presence of binge eating was found among survivors
of the Nazi concentration camps, who survived a period
of extreme food deprivation (Favaro et al., 2000).
Moreover, a 28-year-old man with anorexia and bulimic
eating behavior had a hydrocephalus internus, presumably due to a stenosis of the aquaduct (Pauls et al., 1991).
Anorexia nervosa associated with Klinefelters syndrome
has been described in several cases (El-Badri and Lewis,
1991). Primary amenorrhea occurs in 411% of the
anorexia cases. In case of primary amenorrhea, Kallmann
syndrome, for instance, should be excluded (White et al.,
1993). Medicine-induced eating disorders have been
reported with fluoxetine, clozapine, apomorphine and
amphetamine (Barry and Klawans, 1976; Morgan and
Lacey, 1996). For bulimia associated with KleineLevin
syndrome, see Chapter 27.1.
On clinical grounds, it is difficult to distinguish
anorexia nervosa from Simmonds pituitary cachexia
(Richardson, 1939). Simmonds disease was described
to arise from adenohypophysial failure, but was later
also found to occur in patients with an intact pituitary,
but with tumors or inflammatory processes in the region
of the third ventricle (Kagan, 1958). Heterozygous
carriers for Wolframs syndrome (see Chapter 22.6)
have also been hospitalized for anorexia (Swift et al.,
1991). Moreover, a case with acute pandysautonomia
presented with the diagnosis anorexia nervosa (Okada,
1990).
Since hypothalamic tumors may fully mimic anorexia
nervosa (Chapter 23.2b), one should, in the case of eating
disorders, look, in postmortem tissue, for hypothalamic
conditions that may be involved in the etiology, such as
autoimmune processes. The case of anorexia nervosa of
the bulemic subtype in a 14-year-old girl following withdrawal of oral prednisolone used in the treatment of
asthma (Morgan and Lacey, 1996) supports the possibility of an autoimmune process underlying this condition
(although this possibility is not mentioned as such by the
authors). No great changes in peripheral immunocompetence are generally found in anorexia nervosa (Marcos et
al., 1997; Staurenghi et al., 1997). However, in one case
of anorexia nervosa, vacuolization of the TMN was
observed with moderate gliosis and myelinization of the
vessels. The vacuolization and gliosis extended to the
paraventricular nuclei and the massa intermedia, where a
strong microglial reaction was observed (Martin, 1958).
This observation points to the possibility of a central

immune process as a basis of anorexia nervosa, a concept


that is reinforced by changes in cytokine levels observed
in anorexia and bulimia nervosa (Holden and Pakula,
1996). The possibility that anorexia and bulimia nervosa
are based upon a hypothalamic autoimmune process is
strongly supported by the presence of autoantibodies
against hypothalamic neuropeptides (Fetissov et al.,
2002), and by the five patients mentioned in the literature
who were successfully treated with corticosteroids and
ACTH (Wheatland, 2002).
(d) Therapy
For light therapy in bulimia nervosa, see Chapter 23.2a
(ix). Cognitive psychotherapy is the treatment of choice
in anorexia nervosa (Halmi, 2002) and is reported to be
effective in 6070% of the individuals with bulimia
nervosa, while fluoxetine reduces binge frequency,
although the relapse rate is considerable (Walsh and
Devlin, 1998). Psychoanalytical and family therapy are
said to be of specific value in the outpatient treatment of
adult patients with anorexia (Dare et al., 2001). In a
randomized controlled trial, 16 patients with anorexia and
bulimia were trained to eat and recognize satiety by using
computer support. Fourteen patients (75%) of the treatment group went into remission in the mean time of 14.7
months, while only 1 untreated control went into remission. Only 7% of those who were treated with this method
to remission relapsed, while 93% remained in remission
for 12 months, so this method seems to be effective
(Bergh et al., 2002).
Selective 5-HT reuptake inhibitors are not very useful
when anorexia nervosa patients are malnourished and
underweight. When given after weight restoration, these
medicines may reduce the extremely high rate of relapse
seen in anorexia (Brewerton and Jimerson, 1996; Kaye,
1997; Kaye et al., 1998). In addition, fluoxetine adds a
modest beneficial effect to cognitive-behavioral therapy
in bulimia nervosa (Stunkard, 1997; Walsh et al., 1997).
In bulimia nervosa, cognitive behavioral therapy seems
to be superior to imipramine alone. In anorexia nervosa
the progress in treatment is modest. Family therapy seems
to be more effective than standard, individual supportive
therapy. In addition, tricyclic antidepressants are effective (Brambilla, 2001). When patients recover from
anorexia nervosa, insulin hypersensitivity remained the
insulin response to the meal was blunted and apparently
delayed. There may be a persistent alteration in pancreatic

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Fig. 23C. Ren Magritte, Le Sorcier (autoportrait), 1951. Huile sur toile, 35  46. Galerie Isy Brachot, Bruxelles 1992. By C.H. Adagp
et Flammarion 4, Paris 6, 19 rue Visconti. Imprim en France XF 1055. (Reproduced with permission Ren Magritte Le Sorcier,
c/o Stichting Beeldrecht.)

dominates; whereas, in the second syndrome, neurological


complications are very unusual (Soliman et al., 1996).
Because of the overlapping phenotypes between Bardet
Biedl syndrome and LaurenceMoon syndrome, Beales
et al. (1999) proposed the name polydactyly-obesitykidney-eye syndrome as a unifying descriptive label.
BardetBiedl syndrome (BBS MIM no. 209900) is genetically heterogeneous, with six known loci: BBS1 (11q13),
which is the most frequent one, accounting for about
50% of the cases, BBS2 (16q21), BBS3 (3p13-p12),
BBS4 (15q22.3-q23) and BBS5 (2q31) (Haider et al.,
1999; Woods et al., 1999; Young et al., 1999; Mykytyn
et al., 2002). In families from New Foundland, mutations
in the chaperone-like gene MKKS were found to cause
obesity, retinal dystrophy and renal malformations associated with BardetBiedl syndrome, while mutations in
BBS1 to -5 were excluded (Katsanis et al., 2000). BBS6
is caused by mutations in the gene MKKS (Mykyntyn
et al., 2001). Mutations in the MKKS gene also cause
McKusickKaufman syndrome, which is related to
BardetBiedl syndrome (Schaap et al., 1998; Mykytyn

function, or alternatively this may be a trait marker for


anorexia nervosa (Brown et al., 2003b).
23.3. Other eating disorders (Fig 23C)
(a) LaurenceMoon/BardetBiedl syndrome
LaurenceMoon/BardetBiedl syndrome is a rare
(1:1,000,000), heterogeneous disorder that includes the
following cardinal symptoms: obesity starting at 23
years, hypogenitalism, mental retardation (predominantly
verbal), retinitis pigmentosa (which becomes apparent
around 8 years), short stature, renal abnormalities and
polydactyly or syndactyly. The disorder is also associated
with diabetes mellitus, hypertension and congenital heart
disease (Stoler et al., 1995; Soliman et al., 1996; Beales
et al., 1999). The syndrome has an autosomal recessive
mode of inheritance (Lerner et al., 1995). It is suggested
that this syndrome comprises two disorders: the Laurence
Moon syndrome, and the BardetBiedl syndrome. In the
first syndrome, polydactyly is rare and spastic paraparesis
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et al., 2001, 2002). In spite of the obesity and hypogonadism in LaurenceMoon/BardetBiedl syndrome, there
is so far only little and inconsistent evidence that lesions
of the hypothalamus may account for these conditions.
In some older case histories fewer large cells were
reported in the tuberal nuclei, fewer cells in the corpora
mamillaria, and slight demyelination of the optic tracts
and chiasm. Also, moderate paraventricular gliosis has
been reported, but other studies mention the hypothalamus to be normal (McLoughlin and Shanklin, 1967).
Systematic work with quantitative state-of-the-art techniques is needed to establish whether there is indeed
hypothalamic involvement in this disorder.
(b) Biemonds syndrome

absence of mental retardation, and the combined occurrence of nerve deafness, diabetes mellitus and chronic
nephropathy. Analysis of the family data is compatible
with an autosomal recessive mode of inheritance, and the
multiple clinical manifestations are, therefore, explained
on the basis of homozygosity for mutant genes at a single
autosomal locus (Goldstein and Fialkow, 1973). The gene
ALMS1, which contains sequence variations, including
four frameshift mutations and two nonsense mutations,
segregates with Alstrms syndrome in six unrelated families (Collin et al., 2002).
(d) Night eating syndrome

