EDITORIAL

The psychoses of epilepsy

People who have epilepsy seemparticularly liable to certain
major psychiatric disorders: a chronic interictal psychosis
that closely resembles schizophrenia; and episodic psy-
chotic states, some of which may arise in close temporal
relation with seizure activity. These disorders are conven-
tionally referred to as the psychoses of epilepsy although
some of the episodic forms would be more accurately
described as acute confusional states. These conditions
have for long puzzled and intrigued psychiatrists and neu-
rologists, but in recent years this interest has quickened
especially among biologically minded psychiatrists in
search of a neurological model for schizophrenia. In the
psychoses of epilepsy and in schizophrenia converging lines
of enquiry, in neuroimaging and in neuropathology in par-
ticular, have implicated the mesial temporal structures, the
more so in the dominant hemisphere, and comparable
abnormalities have been reported.
1
This review will seek to
identify areas of progress, areas of diYculty, and persisting
dilemmas.
Epilepsy and schizophrenia
The precise nature of this relation has taxed clinical
observers since before the turn of the century. Over the
past four decades a consensus has begun to take
shapenamely, that certain forms of epilepsy may act as
risk factors for the subsequent development of a chronic
interictal psychosis, a syndrome sometimes referred to as
the schizophrenia-like psychoses of epilepsy (SLPE). This
psychosis does resemble schizophrenia in its phenomeno-
logical manifestations,
2 3
pursues a similar course, is as
responsive to antipsychotic medication, and is largely
uninuenced by concurrent seizure activity. Given these
similarities it is reasonable to question whether this
comorbidity could not have arisen as a result of a chance
association between two relatively common disorders. The
answer should lie in community based comparisons of
unbiased samples of epileptic and non-epileptic subjects
with respect to prevalence of psychosis. Attempts have
been made to do this, yielding a prevalence of schizophre-
nia within an epileptic population that varies between 3%
and 7% (prevalence in general population 1%). However, a
failure to use strictly dened and internationally recog-
nised diagnostic criteria for schizophrenia and to distin-
guish between SLPE and episodic psychoses may have
resulted in a spurious ination in the prevalence gures. In
the past year two studies that have to some extent redressed
this diYculty have been published. In Iceland a case
controlled study
4
found that although there was no excess
of psychiatric illness in epileptic subjects, among those who
were psychiatrically ill a disproportionate number were
psychotic. In Denmark Bredkjaer et al
5
used two national
inpatient registers for epilepsy and for psychosis respec-
tively to compare the subsequent incidence of schizophre-
nia in patients who had at some point undergone admission
to hospital for epilepsy with that in the general population.
A standardised incidence ratio of 1.48 for all epilepsy and
2.35 for psychomotor epilepsy argues strongly for epilepsy
as a risk factor for schizophrenia, but an epilepsy sample
dened by need for inpatient care may be considered
unrepresentative. Although vulnerable to similar criticism,
the neurology clinic based study of Mendes et al
6
report
convincing data. The prevalence of schizophrenia, diag-
nosed according to DSM3Rcriteria, was nine times greater
among clinic attenders with epilepsy than those with
migraine. Taken together these studies provide strong,
though far from conclusive evidence, that the SLPE is a
unique disorder and not an artefact of random association.
The denitive epidemiological study is still awaited. Mean-
while other approaches could be explored: if the SLPE is
indeed a secondary or symptomatic psychosis the preva-
lence of schizophrenia among family members should not
greatly exceed the prevalence in the general population. It
should certainly fall short of that found in the families of
schizophrenic probands. Early studiesfor example, that
of Slater and Glithero,
7
suggest that this is the case, but as
yet no family history study using state of the art
methodology has been published.
Even if it is conceded that epilepsy may be a risk factor
for the development of schizophrenia, it is clear that the
great majority of those with epilepsy do not become
psychotic. Are there epileptic characteristics that predict
such a development? It has long been held that temporal
lobe epilepsy, more so than idiopathic generalised epilepsy,
is a risk factor for psychosis, although this has been
contested
8
on the grounds that the nding is based on data
derived from specialist epilepsy clinics in which temporal
lobe epilepsy is overrepresented. However, recent data,
some of it epidemiologically derived, continue to support
this conclusion.
