Neurologic complication of dialysis

Neurologic Complications of
Dialysis Patients
HuriahM. Putra, MD

The Beginning
• Neurological complications frequently affect
CKD patients
• Important causes of morbidity and mortality
• May affect both central and peripheral
nervous systems
Rizzo, M.A., Frediani, F., Granata, A., et al., 2012. Neurological Complications of Hemodialysis: State of Art.
Journal of Nephrology vol 25(2): 170-182

NEUROLOGICAL COMPLICATIONS
IN DIALYSIS PATIENTS
List them down…

Dialysis dementia
Disequilibrium syndrome
Wernicke’s encephalopathy (thiamine deficiency)
Central pontine myelinolysis
Uremic encephalopathy
Cerebrovascular disorders
Posterior leukoencephalopathy syndrome
Peripheral neuropathy
Headahe
Autonomic dysfunction
Myopathy
Chronic pruritus
Complications secondary to mineral and bone disorders
Sleep disorders
Restless legs syndrome

Uremic Encephalopathy
Pathogenesis
• Disrupted balance of excitatory and inhibitory
neurotransmitters
• Guanidino compounds antagonize GABA
receptors and antagonistic effects on N-
methyl-D-aspartate glutamate receptors
• Asymmetric dimethylarginine inhibits
endothelial nitric oxide synthase
Seifter, J.L., and Samuels, M.A., 2015. Neurologic Complications of Chronic Kidney Disease. In: Comprehensive Clinical
Nephrology5th ed. Philadelphia: 1000-1004

Pathogenesis
• Depletion of norepinephrine and suppresion
of central dopamine ▶ impairment of motor
activity
• Myoinositol, carnitine, indoxyl sulfate,
polyamine have been implicated in the
neuronal dysfunction of uremia
• Secondary hyperparathyroidism ▶ increased
brain calcium ▶ neuroexcitation

Pathogenesis
• Abnormal appetite regulation in uremia
• High rate of tryptophan increase synthesis of
serotonin (major appetite inhibitor)
• High level of cholecystokinin (powerful
anorectic) and low level of neuropeptide Y
(appetite stimulant)
• Cachexia result from anorexia, acidosis, and
inflammation

Clinical Manifestations
• Subtle, not correlating closely to level of
azotemia
• Complex mental changes or motor
disturbances
• Mental findings (emotional changes,
depression, disturbing and disabling cognitive
and memory deficits, delirium, psychosis,
seizures, coma)

Clinical Manifestations
• Stable uremie encephalopathy: fine action
tremor, asterixis, hyper-reflexia
• Asterixis: intermittent loss of muscle tone in
antigravity muscles
• Advanced uremic encephalopathy: reduced
level of conciousness, anorexia, asterixis,
myoclonus, disturbances of gait and speech

Diagnosis and Differential
• Diagnosis: Clinical findings and improvement
after adequate therapy
• CSF is often abnormal: modest pleocytosis (
<25 cells/mm3) and increased protein (<100
mg/dL)
• EEG: Generalized slowing with an excess of
delta and theta waves
• Brain imaging: cerebral atrophy and
enlargement of ventricles

Differential Diagnosis
Hypertensive encephalopathy
Systemic inflammatory response
syndrome
Observed in septic patients
Systemic vasculitis Vasculitis or lupus with cerebral
involvement
Drug induced neurotoxicity
Analgesics Meperidine, codeine, morphine,
gabapentin
Antibiotics High dose penicillins, acyclovir,
ethambutol, erythromycin,
aminoglycosides, nitrofurantoin,
isoniazid
Psychotropics Lithium, haloperidol, clonazepam,
diazepam, chlorpromazine
Immunosuppresasnts Cyclosporine, tacrolimus
Chemotherapeutics Cisplatinum, ifosfamide

