Uremic Encephalopathy

R3

INTRODUCTION

Uremia

the final stage of progressive renal insufficiency

the resultant multiorgan failure
accumulating metabolites of proteins and amino acids and
concomitant failure of renal catabolic, metabolic, and
endocrinologic processes
Uremic encephalopathy (UE) is one of many manifestations
of renal failure (RF).

Neurological complications in renal failure

The incidence and severity of uremic

encephalopathy, atherosclerosis, neuropathy and
myopathy have declined but many patients fail to
fully respond to dialytic therapy.

Dialytic therapy or kidney transplantation induce

neurological complications.

Clinical Neurology and Neurosurgery 107 (2004) 116

Clinical Neurology and Neurosurgery 107 (2004) 116

Pathophysiology of uremic encephalopathy

Complex and poorly understood

Accumulation of metabolites
Disturbance of the intermediary metabolism
Imbalance in excitatory and inhibitory neurotransmitters
Hormonal disturbance

Pathophysiology of uremic encephalopathy

Accumulation of numerous organic substances

Uremic neurotoxins
urea, guanidino compounds, uric acid, hippuric acid,
various amino acids, polypeptides, polyamines, phenols
and conjugates of phenol, phenolic and indolic acids,
acetone, glucuronic acid, carnitine, myoinositol, sulphates,
phosphates and middle molecules

Pathophysiology of uremic encephalopathy

Guanidino compounds

guanidinosuccinic acid, methylguanidine, guanidine and

creatinine : highly increased in serum, CSF and brain
Inhibited responses to GABA and glycine (inhibitory amino
acids)
Guanidinosuccinic acid : inhibits transketolase, a thiaminedependent enzyme of the pentose phosphate pathway
Inhibition of transketolase : demyelinative changes to both
central and peripheral nervous system
Methylguanidine : seizures and uremic twitch-convulsive
syndrome

Pathophysiology of uremic encephalopathy

Decrease in brain metabolic function

Increased levels of creatine phosphate, adenosine

triphosphat(ATP) and glucose
Decreased levels of monophosphate(AMP), adenosine
diphosphate(ADP) and lactate

Activation of the excitatory N-methyl-d-aspartate

receptors and concomitant inhibition of
inhibitoryGABA(A)ergic neurotransmission

Pathophysiology of uremic encephalopathy

Hormonal disturbances
parathyroid hormone, insulin, growth hormone, glucagon,
thyrotropin, prolactin, luteinizing hormone and gastrin are
elevated
PTH : promote the entry of calcium into neurons
Calcium : essential mediator of neurotransmitter release
and plays a major role in intracellular metabolic and
enzymatic processes
disrupt cerebral function by interfering with any of these
processes.

Incidence

The prevalence of UE is difficult to determine.

Depends on the number of ESRD patients

In the 1990s : > 165,000 people

In the 1980s :158,000
In the 1970s : 40,000

As the number of patients with ESRD increased,

presumably so did the number of cases of UE.

Sex: Incidences are equal in men and woman.

Age: People of all ages can be affected

Symptoms and signs

Symptoms begin insidiously.

Progress slowly or rapidly.
Changes in sensorium : loss of memory, impaired
concentration, depression, delusions, lethargy,
irritability, fatigue, insomnia, psychosis, stupor,
catatonia, and coma.
Slurred speech, pruritus, muscle twitches, or
restless legs.

Findings include the following;

Myoclonic jerks, twitches, or fasciculations (ie, uremic

twitch-convulsive syndrome postulated by Adams et al in
1997)
Dysarthria
Agitation
Tetany
Seizures, usually generalized tonic-clonic
Confusion, stupor, and coma

Imaging studies

Brain imaging : limited value.