5 6
Flor-Henry
9
rst reported an association
between left sided temporal lobe epileptic foci and SLPE.
Subsequent published work has also noted, albeit incon-
sistently, a laterality eVect, but this must be balanced
against the nding that in large, relatively unselected sam-
ples, left sided foci predominate in a ratio of 60:40.
10
The
neuropathology of the epileptogenic lesion may be
relevant, but is unlikely to be of major eVect: in one large
neurological series
11
four out of the nine patients with gan-
gliogliomas developed a psychosis, but this group still only
accounted for 15% of the psychotic series. Andermann et
al
12
reported a further six cases, but these seem to have
J Neurol Neurosurg Psychiatry 2000;69:14 1
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represented but a small proportion of the denominator. An
unexplained feature common to both studies is that in
every case psychosis developed for the rst time postopera-
tively. It is likely that the intrinsic neuropathological char-
acteristics of the lesion are of less importance than the stage
of cerebral maturation during which it develops. Those
lesions that arise during foetal development or during the
perinatal period are associated with a greater risk of
psychosis.
13
Most of the risk variance for SLPE still remains
unexplained, but it must be remembered that even if it is
accepted that epilepsy may increase the likelihood of
schizophrenia, any sample of patients with SLPE will
include a proportion, unfortunately unidentiable, the
presence of which is due to chance association; this group
will act as a confounding factor in any search for aetiology.
The episodic psychoses
The most common by far are the postictal psychoses. Oth-
ers include some drug induced psychoses and the alternat-
ing psychoses that arise during periods of improved seizure
control. The salient features of postictal psychoses have
been consistently reported (for example, see Logsdail and
Toone
14
). They usually follow exacerbations, especially
clusters, of complex partial seizures, sometimes without
but more commonly with generalisation. Characteristi-
cally, cessation of seizure activity is followed by a brief
interludea lucid intervalof 12-72 hours before the
mental state deteriorates. The psychosis, which comprises
aVective, schizophrenic, and confusional elements, may
last for up to a week. The EEG may exhibit increased epi-
leptic discharge activity or a slowed dominant rhythm. The
episodes resolve spontaneously, but often recur, usually
displaying similar phenomenology.
The same question that was asked of the SLPE may also
be asked of the postictal psychoses: what factors predispose
the minority of epileptic patients to develop postictal psy-
choses? Although a far from uncommon disorder, postictal
psychoses have received considerably less attention than
SLPE and many of the accounts that have been published
describe an iatrogenic psychosis that occurs for the rst
time after an increase in seizure activity due to anticonvul-
sant withdrawal during presurgical evaluation. Although
such studies may be informative, particularly as they are
prospective and accompanied by telemetric information,
the cases they describe are likely to be unrepresentative of
the spontaneously occurring postictal psychoses. Some
centres report an association between complex partial sei-
zures and postictal psychoses
14 15
; others fail to do so.
16
Postictal psychotic subjects report more seizure clustering
17
and ictal fear (complex partial seizures containing fear as a
major component).
18 19
Bilateral EEG discharges are seen
more often in subjects with postictal psychoses than
non-psychotic controls.
1618
Compared with SLPE, both
age of epilepsy onset
17
and psychosis onset
19
are delayed.
Other forms of episodic psychosis are distinctly uncom-
mon. The phenomenon of forced normalisation, whereby
improved seizure control, usually as a result of change of
anticonvulsant medication, is associated with a normalisa-
tion of the EEG and the emergence of psychotic features,
may underlie some episodes of psychotic behaviour,
particularly those associated with the introduction of novel
antiepileptic drugs. As rst described by Landolt, forced
normalisation occurred in the context of partial epilepsy,
but more recent accounts implicate the succinimide group
in the treatment of primary generalised epilepsy.
20
The use
of vigabatrin
21
and zonisamide
22
may also carry an
increased risk of psychotic disturbance.