Biemonds syndrome type 2 is a recessive inherited condition (MIM no. 210350) comprising mental retardation,
coloboma, obesity, polydactyly, hypogonadism, hydrocephalus and facial dysostosis. Clinically the disorder is
closely related to BardetBiedl syndrome. Several related
clinical forms are distinguished as new nosological entities (Verloes et al., 1997). Short stature and delayed sexual maturation are features also present in BardetBiedl
syndrome. The growth disturbance may partly be due to
the defective testosterone secretion. The presence of an
empty sella has also been described in this syndrome.
Hypogonadism can be attributed in this disorder to
primary gonadal failure with or without hypothalamicpituitary disfunction. Obesity is the major determining
factor of hyperinsulinemia, also in BardetBiedl syndrome
(Soliman et al., 1996). Molecular studies indicate that the
syndrome is genetically heterogeneous with major loci at
chromosome 11q, 15q, 16q and a rare locus at 3q. The
genes have not yet been cloned (Schaap et al., 1998).

A new, related eating disorder that is different from


anorexia nervosa, bulimia nervosa and binge eating, is
the night eating syndrome. It is characterized by morning
anorexia, evening hyperphagia and insomnia and occurs
during periods of stress. Its prevalence has been estimated
at 1.5% in the general population and some 27% of
severely obese persons. The mood of the night eaters falls
during the evening. There are circadian changes, such as
an attenuation of the night-time rise in melatonin and
leptin and elevated levels of plasma cortisol (Birketvedt
et al., 1999). Night-time awakenings are far more common
among night eaters than among controls and more than
half the number of the awakenings are associated with
food intake. The typical neuroendocrine characteristics
are an attenuation of nocturnal rises in melatonin and
leptin and increased diurnal secretion of cortisol. The
CRH-induced ACTH and cortisol response are reduced
in night eaters (Birketvedt et al., 2002). Observations that
light improves the symptoms of night-time eating
syndrome (Friedman et al., 2002) should be further tested
in controlled studies.

(c) Alstrms syndrome

(e) Binge eating disorder

Alstrms syndrome is characterized by profound blindness due to retinal degeneration, infantile obesity,
deafness, diabetes mellitus due to resistance to the action
of insulin, and slowly progressive nephropathy. Males
have a unique variety of hypogonadism in which normal
secondary sexual characteristics occur despite small
testes, low plasma testosterone and elevated gonadotropins. The features that distinguish Alstrms syndrome
from the LaurenceMoon/BardetBiedl syndrome are the

A new diagnostic concept that has provisional status in


DSM-IV is binge eating disorder. Like bulimia nervosa
it has binge eating as a central feature, but there is little
or no weight-control behavior, such as self-induced
vomiting and laxative misuse. Some 40% of the binge
eating disorder cohort met criteria for obesity in a 5-year
follow-up, and this group of patients is highly prevalent
(130% among often extremely obese subjects seeking
weight-loss treatment) (Dingemans et al., 2002; Hsu

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et al., 2002). The rate of childhood emotional abuse is


some 23 times more prevalent in this eating disorder
than in a normative adult female sample. No other forms
of childhood maltreatment, such as physical or sexual
abuse, or emotional or physical neglect, were increased
in binge eating disorder (Grilo and Masheb, 2002). Bingeeating is a major characteristic of subjects with a mutation
in the MC4 receptor (Branson et al., 2003). The treatment of choice is currently cognitive behavioral treatment,
but interpersonal psychotherapy, self-help and SSRIs
seem effective (Dingemans et al., 2002).

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(f) Miscellaneous
Other eating disorders include Frlichs syndrome and
the related ventromedial hypothalamic syndrome (Chapter
26.3), KleineLevin syndrome (periodic somnolence and
morbid hunger; Chapter 28.1) and PraderWilli-like
syndrome, which have a different genetic background
(Chapter 23.1d).

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)


The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved

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CHAPTER 24

Reproduction, olfaction and sexual behavior (Figs. 24A, B)

Long before the human species appeared, the pinnacle of


evolution was already the brain as it had been before
mammals appeared, before land vertebrates, before vertebrates. From this point of view, everything else in the
multicellular animal world was evolved to maintain and
reproduce nervous systems that is, to mediate behavior,
to cause animals to do things. Animals with simple and primitive or no nervous system have been champions at surviving,
reproducing, and distributing themselves, but they have
limited behavioral repertoires. The essence of evolution is
the production and replication of diversity and more than
anything else, diversity in behavior.
T.H. Bullock (1984)

The central peptide for reproduction, luteinizing


hormone-releasing hormone (LHRH), is synthesized as a
92-amino acid precursor that is subsequently cleaved to
form the decapeptide LHRH. Pulsatile LHRH acts at
the LHRH receptor on gonadotropic-hormone-containing
neurons in the pituitary and is required to maintain
gonadotropin synthesis and secretion. Acute administration of LHRH induces a marked release of LH and
follicle-stimulating hormone (FSH). However, chronic
administration of LHRH induces an inhibition of the
gonadal axis through the process of downregulation of
pituitary receptors for LHRH. This is the basis for application of LHRH in gynecology and oncology, e.g. in
treating mamillary, ovarian, endometrial and prostate
cancer and hamartomas (Chapter 19.3). The pituitary
gonadotropins LH and FSH stimulate steroid production
and gametogenesis in males and females. Genetic
abnormalities have been identified on all levels of
the hypothalamopituitarygonadal axis (Ackerman
et al., 2001). The distribution of the LHRH (=
GnRH)-synthesizing neurons and fibers in the hypothalamus and adjacent areas is described in Chapters 11 and
24.2, as well as by Stopa et al. (1991) and Duds

Fig. 24A. Pregnant woman. Marc Chagall, 1913. Stedelijk Museum,


Amsterdam, in bruik-leen van: Instituut Collectie Nederland (with
permission.)