CT and MRI :cerebral atrophy and secondary
ventricular dilatation.
Excluding ICH and SDH
Increased signal intensity in the cortical and subcortical
areas of the parietal and occipital lobes.
resolved after dialysis

EEG

Serial EEG : useful in assessing patients and in

monitoring their progress
Generalized slow wave : more severe as the
condition worsens
In acute uremia,

irregular low voltage with slowing of the posterior dominant

alpha rhythm and occasional theta bursts.
prolonged bursts of bilateral, synchronous slow and sharp
waves or spike waves
Bilateral spike discharge : myoclonic jerks
After dialysis begins, EEG may worsen for up to 6 months
before slowly normalizing as renal function improves

EEG

In chronic uremia,

the EEG stabilizes during long-term dialysis treatment.

Deterioration corresponding to fluctuations in blood urea
levels : diffuse delta and theta activity, generalized spikewave activity, and heightened sensitivity to photic
stimulation.

Brain histologic findings in UE

Meningeal fibrosis, glial changes, edema, vascular

degeneration, focal and diffuse neuronal
degeneration, and focal demyelination.
Small infarcts : due to hypertension or focal
necrosis.
Cerebellar acute granule cell necrosis

TREATMENT
Correct the metabolic disturbance
Dialysis (hemodialysis or peritoneal dialysis)
Renal transplantation
Symptoms improve as renal function
improves

Seizures may be treated with anticonvulsants

Uremic polyneuropathy

Clinical Neurology and Neurosurgery

107 (2004) 116

Uremic polyneuropathy

Uremic polyneuropathy is the most common

neurologic complication of RF : 60%
Affect motor, sensory, autonomic and cranial nerves
Male predominance
GFR

< 12 ml/min : nerve conduction studies become abnormal

< 6 ml/min : Clinical signs of peripheral nerve dysfunction

Clinical manifestations

The neuropathy usually evolves over several months

Distal, symmetrical, mixed sensorimotor neuropathy
Injury is directly related to axon length
Longer axons : first ( more prominent in the lower
extremities)
Sensory symptoms (paresthesias, burning
sensation, pain) tend to precede the motor
symptoms

Clinical manifestations

Early finding

Elevation of the vibratory threshold and impaired

temperature sensibility
Paradoxical heat sensation, paresthesias or pain

Later finding

Ascending hypesthesia to pinprick or touch,

areflexia, restless legs, muscle weakness, cramps
and atrophy

Sensory syndromes

The restless leg syndromes

The burning foot syndrome

Persistent and extremely uncomfortable sensation in the

lower extremities
Relieved by movement of the legs
More prominent at night and interfere with sleep
Severe pain and a burning sensation in the distal lower
extremities
Early days of dialysis : acquired thiamine deficiency

Paradoxical heat sensation

Application of low temperature sensation of high

temperature

Motor symptoms
Motor involvement : more advanced disease
Loss of motor function

Muscle atrophy, myoclonus, paralysis

Autonomic neuropathy

Intradialytic and orthostatic hypotension,

incontinence, diarrhea, constipation, esophageal
dysfunction, hyperhydrosis and impotence
Cardiovascular autonomic test

Neuropathy of cranial nerves

optic, trigeminal, facial and vestibulocochlear

neuropathy

Diagnosis

Electrophysiologic studies

Most sensitive study

Impaired nerve function : 80% of patents
F-wave parameters from the lower limbs, vibration
detection thresholds on the foot, the sural nerve
sensory action potential amplitude and decreased
nerve conduction velocity

Pathogenesis

Axonal degeneration secondary segmental

demyelination

Most severe distal

Demelination of the posterior columns and other CNS

Metabolic and chemical cause

Thiamine deficiency
Decreased transketolase activity
Reduced of biotin and zinc
Accumulation of uremic toxins

Treatment

Dialysis

Stabilize or improve symptoms

Parathesia : rapidly improve once hemodialysis
Other symptoms mostly persist.
Complete resolution may occur only mild
symptoms.

Earlier and more dialysis for the decline

in the incidence of uremic neuropathy

Treatment

Renal transplantation

Supplementation with biotin, pyridoxine, cobalamin

and thiamine

Recovery from neuropathy through remyelinisation

stimulation of nerve metabolism and encouragement of

regeneration

Symptomatic therapy

tricyclic antidepressants and anticonvulsants