Psychosis and temporal lobectomy
In the early days of temporal lobe surgery for treatment of
epilepsy the psychiatrically unwell made up a signicant
proportion, sometimes most of those who went forward for
surgery. One in six was psychotic. There was then a hope,
even an expectation, that surgery might benet psychosis
as it had epilepsy. This was not borne out and the
proportion of epileptic patients with psychosis has
gradually fallen. But as one author has pointed out, it might
still be considered better to be psychotic without seizures
than to be psychotic with them.
23
Chronic schizophrenia
need not be a contraindication and carefully selected
patients may benet from surgery.
24
A history of postictal
psychoses should be considered a positive indication for
surgery. Psychosis may present for the rst timede novo
psychosisafter surgery. The condition was noted in
early surgical series, but has recently received greater
attention. It is diYcult to know whether this represents a
true increase in incidence, better recognition, or a fall in the
age of surgery. The de novo psychoses are a mixed bag:
some are depressive in character, some schizophrenic;
some pursue a chronic course, some are episodic, the de
novo postictal psychoses forming a denite subgroup.
25
Their aetiology may be similarly diverse. In some the
development of psychosis may be predetermined by earlier
events and the surgical procedure an irrelevant artefact. In
a few cases seizure control may lead to forced normalisa-
tion and an alternating psychosis. Only one feature stands
out clearly: preoperatively the presence of SLPE is associ-
ated with a left temporal focus; 85% of de novo psychoses
follow right temporal surgery. The reasons for this are
unclear. There is some indication,
26
hardly yet substanti-
ated, that depression is commoner after right sided lobec-
tomy. The amount of resected tissue is also more generous.
Aetiology of the epileptic psychosis
Epilepsy and psychosis may each arise out of some form of
cerebral dysfunction common to both; or psychosis may be
a consequence of seizure activity. The rst seems more
likely. Most forms of epileptic psychoses occur more
commonly in the partial epilepsies, especially complex par-
tial seizures. Within the surgical series patients with
developmental lesions may be at particular risk. Parallels
have been drawn between anomalies of cerebral architec-
ture in schizophrenia and the epileptogenic cortical
dysplasias
27
but in clinical practice such associations have
yet to be reported. Distinctive patterns of hypometabolism/
hypoperfusion have been reported
28 29
but with no consist-
ency. Dominant hemispheric temporal lobe involvement
may be associated with a more pure form of SLPE.
30
The
role of seizure activity nds its theoretical justication in the
kindling hypothesis but in humans even the kindling of epi-
leptic seizures remains debatable. There is no precedent for
the kindling of behavioural change. Liability to SLPE is not
related to seizure frequency or severity; indeed it often
occurs at a time when seizure frequency is declining. How-
ever, the extent of mesial temporal and, particularly,
extratemporal damage may be a risk factor. Recent
neuroimaging data suggest that mesial temporal lesions may
be associated with loss of tissue volume and with neuronal
damage in areas well beyond the temporal lobes including
the striatum, thalamus, and frontoparietal grey matter.
31 32
Reductions in hippocampal volume, tissue damage, and
neuronal loss may be progressive and may reect the dura-
tion of epilepsy.
33 34
Function may also deteriorate with
chronicity.
35
Extratemporal neuronal damage may also
occur
36
although it may be reversible. Bruton et al
37
reported
ventricular enlargement, periventricular gliosis, and white
matter abnormalities in epileptic patients with psychosis
compared with those without. Subjects with SLPE have
2 Toone
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smaller whole brain and bilateral hippocampal volumes
compared with matched non-psychotic epileptic controls
(Mellers et al, personal communication). The association
between degree of damage and chronicity may explain the
time interval between onset of seizures and onset of
psychosis in both SLPE and postictal psychoses. In conclu-
sion, an accumulation of admittedly less than perfect
evidence strongly suggests an environmental rather than a
genetically determined form of psychosis. The aetiology,
like that of schizophrenia itself, will in all probability prove
to be multifactorial with no one factor predominating.