Others High doses loop diuretics, ephedrine,
methyldopa, aluminium, metoclopramide
Cerebral atheroembolic disease Follows recent aortic or cardiac
angiography; associated with peripheral
manifestations, including lower extremity
cyanosis, livedo reticularis, and
eosinophilia
Subdural hematoma
Posterior leukoencephalopathy Observed particularly following renal
transplantation as result of reversible,
abnormal permeability of the blood-brain
barrier
Often manifests with headache followed
by mental depression, visual loss,
seizures in the context of volume
expansion, acute hypertension, and
often treatment with corticosteroids or
calcineurin inhibitors

Treatment
• Most of the manifestations of central nervous
system involvement are reversible with
dialysis within days or weeks
• But mild signs of UE may persist
• Increasing dialysis dose may improve clinical
findings
• Parathyroid hormone suppression with
vitamin D analogues

Polyneuropathy
• Peripheral neuropathy is the most common
neurological complication of chronic renal
failure
• Occurs in 60-100% of patients
• Characterized by axonal degeneration with
secondary demyelination
• Can affect motor, sensory, and cranial nerves

Polyneuropathy
• Typically distal, symmetric, predominantly
axonal, mixed sensitive and motor
neuropathy afecting the legs more than the
arms
• Probably results from removal of thiamine by
dialysis
• Clinical signs of peripheral nerve dysfunction
starts when GFR is < 12 ml/min

Polyneuropathy
• Most prevalent symptoms are distal
paresthesias associated with loss of vibration
sense in lower limbs and impairment of ankle
reflexes
• More severe form of neuropathy presents as
ascending sensory and motor dysfunction

Principal Differential Diagnosis of Uremic
Polyneuropathy
Diabetes mellitus
Ethanol abuse
Amyloidosis
Malnutrition
Polyarteritis
Lupus erythematosus
Multiple myeloma
Thiamine deficiency
Nicholis A.J., Benz, R.L., Pressman, M.R., Nervous System and Sleep Disorders. In: Handbook of Dialysis 4th ed.
Philadelphia: 701-714

Polyneuropathy
• Adequate removal of dialyzable neurotoxins
may increase nerve conduction velocities, but
hemodialysis itself rarely improves
neuropathy
• Supplementation with biotin, pyridoxine,
cobalamin, and thiamine may be an effective
treatment

Polyneuropathy
• Tricyclic antidepressant (amitriptyline 10-25
mg to 75-150 mg at bedtime)
• Antiepileptic (carbamazepine 200-400 mg to
1200 mg maximally; phenytoin 100-200 mg
initially to 600 mg maximally)

Restless Legs Syndrome
(Ekbom Syndrome)
• Frequent in CKD, particularly in women
• Result from decrease in dopaminergic
modulation of intracortical excitability with
reduced supraspinal inhibition and increased
spinal cord excitability
• Iron deficiency or iron transport into CNS
plays a central role

(Ekbom Syndrome)
• Characterized by unpleasant “creeping”
sensations in the extremities and compulsive
need to move the limbs
• Worsened by periods of rest or inactivity and
relieved by walking
• Ekbom syndrome: restless legs plus OCD
including pica (pagophagia, geophagia,
amylophagia)

(Ekbom Syndrome)
• Iron replacement should be initiated either
oral or IV
• Dopaminergic treatment is often helpful with
dopamine receptor agonists (pramipexole
and ropinirole)
• Levodopa with decarboxylase inhibitors may
be used as well as gabapentin, opioids, and
benzodiazepines

Dialysis Dementia
• Subacute, progressive, and fatal disease
• Occurred in patients chronically dialyzed for
periods exceeding 3 years
• Especially in centers with inappropriately
elevated aluminium levels in the water used
for dialysis (>20 μg of aluminium per liter)

Dialysis Dementia
• Typical manifestation: dysarthria, mutism, and
facial grimacing
• Most frequent manifestation: disturbances in
speech (90%), cognition (66%), movement
(75-93%) and personality changes
• First symptoms are usually intermittent and
characterized by stammering, hesitancy of
speech, and speech arrest

