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Neurologic Aspects of Uremia

Neurological complications in dialysis populations are


common but frequently misunderstood. Some of them relate
to the persistence of uremia, some relate to the dialysis
treatment while others are independent of both uremia and
dialysis.
PERSISTING UREMIC ENCEPHALOPATHY

• Uremic encephalopathy is rarely seen in regular dialysis


patients in presence of adequate effective dialytic treatment.

• Patients with chronic renal failure may or may not develop


symptoms of UE if they are constantly followed by physicians
so that adequate water and electrolyte balance is achieved,
blood pressure is controlled, the nutritional status is normal,
and iatrogenic intoxication is avoided.
• Even after adequate dialytic treatments, some patients may
continue to show some subtle nervous system abnormalities
such as a decrease in alertness and attention span, a reduced
ability to concentrate, an impaired mentation, a generalized
weakness, and signs of peripheral neuropathy.

• Tremors and asterixis are two typical motor abnormalities of a


mild, stable UE.
CNS Alterations in Uremia:
• CNS alterations in uremia may be due to malnutrition or
amino acid imbalance that can alter the levels of putative
neurotransmitters and possibly neuropeptides.

• UE is based on aminoacid derangements and on the


subsequent imbalance of neurotransmitters. This imbalance
stimulates depressing neurotransmitters that causes
disturbances in mental, neurological, motor, and hormonal
functions.
• A number of neurotoxic substances are retained in chronic
renal failure (CRF), among them blood urea nitrogen (BUN)
(>200 mg%), ammonia, cyanide, phenol-like compounds, and
middle molecules. All of these may contribute to UE.

• In uremic patients PTH can directly increase the calcium


content of the brain, which may play an indirect role in the
wasting syndrome and in the amino acid imbalance
contributing to altered prolactin secretion.
• Anemia of chronic renal failure may have a direct effect on
brain function. Abnormalities of cognitive function tests, as
well as electrophysiological measurements of brain function,
significantly improve with correction of the anemia with
recombinant erythropoietin.

• There are at least three possible explanations for the better


CNS function accompanying the rise in hematocrit level;
– Increased hematocrit will lead to enhanced brain oxygen
delivery with a beneficial effect on brain metabolism.

– When the hematocrit rises, cerebral blood flow falls, thus


correcting localized ‘‘brain uremia’’ because of the
decreased delivery to the brain of uremic toxins.

– The decrease in cerebral blood flow may decrease


intracranial pressure and diminish subtle cerebral edema.
• The early phase of UE could be attributed to AA
derangements that causes sensorial clouding, dyskinesias,
asthenia, humoral changes, and reduced sexual activity.

• The late phase of UE causes subcortical dementia, uremic


twitching, seizures, and significant endocrine abnormalities.

• Clinical features of UE can be divided into early and late


disturbances.
Evaluation of Uremic Encephalopathy:
• Many methods of evaluation can be used, such as
electroencephalogram (EEG), evoked potentials (EPs),
psychological testing, cerebrospinal fluid (CSF) analysis, brain
density on CT, and hormonal or amino acid studies.
Effect of Dialysis and Transplantation on UE:
• The functional derangements can be easily reversed when a
patient, even showing severe clinical neurological
manifestations, is transplanted, the whole UE syndrome clears
up within days in parallel with the improvement in renal
function.
• On the other hand, when a patient with severe uremic
complications starts dialysis, the major neurological signs
rapidly disappear within days or weeks, but mild signs of
encephalopathy may persist, or even appear later on, despite
dialysis.
DIALYSIS-ASSOCIATED ENCEPHALOPATHIES

• Dialytic treatment has been associated with the appearance


of some peculiar both acute and chronic disorders of the CNS.