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Fig. 24B. Activating effects of sex hormones on the brain. Arend van Dam, with permission.

et al. (2000). LHRH is present in the human brain in


three isoforms (Chen et al., 1998; Yahalom et al., 1999).
The human hypothalamic LHRH pulse-generating mechanism is located entirely within the mediobasal
hypothalamus, as shown by in vitro perfusion techniques
(Rasmussen, 1992). The frequency and amplitude of
LHRH pulses determine gonadotropin subunit gene
expression and secretion of pituitary LH and FSH. During
ovulatory cycles, an increase in LHRH frequency (more
than 1 pulse per hour) during the follicular phase favors
LH synthesis prior to the LH surge, while, after ovulation, luteal steroids slow LHRH pulses to favor FSH
synthesis. Thus, a changing frequency of LHRH stimulation is one of the mechanisms involved in differential
gonadotropin secretion during ovulatory cycles (Seminara
et al., 1998; Marshall et al., 2001).
A large number of factors modulate the function of the
LHRH neurons, and thus the LH pulsatile secretion. As
found in many species, also in young healthy men, light
exposure increases LH secretion (Yoon et al., 2003).
Genetic abnormalities have been identified on all levels
of the hypothalamopituitarygonadal axis (Ackerman et
al., 2001). The sequential acceleration and deceleration
of the LHRH pulse generator and subsequent LH pulse
frequency during the menstrual cycle are to a certain
degree determined by cyclic changes in endogenous
opioid peptides such as -endorphin, probably derived
from the infundibular nucleus (Ferin et al., 1984; Gindoff

et al., 1987; Kalra et al., 1997; Chapter 31.1). In postmenopausal women this inhibitory opioid tone on LHRH
release diminishes, as appears from the decreased proopiomelanocortin mRNA expression in the infundibular
nucleus (Abel and Rance, 1999). In addition, estradiol
and progesterone act at a hypothalamic site to modulate
LHRH signals. Estradiol primarily affects the amplitude,
while progesterone decreases the frequency of the LHRH
pulse (Ferin et al., 1984). Participation of a number of
hypothalamic neurotransmitters/neuromodulators in the
release of LHRH is apparent, i.e. neuropeptide-Y (NPY),
GABA, galanin, excitatory amino acids, substance-P,
and nitric oxide (Kalra et al., 1997; Duds et al., 2000;
Duds and Merchenthaler, 2002), and catecholamines
modulate the LHRH release. Tyrosine hydroxylase
containing terminals, possibly coming from the supraoptic
(SON), paraventricular (PVN) and periventricular nuclei
are found on LHRH neurons (Duds and Merchenthaler,
2001). Melatonin inhibits the hypothalamopituitary
gonadal axis before the onset of puberty (Lavie and
Luboshitzky, 1997; Chapter 4.5d). Moreover, melatonin
secretion is increased in patients with LHRH deficiency,
irrespective of its etiology (Kadva et al., 1998). Testosterone decreases melatonin secretion to normal levels in
these patients (Luboshitzky et al., 1995, 1996, 1997a),
indicating that pineal function is altered in relation to
the gonadal status. High training activity and dark
photoperiod independently suppress ovarian function

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(Ronkainen et al., 1985). The strongly diminished


estrogen levels in postmenopausal women induce hyperactivity of LHRH neurons (Wise, 1998; Chapter 11f).
In the human male, testosterone exerts both direct and
indirect feedback on LH secretion, whereas its effects on
FSH appear to be mediated largely by aromatization to
estradiol, which is thus the predominant regulator in
FSH secretion (Hayes et al., 2001). There is an attenuation of LH and testosterone secretory pulse amplitude,
and disruption of their orderly patterns of release in
healthy older men (Veldhuis, 2000). Testosterone levels
decline with age in men, but not so dramatically, and
with great interindividual variability (Sternbach, 1998;
Feldman et al., 2002), resulting in a moderate stimulation
of LHRH neurons (Chapter 11f). Bioavailable testosterone
decreases 0.53% per year in men. Dehydroepiandrosterone sulfate (DHEAS) and estrone also decline with
age, whereas dihydrotestosterone rises (Feldman et al.,
2002). The decline of free testosterone in men already
starts when men are in their 30s and 40s. In addition, the
circadian rhythm of testosterone flattens out in the elderly
(Baulieu, 2002; Chapter 4.3).
Functional MRI (fMRI) studies show that sexual
arousal in males, but not in females, is accompanied by
an activation of the right hypothalamus (Arnow et al.,
2002; Karama et al., 2002). This technique does not allow
determination of exactly which hypothalamic structures
are involved. Interestingly, in patients with psychogenic
erectile dysfunction, sublingual administration of apomorphine caused extra activation of the hypothalamus during
video sexual stimulation. Apomorphine acts on the
oxytocinergic neurons in the paraventricular nucleus,
which plays a key role in regulating penile erection
(Chapter 8g; Montorsi et al., 2003). There is a strong
correlation between testosterone levels and male sexual
activity, both in cross-sectional and longitudinal studies.
In addition, correcting testosterone deficiency in hypogonadal men improves sexual desire, activity and mood
(Anderson et al., 1992a; Wang et al., 2000a; Yates, 2000).
Testosterone not only stimulates both male and female
sexual behavior, it is also enhanced by sexual behavior.
Although the salivary testosterone levels in males are
much higher (7.4 ng/dl) than in females (1.4 ng/dl), in
both sexes a similar increase in testosterone levels is
found across the evening when there is intercourse, and
a decrease when there is no intercourse (Dabbs and
Mohammed, 1992). This relationship between testosterone and coitus must, however, be regarded as tentative
in view of the studies finding no change in testosterone

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levels (Meisel and Sachs, 1994). Interestingly, men with


paraphilia have a prompt reduction or total abolition of
all paraphilic activities, while being treated with a longacting analogue of LHRH that serves to reduce
testosterone levels (Rosler and Witzum, 1998). A curious
finding is that expectant fathers have lower testosterone
and cortisol levels, more frequently detectable estradiol
levels, and elevated prolactin levels. The functional
meaning of these changes for fatherhood is not known
at present (Berg et al., 2001).
The ovaries provide approximately half the circulating
testosterone in premenopausal women (Shifren et al.,
2000). The disappearance of androgens such as
androstenedione, testosterone, DHEA and DHEAS after
ovariectomy and adrenalectomy in women is accompanied by a complete loss of libido, whereas substitution
of androgens maintains sexual desires and fantasies after
surgical menopause. Circulating levels of androgens
decline gradually with increasing age and the circadian
rhythm of testosterone disappears in older age (Bremner
et al., 1983). Prudent administration of testosterone to
healthy premenopausal women causes increases in vaginal
arousal, genital sensations and lust (Shifren et al., 2000;
Tuiten et al., 2000; Davis and Tran, 2001; Schill, 2001).
Around the menopause in women there is a continuous
rise in serum FSH and LH and a concomittant fall in
estradiol and estrone levels (Overlie et al., 1999). Some
publications report a decline of androstendione and testosterone 3 years before menopause (Overlie et al., 1999),
while others observe a small rise of these two androgens
in postmenopausal women (Jiroutek et al., 1998). Sex
hormones are thought to play a role in cognition also,
although the literature on the possible effects of estrogens in Alzheimers disease is certainly still controversial
(see Chapter 29.1b). In older men low estrogen and high
testosterone levels predict better performance on several
tests of cognitive function (Barrett-Connor et al., 1999a).
Testosterone has a differential effect on cognitive function, inhibiting spatial abilities while improving verbal
fluency in eugonadal men (OConnor et al., 2001).
Apart from regulating sex hormones (see below and
Chapter 24.5), neuropeptides play a role in sexual
behavior, as has been shown, mainly, but not only in
animal experiments. A facilitatory role for sexual behavior
is assigned to corticotropin (ACTH), alpha-melanotropin
(-MSH) and oxytocin. Oxytocin is acutely released after
orgasm in men, while vasopressin plasma levels remain
unaltered (Krger et al., 2003; see Chapter 8g). Erectogenesis occurs via the MC-4 receptor and may involve
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oxytocinergic pathways (Martin et al., 2002). In contrast,


an inhibitory effect on sexual behavior has been found
for opioid peptides, CRH, cholecystokinin and NPY (see
also Chapter 24.5b). The results of tests with galanin
contrast with those of LHRH (Argiolas, 1999).
24.1. Disorders of gonadotropic hormone regulation
A woman who does not have regular menstrual periods will
endure great suffering and eventually death if the problem
is left untreated.
Hippocrates, cited by Warren and Fried, 2001.