Dialysis Dementia
• Typical EEG findings: paroxysmal and
sometimes periodic sharp-wave or spike-and-
wave activity (up to 500 mV and lasting 1 to
20 s), intermixed with abundant theta and
delta activity
Rizzo, M.A., Frediani, F., Granata, A., et al., 2012. Neurological Complications of Hemodialysis: State of Art. Journal of Nephrology vol 25(2): 170-182
Ropper, A.H., and Samuels, M.A., 2009. The Acquired Metabolic Disorders of the Nervous System. In: Adams and Victor’s Principles of Neurology 9th
Edition. 1081-1105

Dialysis Dementia
• Spongiform changes in outer 3 cortical layers
with elevated aluminium levels in cerebral
cortex
• Neuronal loss, accumulation of lipofuscin
pigment and neurofibrillary degeneration in
the motor cortex and in the red, dentate, and
olivary nuclei

Dialysis Dementia
• Diazepam is effective in reducing myoclonus
and seizures and improving speech
• Increased dialysis time and renal
transplantation do not modify the course of
disease
• Removal of aluminium with desferoxamine
has been proven effective

Dialysis Dementia
• Aluminium in phosphate binders has been
found to induce osteomalacia and
encephalopathy
• Guidelines recommend avoiding use of
aluminium salts as phosphate binders to
prevent osteomalacia and encephalopathy

Disequilibrium Syndrome
• Central nervous system disturbance due to
cerebral edema
• Generated by excessively rapid clearing of
small-sized molecules, such as urea
• Non-specific increase in cerebral membrane
permeability in uremia permit greater entry of
uremic toxins into the brain

Conditions that may Mimic Dialysis
Intracranial bleeding
Subdural
Subarachnoid
Intracranial
Metabolic disorders
Hyperosmolar states
Hypercalcemia
Hypoglycemia
Hyponatremia
Cerebral infarction
Hypotension
Excessive ultrafiltration
Cardiac arrhythmia
Myocardial infarction
Anaphylaxis
Aluminium intoxication (subacute)

• Two main theories:
1. Reverse urea effect; shift of urea between brain
and intracellular space and plasma is not
immediate, causing higher concentration of urea
within the brain and leading to cerebral edema
2. Transient paradoxical metabolic acidosis within
the CNS, displacing sodium and potassium from
organic anions, making them osmotically active
and leading to cerebral edema

• Symptoms: mild headache, nausea, muscle
cramps, convulsions, delirium
• Typically appear 3-4 hours after starting
dialysis, but may manifest 8-24 hours later
• Self-limited, subsiding in hours, but delirium
may persist for several days

• Most common in patients with severe uremia
of long duration and with severe hypertension
• Risk factors: first hemodialysis treatments,
severe uremia, age, pre-existing neurological
disorders, and metabolic acidosis

• Treatment: reverses spontaneously after
period of regular HD
• Preventive measures during hemodialysis
(slow, gentle start of hemodialysis, increasing
dialysate sodium levels, administration of
osmotically active substances)

Wernicke’s Encephalopathy
• Induced by thiamine deficiency
• Clinical manifestations: Ophthalmoplegia,
ataxia, altered conciousness
• Hemodialysis patients are at risk of thiamine
deficiency because of low dietary intake and
accelerated loss during dialysis treatment

• Ocular signs of Wernicke:
1. Nystagmus that is both horizontal and vertical
and mainly evoked by gaze
2. Weakness or paralysis of lateral rectus muscles
3. Weakness or paralysis of conjugate gaze
• In advanced stages, there may be complete
loss of ocular movements and pupils (miotic
and nonreacting)
Ropper, A.H., and Samuels, M.A., 2009. Diseases of the Nervous System Caused by Nutritional Deficiency. In: Adams and
Victor’s Principles of Neurology 9th Edition. 1108-1128