• These disorders include dialysis disequilibrium, dialysis


dementia, subdural hematoma, typical electrolyte disorders,
hydrosoluble vitamin deficiency, acute intoxication with trace
elements, hypertensive encephalopathy, and the effects of
drugs.
Neurological Complications in Dialysis
Acute complications
• Epidural and subdural hematomas
• Subarachnoid bleeding
• Cerebral embolus and infarcts
• Transient ischemic attacks
• Altered body fluid osmolality
• Hypo-hypernatremia
• Intradialytic hypotension
• Epidural abscess – collection of pus
• Hypertensive encephalopathy
• Hypoglycemia
• Hypercalcemia
• Cranial nerve paralysis or convulsions of unknown origin
Chronic complications
• Dialysis encephalopathy
• Dialysis dementia
• Depletion syndrome
• Wernicke-like syndrome
• Autonomic system dysfunction
• Cranial nerve disorders
• Peripheral neuropathy
ACUTE NEUROLOGICAL COMPLICATIONS
ASSOCIATED WITH DIALYSIS
Dialysis Disequilibrium Syndrome
• DDS symptoms suggests an acute metabolic encephalopathy
may develop either during the hemodialysis session or as long
as 24 hours after dialysis has been completed. They range
from mild symptoms like distress, headache, tremors, muscle
cramps, anorexia, dizziness to more severe manifestations like
restlessness, blurring of vision, emesis, hypertension,
confusion, stupor, which may progress to convulsions and
coma.
• Such episodes are rarely fatal, tend to resolve themselves
within a few days and usually occur when dialysis therapy is
being initiated rather than during chronic treatment.
• Dialysis disequilibrium syndrome is more common in younger
patients.

• DDS; they usually are of relatively short duration, but in case


of major symptoms, recovery may take 2 to 3 days.

• DDS was originally attributed to a plasma-brain urea


imbalance, followed by an osmotic gradient, causing a shift of
water inducing cerebral edema and brain swelling.

• A gradual reduction of elevated blood urea, together with the


addition of osmotically active solutes like glucose, glycerol,
fructose, NaCl, mannitol in the dialysate was suggested as
prevention.
Whatever the cause of DDS, the following must be taken into
account:

1. Since the introduction of bicarbonate HD instead of acetate


HD, the frequency of DDS has been greatly reduced.

2. Any technique leading to pure ultrafiltration (without dialysis)


avoids the appearance of DDS.

3. DDS can be prevented by decreasing dialysis length and


reducing dialysis efficiency.

4. At the initiation of HD treatment, it is advisable to perform


‘‘soft sessions’’, i.e., sessions of brief duration, with a low
blood flow and a minimal weight loss.
5. In PD patients, DDS has been observed only in intermittent
peritoneal dialysis (IPD) patients treated with hyperosmolar
solutions which are at present in disuse.

6. A DDS-induced coma in a HD patient is normally reversed


several hours after the HD session, even though no
pharmacological intervention, except bedrest, has been
utilized.

• Dialysis disequilibrium is associated with cerebral edema.


Urea removal from the blood would occur more rapidly than
from the CSF and brain tissue, and a urea osmotic gradient
could be generated, causing a movement of water into brain
cells.
Differential Diagnosis of Dialysis
Disequilibrium Syndrome
• Acute cerebrovascular • Hypoglycemia
accident • Malignant hypertension
• Cardiac arrhythmia • Nickel intoxication
• Cerebral embolus secondary • Nonketotic hyperosmolar
to shunt clotting coma with hyperglycemia
• Copper intoxication • Subdural hematoma
• Depletion syndrome • Uremia
• Dialysis dementia • Wernicke’s encephalopathy
• Excessive ultrafiltration • Malfunction of fluid-
• Hyperparathyroidism with proportioning system
hypercalcemia (serum Ca >14)
• Hyponatremia (serum Na <125
mEq/L)
OTHER ACUTE NEUROLOGICAL
COMPLICATIONS
Hemorrhagic Complications:
• Hypertension and anticoagulant therapy are the two main
nontraumatic causes of intracranial hemorrhage.
• Subdural hematoma is one of the major cause of death in HD
patient.
• Subacute and chronic subdural hematoma may cause
pseudodementia, drowsiness, confusion, and mild
hemiparesis. The diagnosis can usually be made by CT scan or,
when available, by magnetic resonance imaging (MRI).
• Subarachnoidal bleeding can be considered as an important
cause of death in HD and is often related to excessive
anticoagulant therapy or to congenital defects of the
cerebrovascular bed.

• Any intracranial hemorrhage may first appear as convulsions


and subsequently evolve to coma.
• A CT scan may help in the diagnosis in showing hemorrhages
of 1.5 cm wide. Puncture of CSF should be avoided in the
presence of signs of intracranial hypertension.