(a) Hypogonadotropic hypogonadism


Patients with hypogonadotropic hypogonadism manifest
irreversible pubertal delay, infertility and low serum levels
of FSH and LH. Hypogonadotropic hypogonadism may
have a number of different congenital causes, including
genetic ones (for reviews see Whitcomb and Crowley,
1993; Yen, 1993; Warren, 1996; Hayes et al., 1998;
Seminara et al., 1998). Increased melatonin levels were
found in patients with hypogonadotropic hypogonadism
(Luboshitzky and Lavie, 1999). In its turn, melatonin
suppresses the gonadal axis (Chapter 4.5).
Mutations have been identified in 510% of the patients
with hypogonadotropic-hypogonadism (Layman, 1999a).
Although no specific mutations have been found in the
LHRH gene so far (Layman, 1999a, b), hypogonadism,
involving the LHRH locus (Achermann et al., 2001a, b),
has been described in some patients with 8p deletions. A
family has been described with hypogonadotropic hypogonadism without anosmia with compound heterozygous
mutations of the pituitary LHRH receptor genes. The
disorder was transmitted as an autosomal recessive trait.
One mutation in the first extracellular loop of the receptor
dramatically decreased LHRH binding to its receptor. The
other mutation, in the third intracellular loop, did not
modify the binding of the hormone but decreased the activation of phospholipase C (De Roux et al., 1997; Layman,
1999a, b). Kallmanns syndrome, characterized by hypogonadotropic hypogonadism and anosmia and based on,
e.g. an X-linked recessive mutation of the KAL gene, is
discussed in Chapters 24.2 and 24.3. Moreover, patients
have been described with hypogonadotropic hypogonadism, inherited obesity, abnormal glucose homeostasis,
hypocortisolism, a very low plasma insulin level and
elevated plasma proinsulin and pro-opiomelanocortin
due to a mutation of the endopeptidase prohormone

convertase 1 (PCSK1), which prevents the processing


of various prohormones (ORahilly et al., 1995; Jackson
et al., 1997). A few families have been described with
autosomal recessive mutations in the leptin gene or the
leptin receptor gene (see Chapter 23). In addition to
morbid obesity, these patients had hypogonadism and did
not progress to puberty, suggesting that leptin not only
controls body mass but is also a necessary signal for the
initiation of puberty in human (Clement et al., 1998;
Strbel et al., 1998).
PraderWilli syndrome is dealt with in Chapter 23.1
and Klinefelters syndrome in Chapter 24.4. The fertile
eunuch syndrome represents a partial LHRH deficiency
with preservation of spermatogenesis (Hayes et al., 1998;
Seminara et al., 1998). Moreover, LaurenceMoon/
BardetBiedl, Biemond II and Alstrms syndromes
(Chapter 23.3) are characterized by hypogonadotropic
hypogonadism, possibly due to an abnormality in LHRH
secretion accompanied by mental retardation, obesity,
retinitis pigmentosa and often by dysmorphic extremities
(Whitcomb and Crowley, 1993; Yen, 1993; Warren, 1996;
Young et al., 1999). In addition, hypogonadotropic hypogonadism is frequently associated with X-linked congenital
adrenal hypoplasia, an autosomal recessive disease due
to mutations of the DAX-1 gene (NROB1). This gene is
a member of the nuclear hormone receptor family, located
on chromosome Xp21, and is responsible for the normal
development of the hypothalamopituitarygonadal axis.
More than 60 different mutations have been described in
the DAX gene so far (Layman, 1999a, b; Achermann
et al., 2001a, b). DAX-1 is an orphan nuclear receptor
that is expressed in the adrenal gland, ventromedial hypothalamus and pituitary gonadotropins. NROB1 mutations
abrogate its ability to act as a transcriptional repressor of
steroidogenic factor-1, also an orphan nuclear receptor
(Achermann et al., 2001a, b). Although it is not clear at
present whether the origin of this disorder is pituitary,
hypothalamic or both, the successful induction of pubertal
gonadotropins and sex steroid concentrations after therapy
with pulsatile LHRH in some cases suggests a hypothalamic origin. This was, however, not confirmed by others
(Seminara et al., 1999). In affected males an intrinsic
defect in the spermatogenesis may be present which is
not responsive to gonadotropin therapy (Seminara et al.,
1999). It is interesting to note that a patient with this
disorder showed the normal neonatal increase in testosterone levels, possibly stimulated by human chorionic
gonadotropin (HCG) from the placenta (Takahashi et al.,
1997; Bassett et al., 1999; Caron et al., 1999; Wang

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et al., 1999). PROP1 gene mutations lead to combined


hypogonadotropic hypogonadism and pituitary deficiency,
and HESX1 mutations to septo-optic dysplasia (Chapter
18.3b). Idiopathic hypothalamic syndrome of childhood
and hypothalamic atrophy are rare disorders, described
in Chapters 32.1 and 32.2, respectively. Salla disease,
due to sialic acid storage, may also be accompanied by
hypogonadotropic hypogonadism (Grosso et al., 2001).
The most common cause of adult onset of hypogonadotropic hypogonadism in males is a tumor of the
hypothalamic-pituitary region, such as a pituitary tumor,
which often goes together with acquired erectile dysfunction (Citron et al., 1996; Ben-Jonathan and Hnasko, 2001).
Prolactinoma cause amenorrhea, infertility, decreased
libido and increased anxiety and depression. Adult-onset
hypogonadotropic hypogonadism may also be due to craniopharyngioma (Chapter 19.5) or hypothalamic tumors
such as germinoma (Chapter 19.2), astrocytoma (Chapter
19.4) or hamartoma (Chapter 19.3). Hypothalamic hypogonadism is found in 32% of adult patients who received
radiation therapy for brain tumors outside the hypothalamic-pituitary region (Arlt et al., 1997; Chapter 25.3).
Insulin-dependent diabetes has been associated with
reproductive impairment in both men and women. The
neuroendocrine lesion may be at the level of the hypothalamus (Baccetti et al., 2002).
Rather rare diseases in which an infiltrating process is
involved in hypogonadotropic hypogonadism include
neurosarcoidosis (Murialdo and Tamagno, 2002; Chapter
21.1), histiocytosis-X (also called Langerhans-cell histiocytosis or HandSchllerChristian disease; Chapter
21.3), and lymphocytic hypophysitis, an autoimmune
process that may cause amenorrhoea in combination with
polyuria (Chapters 22.1, 22.2). Exceedingly common are
infectious disorders of a viral or bacterial nature that lead
to hypogonadotropic hypogonadism. In addition, alcohol
may not only act directly on the testes but also affect the
LHRH neurons.
Moreover, head injuries, especially those sustained in
head-on automobile collisions, can cause hypothalamic
damage resulting in hypopituitarism and elevated prolactin levels. While mildly elevated prolactin levels can
cause interruptions in LHRH secretion in women, this is
unusual in men. Whiplash injury may cause transsection
of the pituitary stalk. A few cases with amenorrhea, sexual
immaturity and a history of head trauma have been
described. In a 17-year old girl, provocative testing of
the pituitary revealed intact pituitary function with
hypothalamic insufficiency. MRI demonstrated loss of