• Ataxia is one of stance and gait
– In acute stage, it may be so severe that the
patient cannot stand or walk without support
– Lesser degrees: wide-based stance and a slow,
uncertain, shot-stepped gait
– Mildest: Tandem walking

• Disturbances of conciousness and mentation:
– Most common disturbance is global confusional state
– Apathetic, inattentive, indifferent to his surroundings
– Spontaneous speech is minimal, many questions left
unanswered
– Patient may suspend conversation and drift off to
sleep, but can be aroused without difficulty
• If left untreated, can progress to stupor, coma,
and death in a matter of a week

• The most dramatic improvement after administration
of thiamine is ocular manifestations
• Recovery begins within hours or sooner after
administration of thiamine (always within several
days)
• Horizontal nystagmus disappears in minutes
• Sixth nerve palsies, ptosis, vertical gaze palsies
recover completely within a week or two
• Vertical nystagmus may persist for several months

• Improvement of ataxia is delayed
• Approximately 40% of patients recover
completely from ataxia
• Remainder recover incompletely or not at all
and are left with a slow, shuffling, wide-based
gait and inability to walk tandem

Seizures
• Not uncommon in dialysis patients
• Generalized seizures are an integral feature
of advanced uremic encephalopathy
• Can also be a manifestation of severe
disequilibrium syndrome

Etiology of Seizures in Dialysis Patients
Uremic encephalopathy (unlikely in dialysis patients)
Disequilibrium syndrome
Aluminium encephalopathy
Hypertensive encephalopathy
Intracranial hemorrhage
Alcohol withdrawal
Toxins (star fruit ingestion)
Other (metabolic)
Hypocalcemia
Hyperosmolality due to peritoneal dialysis
Hypernatremia or hyponatremia
Anoxia
Arrhythmia
Anaphylaxis
Severe hypotension
Air embolism

Seizures
Predisposing Factors
• Predialysis hypocalcemia can result in
seizures during or soon after dialysis due to
the fall in serum ionized calcium level
associated with rapid correction of acidosis
• EPO use; associated with hypertension,
hypertensive encephalopathy, and seizures

Seizures
Management
• Stop dialysis
• Ensuring patency of the airway
• IV glucose should be administered if
hypoglycemia is suspected
• If persists, 5-10 mg diazepam infused slowly
IV; repeat every 5 minutes, max 30 mg

Pharmakokinetics of Anticonvulsants in Dialysis Patients
Plasma Half Life (hours)
Drug Renal
excretio
n (%)
Non
uremic
dosage
range
(mg/day)
Usual
dosage for
ESRD
patients
(% of non
uremic
dose)
Non
uremic
patients
ESRD
patients
Removed
by hemo-
dialysis
Carbamazepine 3 600-1600 100 10-20 Same No
Clonazepam <1 0.5-20 100 17-28 Same No
Diazepam <1 5-10 50 20-70 Same No
Ethosuximide >30 750-20 100 50-60 Same Yes
Phenobarbital 10-40 60-200 75 100 120-160 Yes
Phenytoin <5 300-600 100 10-30 Same
Primidone 40 500-2000 Caution 5-15 Same Yes
Valproic acid <4 750-2000 75-100 6-16 Same Yes
Vaigabatrin 50 2000-4000 25 7 14 Unknown

Seizures
Phenytoin
• Reduced plasma half-life
• Increased free fraction in uremia
– Unbound phenytoin fraction can increase from 10-
30%
– More marked drug effect
• Falsely high levels with immunoassay methods
in uremia
• Therapeutic recommendations
– Divided daily maintenance dosage because of
reduced plasma half life
– Target blood level should be 4-10 mg/L

CVD: Atherosclerosis
• Atherosclerosis in CKD patients is generally
more diffuse, affecting more distal sites
• Tissue and vascular calcifications secondary
to CKD-mineral and bone disorder increase
arterial stiffness