• The therapeutic possibilities are few, but surgical drainage is


mandatory in the case of a large (>3 cm) cerebellar hematoma
with mild dysfunction of brain stem.

• The prognosis is poor when large hematomas are present.


Small hematomas may be associated with a better recovery of
brain function than ischemic brain infarcts because the brain
tissue is often displaced rather than destroyed.
• Cerebral embolus must be suspected when a sudden
neurological complication appears after a maneuver of shunt
declotting or of declotting of a central venous catheter. Such a
complication is very rare, considering the thousands of
catheters placed in HD patients.
• The heart is the main source of cerebral emboli, with atrial
fibrillation being the most common cause.
• Anticoagulants are effective in preventing such embolisms,
but anticoagulation must be delayed for several days if the
infarct is hemorrhagic.
Cerebral Infarcts:
• A thrombotic stroke may be the consequence of a progressive
process, lasting hours or days. The main event happens during
sleep or in the period shortly after awakening.

• Size and localization of infarcts will condition the clinical


neurological pattern. Cerebral infarcts may be shown by
magnetic resonance within hours and by CT scan within days.
Transient Ischemic Attacks:
• Transient ischemic attacks (TIA) are temporary focal cerebral
deficits mainly due to ischemia.
• They are transient or temporary because they last less than 24
hours, ranging from a few seconds to several hours.
• TIAs are often associated with stenosis of several arteries and
are predictors of both cerebral infarcts and extracerebral,
mainly myocardial infarcts.
• The main cause of TIA is the embolization of fibrin platelet
material related from atherosclerotic sites.
Transient Ischemic Attacks

Area of damage Symptoms


• Carotid territory • Controlateral weakness
• Controlateral paraesthesiae
• Ipsilateral visual
disturbances.
• Vertebrobasilar system
• Hemianopia
• Diplopia
• Dysarthria
• Weakness (one or both
sides)urbances
• Middle cerebral artery
• Stroke (Single attack)
Osmolality Changes:

• Altered body fluid osmolality can be caused by an improper


proportioning of dialysate with consequent hypo- or
hypernatremia. In both cases acute neurological
complications like seizures and coma can appear.
• In acute hypernatremia, the pattern is characterized by thirst,
spasticity, muscle rigidity followed by irritability, seizures, and
coma.
• In acute hyponatremia (serum Na <125 mEq/L), the clinical
pattern is characterized by weakness, fatigue, dulled
sensorium progressing to seizures, coma, and respiratory
arrest.
• In both cases death may occur if the problem is not properly
identified, the treatment is not stopped, and the dialysis
monitor is not changed.
Infections:
• Infections of vascular access, mycotic aneurysms, pulmonary
infections, toxoplasmosis, and systemic infections may all
involve the CNS causing the appearance of meningitis, acute
encephalopathy, and/or hemorrhage.

• Headache is associated with a fast decline of neurological


status in HD patients and should always be carefully
evaluated, especially when it appears at the end of dialysis.
HYPERTENSIVE ENCEPHALOPATHY

• Hypertensive encephalopathy is caused by a sharp rise in


blood pressure to very high levels.

• Nausea, vomiting, drowsiness, confusion, agitation,


convulsions, and sometimes neck stiffness may appear due to
hypertensive encephalopathy.

• A raised CSF pressure, a brain swelling of the white matter on


CT scan, irregular vascular changes, and permeability changes
of penetrating arterioles all rapidly appear after the onset of
the acute blood pressure elevation.
• The rapid increase in blood pressure is counterbalanced by a
sharp rise in cerebrovascular resistance, mainly at the
intracerebral small arteries situated at the level of the second
and third cortical cell layers.

• Malignant hypertension is a well-known cause of acute


encephalopathy in both normal subjects and HD patients.

• Malignant hypertension occurs frequently in the early days of


dialysis when there is abnormal sodium and water balance
during a dialytic session.
• This abnormal sodium and water balance is reduced by
improvements in:
1. Better interdialytic pressure control, due to the effective of
several antihypertensive drugs.
2. Better definition of the ‘‘ideal dry weight’’ in each patient
due to strict clinical evaluation and the use of bioimpedance
and weight formulas.
3. The tailoring of treatment to individual clinical needs.
4. Automatic strict ultrafiltration control.
• Malignant hypertension is in fact relatively more frequent in
patients with very high diastolic blood pressure values for a
long period before institution of dialysis.