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the hypothalamic infundibulum. Traumatic damage to the


infundibulum or pituitary stalk is supposed to lead to
hypothalamic atrophy (Grossman and Sanfield, 1994). A
male patient with hypothalamic hypogonadism and
growth hormone deficiency associated with pituitary stalk
amputation was treated with intermittent administration
of LHRH. The treatment initially improved LH, FSH and
testosterone secretion. However, within 3 years of the start
of the treatment, LHRH failed to be effective any longer
(Mori et al., 1998).
Features that distinguish the failure of pituitary cells
from a lack of hypothalamic releasing hormones are: (i)
hyperprolactinemia, (ii) pituitary hormone deficiencies in
provocative testing, i.e. when exogenous pulsatile LHRH
invokes LH and FSH secretion, (iii) visual impairment,
(iv) diabetes insipidus, and (v) behavioral manifestations
(Yen, 1993; MacColl et al., 2002). In addition, (vi)
pulsatile LHRH administration may be used to assess the
functional integrity of pituitary gonadotropin (Begon et
al., 1993). For therapeutic considerations of hypothalamic
hypogonadism, see Hayes et al. (1998). In hypogonadotropic hypogonadal men, testosterone replacement
may improve both sexual function and mood (Wang
et al., 2000a).
Secondary amenorrhea or hypothalamic amenorrhea is
a form of hypogonadotropic hypogonadism that may
occur after severe dieting, heavy physical training or
intensely emotional events, and places women at a greatly
increased risk of stress fractures, osteopenia, osteoporosis
and other bone complications (Warren and Fried, 2001).
Strenuous physical exercise, particularly in runners,
strongly affects the hypothalamopituitarygonadal axis
function in women and only mildly in men. The increased
CRH drive in this condition may play a role in the pathogenetic mechanism of this type of amenorrhea, since
serum testosterone is also reduced by chronic glucocorticoid therapy. Anabolic steroid use by athletes may also
cause a hypogonadal state (MacAdams, 1986). Idiopathic
hypothalamic hypogonadism (Bchter et al., 1998) in
weight-stable nonathletic women may be due to subclinical eating disorders (Laughlin et al., 1998; Chapter
23.2). The condition may be effectively treated by LHRH
(Begon et al., 1993; Schopohl, 1993). The phrase functional hypothalamic amenorrhea refers to the presumed
nonorganic nature and the reversibility of this form of
secondary amenorrhea. The presence of identifiable
psychogenic factors in some cases and the reversal of
the amenorrhea following counseling is mentioned as
an argument for a suprahypothalamic site as a primary
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cause in psychogenic amenorrhea, but neither the


hypothalamus nor the suprahypothalamic structures
that would be involved have ever been studied in this
disorder. A slow frequency of LH pulses is typical in
these patients (Genazzani et al., 2001; Marshall et al.,
2001). Multihormonal abberations occur in this syndrome
and opiate systems are presumed to be involved, since
some patients have shown LH secretion improvements
following naloxon or naltrexone (Wildt et al., 1993; Yen,
1993).
A multitude of neuroendocrine changes are described
in secondary amenorrhea. Patients suffering from this
syndrome show an increased activation of the hypothalamopituitaryadrenal (HPA) axis as appears from higher
basal hormone levels and from an augmented adrenal
hormone response to CRH administration. Changes in the
adrenal androgen enzymatic pathway are presumed to be
present (Genazzani et al., 2001). The hypersecretion of
cortisol due to an increased CRH drive in these patients
may be reversed by naloxon. Both the increased CRH
drive and the increased nocturnal melatonin levels may
contribute to the inhibition of LHRH secretion (Nappi et
al., 1993; Yen, 1993; Luboshitzky and Lavie, 1999).
Animal experiments have shown that increased CRH may
either directly or indirectly inhibit LHRH release. Cortisol
secretion is higher in women with functional hypothalamic amenorrhea than in women with other causes of
anovulation or in eumenorrheic women. These observations thus underscore the concept that functional
hypothalamic amenorrhea develops in response to stressinduced alterations in the hypothalamus (Berga et al.,
1997). In addition, increased serum levels of melatonin
have been reported (Luboshitzky et al., 2001). Although
the 24-h serum prolactin levels in psychogenic amenorrhea are lower, the sleep-associated increments are
greater. Growth hormone is preferentially increased
during the nocturnal hours (Yen, 1993). A specific correlation exists between body-weight loss and the occurrence
of amenorrhea. Functional hypothalamic amenorrhoea
may be a consequence of low-calorie intake as observed
in anorexia nervosa (see Chapter 23.2) and intensive
physical exercise (Couzinet et al., 1999). Leptin levels in
women with functional hypothalamic amenorrhea are
significantly lower than in controls, even in those who
have a normal body weight and body-mass index (Andrico
et al., 2002). A critical leptin level, produced by fat cells,
is necessary to maintain menstruation, as shown in
anorectic patients (Kpp et al., 1997; Chapter 23.2). NPY
from the infundibular nucleus is presumed to play a

crucial role in this relationship. This peptide, which stimulates food intake, is inhibited by leptin (Chapter 23). In
rhesus monkey the LHRH pulse generator activity is
inversely related to the activity of the NPY gene, and
central administration of an NPY antagonist to juvenile
animals elicits precocious LHRH release. NPY thus seems
to restrain the onset of puberty. The gonadotropin
deficiency that is due to malnutrition is partial and
may be reversible after improvement of nutritional
intake and body composition (Couzinet et al., 1999).
Patients with weight-loss amenorrhea and no signs of
anorexia nervosa have an augmented growth hormonereleasing hormone (GHRH)-induced growth hormone
response. Some of them have reduced levels of insulinlike growth factor-I (IGF-I) (Genazzani et al., 1996).
Despite normal thyrotropin (TSH) levels, T3 and T4 are
significantly reduced (Yen, 1993), which may also
contribute to the amenorrhea. In functional hypothalamic
amenorrhea, a reduced thyroid-binding, globulin-binding
affinity explains the disparity between normal levels of
free T3, free T4 and binding proteins in the face of
reduced levels of total T3 and T4 (Domininguez et al.,
1997). Nocturnal melatonin secretion is three-fold
increased (Yen, 1993).
Women with functional hypothalamic amenorrhea, in
addition, show increased cognitive dysfunction and
psychiatric morbidity. They have greater difficulty coping
with daily stress and more often have a history of psychiatric disorders. Indeed, 31% meet the criteria for major
depression, and 19% for generalized anxiety disorder
(Giles and Berga, 1993). In those women who recovered
from functional hypothalamic amenorrhea, the body-mass
index increased or remained stable, while this index
decreased or remained stable in women who did not
recover in an 8-year follow-up. The body-mass index
plays a fundamental role in the resolution of this disorder
(Falsetti et al., 2002).
In men, adult-onset idiopathic hypogonadotropic hypogonadism is an extremely rare neuroendocrine disorder.
Normal puberty is followed by a postpubertal or adult
decrease in libido and fertility, pulsatile LH and low serum
testosterone. The function of the pituitarygonadal axis is
restored and the erectile and ejaculatory disorders respond
well to exogenous LHRH replacement. A cause for this
condition has so far not been found (Seminara et al., 1998;
Kobayashi et al., 2002).
Amenorrhea in anorexia nervosa and bulimia nervosa
is dealt with in Chapter 23.2. The critical blood level of
leptin that is necessary to trigger reproductive ability in

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women and to maintain menstruation (Kpp et al., 1997)


may not be maintained in these disorders. It is, moreover, interesting from an evolutionary point of view that
the desert-dwelling hunter-gatherers of the !Kung San
(Bushman) population of Botswana in the Kalahari
desert, South Africa, have a seasonal suppression of
ovulation in relation to the seasonal changes in nutrition,
body weight and activity (Yen, 1993). In mitochondrial
encephalopathies gonadal dysfunctions are found, i.e.
amenorrhea, impotence, and poor development of
secondary sexual characteristics. Several hypothalamopituitary dysfunctions are found in these patients (Chen and
Huang, 1995). Menstrual disorders are also observed in
patients with hereditary glucocorticoid resistance
(Lamberts, 2001).