CVD: Hemorrhagic
• Uremia causes platelet dysfunction and
altered platelet-vessel wall interaction
• Intradialytic anticoagulation itself may also be
an important cause of hemorrhages

Posterior Leukoencephalopathy
Syndrome
• Typical neurological complication of uremia,
predominantly affecting cerebral white matter
• Manifestations: headache, nausea, vomiting,
visual disturbances, focal neurological
deficits, seizures
• Best visualized with MRI: diffuse
hyperintensity selectively involving the
parieto-occipital white matter

Posterior Leukoencephalopathy
Syndrome
• Pathogenesis is unclear
• Potential etiological factors: hypertension,
drugs, uremia, fluid/electrolyte disturbances
• Often associated with abrupt increase in
blood pressure
• Early diagnosis and aggressive treatment of
hypertension can reverse syndrome

Central Pontine Myelinolysis
• Induced by rapid correction of hyponatremia
causing extracellular fluid to be relatively
hypertonic
• Initial symptoms: progressive gait
disturbance, postural instability,
hallucinations, mild cognitive dysfunction
• Progress to paraparesis or quadriparesis,
dysphagia, dysarthria, diplopia, and loss of
conciousness

Mononeuropathy
• Includes carpal tunnel syndrome, ischemic
monomelic neuropathy, and anterior ischemic
optic neuropathy
• May occur because of an increased
susceptibility of nerves to injury or as a
vascular steal phenomenon after AV fistula
surgery

Mononeuropathy
• Symptomatic treatment: antiinflammatory
drugs, steroids, or anticonvulsant
• Surgery decompression is more effective and
long lasting
• Optimal dialysis can prevent dialysis-
associated amyloidosis

Mononeuropathy
• Rare cases of anterior ischemic optic
neuropathy have been reported
• Due to interference with the posterior ciliary
artery blood supply to the optic nerves, coupled
with predisposing factor such as hypertension,
hypotension, anemia, and atherosclerosis
• Dialysis, corticosteroid, correction of anemia,
and adequate blood pressure control may
restore vision loss

Hemodialysis Headache
• Incidence of 5%
• Usually appears during the third hour of
dialysis and lasts less than 4 hours
• Moderate intensity, bilateral, described either
throbbing or nonpulsating
• Mechanism: marked differences of
pretreatment and posttreatment urea level,
intradialytic hypotension, changes in
magnesium levels

Hemodialysis Headache
• Diagnosis requires at least 3 attacks of acute
headache fulfilling the following:
– Headache developing during at least half of
hemodialysis sessions
– Resolving within 72 hours after each
hemodialysis
– Ceasing altogether after successful
transplantation

Autonomic dysfunction
• Hypotension is common complication of
hemodialysis; may be secondary to
autonomic neuropathy
• Hemodialysis-induced hypovolemia can
trigger a vasodepressor reaction, a sudden
decrease in sympathetic activity, resulting in
bradycardia and vasodilation, and exacerbate
the volume-dependent fall in blood pressure

Uremic Myopathy
• Characterized by proximal limb weakness,
muscles wasting, limited exercise endurance,
and rapid fatigability
• Possible predisposing factors: accumulation
of uremic toxins, abnormalities in vitamin D
metabolism, insulin resistance, carnitine
deficiency, malnutrition, anemia and
abnormalities in mineral and bone
metabolism

Uremic Pruritus
• Affecting 33% of dialysis patients
• Pathogenesis involving uremic toxins, dry skin,
inadequate control of calcium-phosphorus
metabolism, and allergy
• Several effective strategies:
– Optimization of dialysis
– Use of more biocompatible membranes
– Treatment of mineral bone disorder
– Symptomatic therapy (skin emolients, UVB light,
gabapentin, k-opioid agonist nalfurafine)

Neurologic complication of dialysis

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Neurologic complication of dialysis

Similar to Neurologic complication of dialysis (20)

Recently uploaded

Recently uploaded (20)

Neurologic complication of dialysis

Editor's Notes