• Clinical symptoms appear—headache, cramps,nausea,


vomiting, and muscular spasticity—as signs of central nervous
involvement.
BIOCHEMICAL CHANGES

Hypoglycemia:
• Hypoglycemia is a rare dialysis complication, because many
dialysate solutions contain glucose at a concentration equal to
the blood glucose level, and even in absence of glucose in
dialysate, neurological complications linked to moderate
hypoglycemia can usually be avoided if short sessions are
used and if a snack is given to patients during or after the
session.
Hypercalcemia:
• Hypercalcemia has been reported in HD patients receiving
dialysis with inappropriately high dialysis fluid calcium
concentrations and/or large doses of vitamin D and/or
calcium-based chelating agents.
• Whatever the cause, these patients show evidence of a severe
encephalopathy, ranging from impaired intellectual
functioning to delirium, stupor, and coma. The handling
includes hemo- or peritoneal dialysis with calcium-free
solutions.
Malnutrition
• Folate, water-soluble vitamins, and vitamin C are removed
during dialysis. Folate deficiency, leading to axonal
degeneration, demyelination, and neuronal death, and
thiamine (B1) and B12 deficiencies may all induce the classical
signs of metabolic encephalopathies.
• These deficiencies may be associated with high homocysteine
blood levels, which carry an elevated risk for atherosclerosis.
• In some patients plasma homocysteine levels may be normal:
due to supplementation of folic acid and water-soluble
vitamins.
• Low-dose megestrol (20 mg orally, twice daily) may increase
serum albumin levels of malnourished HD patients.
Role of Erythropoietin

• CNS encephalopathy induced by EPO is hypertensive


encephalopathy.

• Patients present with EPO induced Hypertension, headache


and seizures.

• This EPO induced hypertensive encephalopathy can be


managed by prompt antihypertensive and anticonvulsant
treatment and by discontinuation of EPO.
Aluminum Encephalopathy

• Anemia encephalopathy, and bone disease may occur when


treated with improperly processed dialysis water and
administration of aluminum compounds and are the major
causes of aluminum toxicity in uremic patients.

• DFO (Deferoxamine) therapy is useful for the diagnosis of


aluminum toxicity.
Neurocognitive Function in HD Patients

• Well-dialyzed HD patients do not show neuropsychological


deficit when compared with age- and education matched
medical controls.

• Neurocognitive abnormalities are observed in dialysis patients


due to low dialysis delivery.

• Deficits in language ability, poor inteligance and depression


were seen in these patients.
DIALYSIS DEMENTIA

• Dialysis dementia (DD) is related to UE and to some acute


neurological changes.

• Dialysis dementia is considered as a multisystemic disease


involving the brain (encephalopathy), bone osteomalacia,
muscle (proxima myopathy), and bone marrow.
• DD can be divided into three major forms:
1. A childhood form, in which DD is associated with congenital
or postpartum uremia and in which the young brain, exposed
to uremic toxins, may develop several neurological disorders.

2. An adult sporadic-endemic form, in which aluminum does


not play any role.

3. An adult epidemic type in which a relationship between


aluminum-contaminated dialysate and the syndrome has
been suggested.
• Symptoms of DD include; slurring and stuttering of the speech
(due to dysarthria), personality changes (mainly depression),
decreased memory and loss of attention, difficulty of
concentration, slowing of comprehension, and more severe
signs—myoclonus, seizures, dementia, apathy, and lethargy.

• Symptoms initially appear intermittently and worsen during


session.
Features of Dialysis Dementia

Groups
• Infants-childhood:
– Uremic toxins on immature brain
– Al-independent
• Adult sporadic-endemic:
– Worldwide distribution,
– Al-independent,
– No therapy
• Adult epidemic:
– Geography dependent,
– Al dependent (Al in dialysis water)
– Epidemic,
– Trace elements in water
Differential diagnosis

– In dialysis dementia, Al accumulates in brain structures (cortical gray


matter, glial cells, choroid epithelia) different from those (nucleus,
neurofibrillary tangles) found in Alzheimer’s disease.