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the rhesus monkey embryonic olfactory placode release


LHRH in a pulsatile manner at approximately 50-min
intervals. This indicates that the pulse generator for LHRH
is present within these neurons (Terasawa et al., 1999).
The marked increase in amplitude of LHRH-induced
LH pulses at puberty is accompanied by much more
modest changes in frequency (Seminara et al., 1998).
The response of the free -subunit of LH to LHRH administration distinguishes prepubertal individuals with a
functional hypothalamic hypogonadism from adult
males with a permanent hypogonadotropic hypogonadism
(Mainieri et al., 1998).
Delayed puberty occurs in 1% of the population and
may result from decreased LHRH release or gonadal
failure. The most common cause of a permanent absence
of pubertal development is Kallmanns syndrome, which
combines failure of LHRH activity and impairment of
the sense of smell (Chapters 24.2, 24.3). The cause of
Kallmanns syndrome is proposed to be a lack of production of adhesion molecules coded by the KAL gene
(KAL1), located at Xp22.3, which prevent the LHRH
neurons from migrating from the nasal placode to the
hypothalamus (Styne, 1997). Delayed puberty is also
found in Klinefelters syndrome (Chapter 24.4), Noonans
syndrome (Chapter 18.6) and in female carriers of NROB1
mutations (Ackermann et al., 1999; Seminara et al., 1999).
Precocious puberty is the appearance of any sign
of secondary sexual maturation, such as pubic hair,
before the age of 8 years (or menarche before the age of
9 years) in girls and 9 years in boys. The female-to-male
ratio is approximately 10:1 (Partsch and Sippell, 2001;
Table 24.1). Central precocious puberty is, by definition, physiologically normal but chronologically early,
resulting from hypothalamic LHRH secretion. True,
LHRH-dependent or central precocious puberty is
induced by the activation of the hypothalamic LHRH
pulse generator. Most girls (95%) and nearly 50% of boys
have idiopathic true precocious puberty, for which the
therapy of choice is the administration of LHRH agonists
that inhibit the pulsative release of gonadotropins (Styne,
1997). Before the advent of LHRH analogues, cyproterone acetate was widely used for the treatment of
idiopathic precocious puberty. Although this treatment
was usually well tolerated, liver toxicity has been recognized as a complication of long-term use (Garty et al.,
1999). Following discontinuation of LHRH therapy in
boys with precocious puberty due to hypothalamic hamartomas (see Chapter 19.3 and below), these boys reentered
puberty (Feuillan et al., 2000).

(b) Disorders of puberty


While the exact mechanism that triggers the onset of
augmentation of LHRH is still unclear, potential factors
involved include decreased melatonin production
(Chapter 4.5d), metabolizing enzymes responsible for
LHRH secretion, neurotransmitters such as noradrenaline,
NPY, which restrains the onset of puberty, aspartate,
GABA, glutamate, glial growth factors such as transforming growth factor-, and metabolic signs such as
leptin (Seminara et al., 1998; Ebling and Cronin, 2000).
A male patient with prelingual deafness due to a connexin26 gene mutation also had a partial hypogonadotropic
hypogonadism. This supports the possible role of
connexins, the constitutive proteins of gap junctions, in
puberty initiation. Connexins may play a part in the coordination and synchronization of LHRH release (Houang
et al., 2002).
The onset of puberty is associated with increases in
gonadotropin and sex steroid levels. The first sign of
puberty is a sleep-entrained activation of the reproductive axis (Hayes et al., 1998). Serum LH and FSH levels
increase with developing puberty and show day/night
rhythms with pulsatile secretions. Serum testosterone
levels in boys increase with developing puberty and show
a diurnal rhythm with an augmentation in the early
morning. However, there is already some diurnal rhythmicity of LH, FSH and testosterone much earlier on,
i.e. from 4 to 5 years of age; although serum LH, FSH
and testosterone in pubertal boys are higher than in prepubertal boys, and the preparation for the onset of puberty
in boys thus seems to begin at the age of 45 years
(Mitamura et al., 1999). LHRH neurons cultured from
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TABLE 24.1
Etiology of central precocious puberty (gonadotropin-dependent, true precocious puberty).
Category

Underlying disease

Permanent precocious puberty


Idiopathic true or central
precocious puberty

Sporadic
Familial (gain of function mutation of LH receptor)

CNS tumors, abnormalities or lesions

Dysmorphic syndromes
Chemical effects
CNS maturation with central precocious
puberty secondary to prolonged sex
steroid exposure
Transient precocious puberty

Variants of pubertal development


(partial or incomplete precocity)

Hypothalamic hamartoma (Chapter 19.3)


Tumors (Chapter 19): astrocytoma, craniopharyngioma, ependymoma, glioma often associated
with neurofibromatosis, Langerhans cell histiocytosis, LH-secreting adenoma, pinealoma
Congenital malformations: arachnoid cyst, suprasellar cyst, phakomatosis, hydrocephalus
( spina bifida), myelomeningocele, septo-optic dysplasia
Acquired disease: inflammatory CNS disease, abscess, radiation, chemotherapy, headtrauma,
empty sella, vascular lesion
WilliamsBeuren syndrome, McCuneAlbright syndrome, Klinefelter syndrome (Chapter 24.4)
Following diabetic ketoacidosis, hyperglycinemia
Congenital adrenal hyperplasia
Sex steroid-producing tumors
Male-limited precocious puberty (constitutively activated LH receptor)
Idiopathic sporadic
Arachnoid cyst (Chapter 19.10)
Hydrocephalus (Chapter 18.7)
Premature thelarche
Premature pubarche
Premature menarche

Adapted from Partsch and Sippell, 2001 and Grumbach, 2002.

A familial form of precocious puberty limited to males,


with gain-of-function mutations of the LH receptor,
has been reported (Grosso et al., 2000). A cranial MRI
is indicated in central precocious puberty since it may be
caused by CNS tumors of the suprasellar and pineal areas
(Chapters 17.3, 19.1, 19.4; Ng et al., 2003), possibly by
factors secreted by the tumors that advance the tempo
of LHRH maturation (Rivarola et al., 2001). Radiation
therapy (Chapter 25.3) may also cause true, central
precocious puberty. Optic and hypothalamic gliomas,
often associated with neurofibromatosis (Chapter 19.4)
and a patient with precocious puberty has been described
with a neurofibromatosis type 1 in the presence of a hypothalamic hamartoma (Biswas et al., 2000), Langerhans
cell histiocytosis (Municchi et al., 2002), astrocytomas
(Chapter 19.4) and, in rare cases, with craniopharyngiomas (Chapter 19.5) or suprasellar arachnoid cysts
(Chapter 19.10), may also be the cause of true precocious puberty. Hamartomas of the tuber cinereum contain
LHRH neurosecretory neurons and may be associated
with true precocious puberty, often before the age of
3 years (Chapter 19.3). In addition, precocious puberty

may occur secondary to encephalitis, brain abscess, static


cerebral encephalopathy, sarcoid granulomas, tuberculous
granulomas of the hypothalamus with and without
tuberculous meningitis, histiocytosis, head trauma,
cerebral atrophy, focal encephalomalacia (Styne et al.,
1997; Beswick et al., 2002), or following an acute
cerebral complication of diabetic ketoacidosis (TubianoRufi et al., 1992). The association between precocious
puberty and partial empty sella is exceptional, which
is not surprising, as it combines hypoplasia and hyperfunction of the pituitary (Zucchini et al., 1995).
Precocious puberty also occurs 5.5-fold more often
than expected in Klinefelters syndrome (Bertelloni
et al., 1999; Chapter 24.4). Also other chromosomal
abnormalities may lead to central precocious puberty
such as triple-X syndrome, three copies of the
PraderWilli syndrome region on chromosome 15q-1113, and a duplication of the long arm of chromosome 9
(Grosso et al., 2000). Moreover, children with hydrocephalus or arachnoid cysts may have true precocious
puberty (Styne, 1997; Starzyk et al., 2003). Precocious
puberty that later failed to progress was reported in