B K TOONE
Kings College Hospital, Department of Psychological Medicine,
Kings College Hospital, Denmark Hill, London SE5 9RS, UK
Correspondence to: Dr B K Toone, Kings College Hospital, Department of
Psychological Medicine, Kings College Hospital, Denmark Hill, London
SE5 9RS, UK
brian.toone&kcl.ac.uk
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EDITORIAL COMMENTARY
Isolated Horners syndrome and syringomyelia
How far do you investigate the isolated Horners
syndrome? The sympathetic pathway to the pupil is long
originating in the hypothalamus from where the central
neuron descends to the intermediolateral column of the
upper three dorsal spinal segments. The preganglionic
neuron then ascends to the superior cervical ganglion and
the postganglionic neuron travels from there via the inter-
nal carotid artery to the eye. There is little evidence of dec-
ussation and thus Horners syndrome has long been known
as a good lateralising but a poor localising sign.
Individual case reports relate isolated Horners syn-
drome to various diseases including malignancy at the lung
apex, dissection, arteritis or trauma of the internal carotid
artery, jugular venous ectasia, and migraine or cluster
headache.
1
The paper by Kerrison et al (this issue, pp
131132)
2
adds syringomyelia to this list of possible causes
of isolated Horners syndrome and recommends that any
such patient in which the lesion is thought to be of the cen-
tral or preganglionic neuron should be investigated by MRI
of the brain and cervical cord.
The available literature does not make it easy to develop
a rational approach to the investigation of isolated Horners
syndrome. The incidence of central Horners syndrome
varies from 2.5% in ophthalmological reviews to 63% in
the neurological literature. Preganglionic Horners syn-
drome represented 21% of a neurological series and 67%
Isolated Horners syndrome and syringomyelia 3
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of an ophthalmological series.
3
Most series agree that
vascular disease is the usual cause of central Horners syn-
drome and that trauma or tumour explains most pregangli-
onic lesions. Postganglionic lesions occur in between 0.5%
and 57% of patients reported and arise from various
pathologies including vascular disease and tumour.
4
The localisation of the lesion by clinical and pharmaco-
logical means is important and inuences the need to
investigate. To neurologists clinical localisation is a familiar
task, pharmacological localisation less so. In practice most
cases of Horners syndrome are not truly isolated and the
association of neighbourhood symptoms or physical signs
and the extent of any sweating impairment will enable the
lesion to be placed with some precision. When this is not
possible the use of cocaine and pholedrine eye drops
5
can
be helpful in determining the direction of investigation, the
depth and pace of which is aimed at the rapid diagnosis of
conditions in which intervention may alter the natural his-
tory. Thus diagnosing an apical bronchial carcinoma or
dissection of the carotid artery is of potentially greater
immediate importance than the diagnosis of syringomyelia.
Clinical assessment, pharmacological localisation, and
imaging enable the full assessment of cases of isolated
Horners syndrome. How far and how fast we should
undertake this process will be inuenced by the clinical
presentation and the local availability of investigative facili-
ties.
C J K ELLIS
Department of Neurology, Poole General Hopsital, Longeet Road, Poole
BH15 2JB, Dorset, UK
cellis@poole-tr.swest.nhs.uk
1 Keane JR. Oculosympathetic paresis. Analysis of 100 hospitalised patients.
Arch Neurol 1979;36:1316.
2 Kerrison JB, Biousse V, Newman NJ. Isolated Horners syndrome and
syringomyelia. J Neurol Neurosurg Psychiatry 2000;69:1312.
3 Grimson BS, Thompson HS. Horners syndrome: overall view of 120 cases.
In: Thompson HS, DaroV R, Frisen L, et al, eds. Topics in neuro-
ophthalmology. Baltimore: Williams and Wilkins 1979:1516.
4 Loewenfeld IE. Impairment of sympathetic pathways. In: The pupil, anatomy,
physiology, and clinical applications. Detroit: Iowa State University Press,
1993:113187.
5 Bates AT, Chamberlain S, Champion M, et al. Pholedrine: a substitute for
hydroxyamphetamine as a diagnostic eye drop test in Horners syndrome. J
Neurol Neurosurg Psychiatry 1995;58:21517.
4 Ellis
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doi: 10.1136/jnnp.69.1.1
2000 69: 1-3 J Neurol Neurosurg Psychiatry

B K TOONE

The psychoses of epilepsy

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