Possible causes

– Al intoxication, in the adult epidemic form


– Trace elements intoxication
– Neurotransmitter imbalance
– Malnutrition
– Aging
– Normal pressure hydrocephalus
– Slow virus infection
– Cerebral blood flow alterations
• The best water treatment, the use of new phosphate binders,
and attention to the dialytic adequacy and the nutritional
status have reduced but not eliminated DD.

• DD is a syndrome frequently associated with some basic risk


factors, such as a biological aging greater than the natural
aging and evident malnutrition.

• DD can be seen as the final stage of a metabolic


encephalopathy caused by several factors and possibly by
different mechanisms.
• No satisfactory treatment exists. There is a 6- to 18-month
interval between diagnosis and death.

• Several approaches have been tested: increase in dialysis


frequency with soft dialysis, administration of parenteral
nutrition during the dialysis sessions, the use of keto-analogs
of branched-chain amino acids, bromocriptine, and
deferoxamine.

• The use of deferoxamine has not changed the natural history


of DD patients in the last 15 years. None of the other
approaches have been successful except kidney
transplantation. The latter may reverse both dialysis-
associated encephalopathy syndrome and DD.
WERNICKE SYNDROME

• This syndrome is characterized by ataxia and changes in ocular


motility: nystagmus, abducens palsy, or palsy of conjugate
gaze.
• patients show defective recent memory, confusion, and
confabulation.
• High doses of thiamine reduce the ataxia and the ocular
disturbances, while they show no effect on the mental
symptoms.
• Vomiting, restricted food intake, and neurotoxic drugs may
play a role.
AUTONOMIC SYSTEM DYSFUNCTION

• Autonomic dysfunction is common in predialysis patients.


• In patients with ASD the cold pressure test and the response
to sudden loud noise are usually normal the expiration :
inspiration ratio, the lying : standing ratio, the Valsalva ratio,
and the baroreceptor sensitivity slope were found to be
significantly abnormal in nondialyzed patients.
• The development of bradycardia and hypotension during
hemodialysis appears to be related to a sudden
parasympathetic vagal overactivity and could be attributed to
the Bezold-Jarisch reflex.
• Other signs of ASD are postural hypotension impaired
sweating, low heart rate response to standing, and a
significant reduction of day/ night blood pressure variations.
CRANIAL NERVE DISORDERS

• Cranial nerves can be affected in uremic subjects.

• Facial asymmetry, miosis, transient nystagmus, and


heterophoria are sometimes observed in CND.

• When the eighth cranial nerve is affected, both auditory and


vestibular divisions are involved. Varying degrees of
nystagmus, hearing loss, and sixth nerve palsy can be seen.
PERIPHERAL NEUROPATHY

• Polyneuropathy (PN) is one of the most frequent


complications of uremia, with an incidence ranging from 10 to
83%.

• Severity and progression of dialysis PN are extremely


different; the changes are usually slow, but in the case of
severe superimposed clinical illness, lower motor neurons
(LMN) or primary sensory neurons (PSN) can be affected.

• Muscle cramps and the restless legs syndrome are early


manifestations of LMN involvement: they usually disappear
when clinical signs of neuropathy appear.
• Only a minority of patients show clinical signs of neuropathy
in the upper limbs, although alterations of conduction velocity
are present in all limbs.

• The neurophysiological investigations of HD patients have


demonstrated a slowing of conduction in all the peripheral
nerves: motor and sensory nerve fibers are equally affected in
the four limbs.

• Adequate HD prevents deterioration of neuropathy and may


even show a slow improvement, even though Nerve
conduction velocity (NCV) shows only minor changes.
• In uremic neuropathy, the degeneration of nerve fibers is
characterized by a structural impairment of axons and myelin
sheathes.

• Besides morphological changes, functional lesions are also


present, being responsible for some functional disturbances
and probably caused by some removal of circulating toxins.

• The etiology of PN is unclear. Some major pathogenetic


mechanisms have been proposed: deficiency, uremic toxins,
and hormonal imbalance.
• As far as toxins are concerned, PN could be caused by some
toxins inducing the inhibition of several enzymes. Many toxins
that causes PN are middle molecules, methylguanidine,
myoinositol etc.

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