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idiopathic hypothalamic syndrome of childhood (Chapter


32.1). In an 11-month-old girl, precocious puberty was
observed together with nonketotic hyperglycinemia, probably due to an effect of glycine on N-methyl-D-aspartate
(NMDA) receptors. Repression of pubertal development
during anticonvulsant therapy with GABA agonists
suggests that the stimulatory effect of glycine can be overcome by GABA receptor-mediated inhibition. This idea
has been confirmed in animal experiments (Bourguignon
et al., 1997). Precocious puberty has also been described
in children raised in an environment with malnutrition
who were adopted after the age of 3 years (Styne, 1997).
Girls with a premature pubarche have lower birth weight
than normal girls. The girls who subsequently develop
functional ovarian hyperandrogenism have even lower
birth weights. The lowest birth weights are found in girls
with premature pubarche who also have pronounced
hyperinsulinism. This combination of symptoms thus
indicates an increased risk of a polyendocrine-metabolic
disorder (Ibez et al., 1999). In addition, patients with
McCuneAlbright syndrome, consisting of polyostotic
fibrous dysplasia, caf-au-lait pigment, autonomous
disorders (see Chapter 30), various forms of endocrine
hyperfunctions including a risk for developing acromegaly, may have precocious puberty. In girls there is
a 50% probability of peripheral precocious puberty at
4 years of age (De Sanctis et al., 1999) by estrogen
hypersecretion (Feuillan et al., 1995; Syed and Chalew,
1999). McCuneAlbright syndrome is based upon an activating missense mutation at cordon 201 of the GNAS
gene encoding the -subunit of the G protein (GS),
which stimulates the adenylcyclase, intracellular cyclic
AMP and, subsequently, precocious steroid production
and pituitary gigantism. In addition, elevated sex
hormones, hyperthyroidism, hyperprolactinemia and
hypercortisolism have been described in this disorder
(Tinschert et al., 1999). Ketoconazole has been used to
block gonadal steroidogenesis (Syed and Chalew, 1999).
Decreased melatonin levels were observed in precocious
puberty (Luboshitzky and Lavie, 1999), suggesting that
this inhibitory factor has stopped to suppress the gonadal
axis.
Menstrual bleeding during the neonatal period is
commonly related to the withdrawal of maternal estrogens
and not to precocious puberty. Vaginal bleeding has also
been reported in female infants with congenital adrenal
hyperplasia due to a treatment-induced activation of the
hypothalamic-pituitaryovarian axis. A decline of adrenal
androgens after glucocorticoid treatment results in an

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increase in gonadotropin levels, which then triggers the


occurrence of menses (Uli et al., 1997).
(c) The hypothalamopituitary gonadal axis in aging
and menopause
Age at menopause has a strong genetic component that
is influenced by estrogen receptor polymorphism (Weel
et al., 1999). One theory on the genesis of menopause is
that it is due to the ovarian exhaustion of follicles. Others
maintain that the hypothalamus is the pacemaker that
initiates the cascade of events leading to menopause. Hot
flushes already occur in normally cycling women during
the fourth decade, when there are still many follicles
present in the ovary. In addition, the finding of the change
of rhythmicity of many neurotransmitters with age has
led to the hypothesis that the deterioration of the biological clock, the suprachiasmatic nucleus (SCN), underlies
such desynchronization (Wise et al., 1996). Indeed, we
have found a loss of circadian and seasonal changes in
the SCN after the age of 50 years (Chapter 4.3a).
The first hormonal change that indicates the onset
of menopause is a rise in FSH, based upon increased
LHRH activity in the hypothalamic infundibular nucleus.
The increase in LHRH secretion occurs despite the 30%
decrease in LHRH pulse frequency with aging (Hall and
Gill, 2001). Typical symptoms of the acute climacteric
syndrome are vasomotor phenomena, e.g. hot flushes,
night sweats, and psychosomatic symptoms such as poor
concentration, memory impairment, loss of confidence and
insomnia (see Chapter 11f).
In aging men total and free testosterone gradually
decline as gonadotropins increase, while there is an
attenuation of the LH and testosterone secretory pulse
amplitude, and an associated disruption of their orderly
patterns of release. Detailed research showed that the
LH pulsing mechanism in healthy older men maintains
an increased mean frequency and lower amplitude of
bursting activity, a reduced uniformity of serial LH
pulse-mass values, and an impaired variability among
interpulse-interval lengths (Keenan and Veldhuis, 2001).
In the elderly, the circadian testosterone rhythm attenuates a pattern that is observed for many circadian rhythms
(Chapter 4.3). The decreased testosterone levels roughly
parallel the decline in sexual activity, libido and potency.
Aging and hormonal changes were more strongly related
to sexual activity and nocturnal erections than to
libido (enjoyment, drive and thoughts) (Davidson et al.,
1983; Veldhuis, 2000; Schill et al., 2001). Using total
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testosterone criteria, the incidence of hypogonadal testosterone levels increased to about 20% of men over 60,
30% over 70 and 50% over 80 years of age, and even
greater percentages when free testosterone index criteria
were employed (Harman et al., 2001). Testosterone
administration to elderly men improved spatial cognition
(Janowsky et al., 1994). Androgen supplementation for
3 months in older men with partial androgen deficiency,
using a transdermal dehydrotestosterone gel, demonstrated the expected androgenic effects but no change in
physical or cognitive functioning (Ly et al., 2001).
(d) Polycystic ovary syndrome
Polycystic ovary syndrome is a common disorder in which
multiple ovarian cysts are associated with menstrual
disorders, bilaterally enlarged ovaries, subfertility, hyperandrogenism such as hirsutism and acne, and often central
obesity and hyperinsulinemia. Gonadotropin concentrations are high, with a high ratio of LH to FSH, excessive
ovarian androgen production, chronic anovulation and
acyclic estrogen production in the prototype form of the
syndrome, the SteinLeventhal type of polycystic ovary
syndrome (Hall et al., 1998). LH pulses have a persistently accelerated frequency and higher amplitude of
pulses and favor LH synthesis, hyperandrogenism and
impaired follicle maturation (Marshall et al., 2001).
Heightened LHRH drive of gonadotropin secretion and a
steroid-permissive milieu appear to jointly promote LH
secretion. Positive feedback of estrogens is also implied
(Barontini et al., 2001). An insensitivity of the hypothalamic LHRH pulse generation to estradiol and
progesterone is present in polycystic ovarian syndrome
(Hall et al., 1998). Hypotheses explaining the disorder
include an abnormality on the level of the hypothalamus,
and it has been suggested that it may originate during
intrauterine development. Animal experiments have
shown that the pattern of gonadotropin release by the
hypothalamus is programmed by the concentration of
androgens during early development. Female rats exposed
to high androgen levels during development have
persisting changes in sexual physiology, including an
ovulatory sterility and polycystic ovaries (Cresswell et
al., 1997). However, observations in androgen-treated,
female-to-male transsexuals show that the histology of
the ovaries met the criteria for the diagnosis of polycystic
ovaries, which shows that elevated levels of androgens
in adulthood alone may also induce polycystic changes
(Pache et al., 1991). Women with polycystic ovary

syndrome have increased melatonin secretion, which is


associated with their increased testosterone levels
(Luboshitzky et al., 2001). In addition, multifaceted
dysregulation of the HPA axis is present in this syndrome
(Invitti et al., 1998). The abnormalities of the HPA axis
are presumed to be central in origin and abdominal obesity
may play a key role in the hyperactivity of the HPA axis
when tested with naloxone. There does not appear to be
any altered sensitivity of the HPA axis to opioids
(Ciampelli et al., 2000). Alternatively, polycystic ovary
syndrome may be primarily an ovarian disorder of
androgen secretion (Rosenfield, 1997).
Familial clustering of cases suggest that genetic factors
are present (Goudas and Dumesic, 1997). There is familial
aggregation of hyperandrogenemia, with or without
oligomenorrhea in polycystic ovary syndrome kindreds.
In affected sisters only half have oligomenorrhea and
hyperandrogenemia, characteristic of polycystic ovary
syndrome, whereas the other half have hyperandrogenemia per se (Legro et al., 1998). Several genes and
pathways have been implicated in this syndrome.
Evidence is present for a role for the insulin gene
minisatellite, for the genes encoding the insulin receptor
substrate protein-2, for an the association with insulin
variable number of tandem repeats, and for the gene
encoding for P450 cholesterol side-chain cleavage in
polycystic ovary syndrome and in the mechanism of
excessive androgen secretion in this syndrome (Franks et
al., 1997; Xita et al., 2002), and for an interstitial deletion of the long arm of chromosome 11 (Meyer et al.,
2000).
One study has proposed that there are two common
forms of polycystic ovary syndrome that probably have
different origins in intrauterine life. First, obese, hirsute
women with polycystic ovaries have an ovarian secretion
of androgens that is higher than normal. They also have
high LH levels and are associated with high birth weight
and maternal obesity. Secondly, thin women with polycystic ovaries have altered hypothalamic control of
LH release, which is found with prolonged gestation;
and they have high LH but normal androgen levels. The
hypothesis is that an altered hypothalamic-pituitary setpoint for LH release occurred in the second type as
a consequence of long gestation and the presence of a
placental failure associated with postmaturity leading to
an increased exposure of androgens (Cresswell et al.,
1997). This hypothesis should be further explored, and
the hypothalamic changes caused in development still
have to be shown. It has also been proposed that a low

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hypothalamic dopamine tone is involved in the inappropriate LH and prolactin secretion. In addition, changes in
prolactin bioactivity may play a role in the development
of hyperinsulinemia (Hernndez et al., 2000). A case has
been described of a woman with idiopathic intracranial
hypertension, polycystic ovary syndrome and visual loss
(Au Eong et al., 1997). A subset of women with polycystic ovarian syndrome may develop hirsutism and
virilization in pregnancy, especially in the context of
reproduction techniques such as in vitro fertilization (De
Bustros and Hatipoglu, 2001).
One of the widely used therapies for polycystic ovary
syndrome is an estrogen/progesterone combination.
However, also LHRH agonists and antiandrogens are used
(Toscano, 1998). Administration of progesterone can
slow down LHRH pulse secretion, favor FSH secretion
and induce follicular maturation (Marshall et al.,
2001). In obese women with polycystic-ovary syndrome
D-chiro-inositol, a fungal metabolite, induced ovulation
and decreased testosterone levels (Nestler et al., 1999).
Both clinical and animal experimental observations indicate that electroacupuncture may be an effective
treatment.
There is a close association between bulimia nervosa
(Chapter 23.2) and polycystic ovary syndrome, in that
some 75% of bulimic women seem to have this syndrome.
The connection between the two conditions may be
explained by altered peripheral sensitivity for insulin
(Morgan et al., 2002).

203

that human olfactory sensibilities are in decline. Some


70% of human olfactory receptor genes are pseudogenes (Keverne, 1999). Axons from the olfactory neurons
course through the cribiform plate of the etmoid bone,
and synapse in the olfactory bulb. From the olfactory
bulb, axons project predominantly to the periform cortex
in the medial aspects of the temporal lobes via the lateral
olfactory tract (Figs. 24.1, 24.2). These connections with
the temporal cortex may be crucial in the development
of olfactory deficits in Alzheimers disease (see below).
There are some very small leftright connections transporting olfactory information in the rostral part of the
anterior commissure (Sylvester, 1986). In addition, axons
project from the olfactory bulb to structures of the limbic
system, including the anterior olfactory nucleus, preperiform cortex, periamygdaloid complex and the
olfactory tubercle (Figs. 24.1, 24.2). Widespread
connections with many other areas, including the hypothalamus, spring from these brain regions. Electrical
responses have been recorded in the medial and lateral
hypothalamus in these brain areas after electrical and
odorant stimulation of the olfactory bulb (Martzke et al.,
1997). The olfactory bulb is innervated cholinergically
by the nucleus basalis of Meynert (Price, 1990).
In contrast to the main olfactory connections, the
vomeronasal organ (see below) projects to the accessory
olfactory bulbs, and from there directly to the hypothalamus (Tirindelli et al., 1998).
(b) Anosmia

24.2. Olfaction, anosmia, the vomeronasal organ


(Jacobsons organ) and the embryology of LHRH
neurons

Anosmia can result from a congenital defect, inflammation, head trauma or neoplasm. Congenital anosmia is
defined as a complete inability, present from birth, to
smell. It arises secondarily to abnormal embryological
development of the olfactory system. The disorders range
from holoprosencephaly (Chapter 18.3) via Kallmanns
syndrome (Chapter 24.3), to congenital anosmia, the
mildest manifestation of the arhinencephalic spectrum.
Aplasia or hypoplasia of the olfactory bulbs is revealed
by MRI in the case of isolated congenital anosmia.
Outgrowth of the fibers from the neurosensory cells of
the olfactory pits is necessary for the later induction
of the olfactory bulbs and tracts. In congenital anosmia
this outgrowth appears to be arrested prematurely for
unknown reasons between 7 and 16.5 weeks of gestation.
The migration deficiency may be a subtle abnormality of
the nasal placodes that normally allow their invagination
and, in case of a disorder, prevent the growth and contact

Give me a man with a good allowance of nose . . . I always


choose a man, if suitable otherwise, with a long nose.
Napoleon Bonaparte

(a) Olfaction
Odor perception is the result of stimulation of bipolar
neurons in the olfactory mucosa by volatile chemicals. A
family of approximately 1000 genes coding for odorant
receptors with seven transmembrane helices was discovered. Individual olfactory neurons express a single
receptor that recognizes a limited range of ligands. There
is a striking convergence of all the neurons expressing
one type of receptor to one or a few glomeruli (Tirindelli
et al., 1998). However, molecular genetic studies suggest
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Fig. 24.1. Olfactory structures within or in close relation to the anterior perforated space. Whereas the monkey (A) has a clearly identifiable olfactory tubercle (Tu), it is more difficult to identify a tubercle in the human (B, C, D). The region indicated by an asterisk in D is usually referred
to as the olfactory trigone. Note the continuation between the olfactory peduncle (o. ped.) and the olfactory tract (olf) in the monkey (A). The
olfactory tract continues in a caudolateral direction towards the limen insulae (white arrowhead) where it makes a sharp bend to enter the temporal
lobe. The olfactory tract is more difficult to appreciate in the human (D). The large arrow in B points to the anterior choroidal artery and the
small arrows to striate arteries. AO, anterior olfactory nucleus; Ant perf., anterior perforated space; db, diagonal band; GR, gyrus rectus; olfs,
olfactory sulcus; opt, optic tract; ox, optic chiasm; U, uncus. (From Sakamoto et al., 1999, Fig. 1 with permission.)

of the neurosensory cells with the telencephalon. Without


that contact the formation of the the olfactory bulbs and
tracts never occurs. Alternatively, a deficiency in the
molecules necessary for the growth and contact of the
olfactory nerves may be the cause of this disorder, as is

proposed for Kallmanns syndrome. It should be noted,


though, that congenital anosmia is not accompanied by
hypogonadism. This means that the LHRH neurons have
reached their normal destination; some connection
between the olfactory pits and the telencephalon should

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