Uremic Encephalopathy

신장내과
R3 박정은
INTRODUCTION
 Uremia
 the final stage of progressive renal insufficiency
 the resultant multiorgan failure
 accumulating metabolites of proteins and amino acids and c
oncomitant failure of renal catabolic, metabolic, and endocri
nologic processes
 Uremic encephalopathy (UE) is one of many manifestations
of renal failure (RF).
Neurological complications in renal failure
 The incidence and severity of uremic encephalopath
y, atherosclerosis, neuropathy and myopathy have d
eclined but many patients fail to fully respond to dial
ytic therapy.

 Dialytic therapy or kidney transplantation induce neu

rological complications.
Clinical Neurology and Neurosurgery 107 (2004) 1–16
Clinical Neurology and Neurosurgery 107 (2004) 1–16
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, variou
s amino acids, polypeptides, polyamines, phenols and conj
ugates of phenol, phenolic and indolic acids, acetone, glucu
ronic acid, carnitine, myoinositol, sulphates, phosphates an
d middle molecules
Pathophysiology of uremic encephalopathy
 Guanidino compounds
 guanidinosuccinic acid, methylguanidine, guanidine and cre
atinine : highly increased in serum, CSF and brain
 Inhibited responses to GABA and glycine (inhibitory amino
acids)
 Guanidinosuccinic acid : inhibits transketolase, a thiamine-
dependent enzyme of the pentose phosphate pathway
 Inhibition of transketolase : demyelinative changes to both
central and peripheral nervous system
 Methylguanidine : seizures and uremic twitch-convulsive sy
ndrome
Pathophysiology of uremic encephalopathy
 Decrease in brain metabolic function
 Increased levels of creatine phosphate, adenosine triphosp
hat(ATP) and glucose
 Decreased levels of monophosphate(AMP), adenosine diph
osphate(ADP) and lactate

 Activation of the excitatory N-methyl-d-aspartate rec

eptors and concomitant inhibition of inhibitoryGABA
(A)ergic neurotransmission
Pathophysiology of uremic encephalopathy
 Hormonal disturbances
 parathyroid hormone, insulin, growth hormone, glucagon, t
hyrotropin, prolactin, luteinizing hormone and gastrin are el
evated
 PTH : promote the entry of calcium into neurons
 Calcium : essential mediator of neurotransmitter release an
d plays a major role in intracellular metabolic and enzymatic
processes
→ disrupt cerebral function by interfering with any of these p
rocesses.
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 co
ncentration, depression, delusions, lethargy, irritabili
ty, fatigue, insomnia, psychosis, stupor, catatonia, a
nd coma.
 Slurred speech, pruritus, muscle twitches, or restles
s legs.
 Findings include the following;
 Myoclonic jerks, twitches, or fasciculations (ie, uremic twitc
h-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 ventric
ular dilatation.
 Excluding ICH and SDH
 Increased signal intensity in the cortical and subcortical are
as of the parietal and occipital lobes.
→ resolved after dialysis
EEG
 Serial EEG : useful in assessing patients and in moni
toring their progress
 Generalized slow wave : more severe as the conditio
n 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 b
efore 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 le
vels : diffuse delta and theta activity, generalized spike-wav
e activity, and heightened sensitivity to photic stimulation.
Brain histologic findings in UE

 Meningeal fibrosis, glial changes, edema, vascular d

egeneration, focal and diffuse neuronal degeneratio
n, and focal demyelination.
 Small infarcts : due to hypertension or focal necrosi
s.
 Cerebellar acute granule cell necrosis
TREATMENT
 Correct the metabolic disturbance
 Dialysis (hemodialysis or peritoneal dialysis)
 Renal transplantation
 Symptoms improve as renal function improv
es
 Seizures may be treated with anticonvulsants
Uremic polyneuropathy
Clinical Neurology and Neurosurgery
107 (2004) 1–16
Uremic polyneuropathy
 Uremic polyneuropathy is the most common neurolo
gic 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 sensatio
n, pain) tend to precede the motor symptoms
Clinical manifestations
 Early finding
 Elevation of the vibratory threshold and impaired t
emperature sensibility
 Paradoxical heat sensation, paresthesias or pain
 Later finding
 Ascending hypesthesia to pinprick or touch, arefl
exia, restless legs, muscle weakness, cramps and
atrophy
Sensory syndromes
 The restless leg syndromes
 Persistent and extremely uncomfortable sensation in the
lower extremities
 Relieved by movement of the legs
 More prominent at night and interfere with sleep
 The burning foot syndrome
 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, incontin
ence, diarrhea, constipation, esophageal dysfunct
ion, hyperhydrosis and impotence
 Cardiovascular autonomic test
 Neuropathy of cranial nerves
 optic, trigeminal, facial and vestibulocochlear neu
ropathy
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 s
ensory action potential amplitude and decreased
nerve conduction velocity
Pathogenesis
 Axonal degeneration → secondary segmental demye
lination
 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 sympto
ms.
→ Earlier and more dialysis for the decline i
n the incidence of uremic neuropathy
Treatment
 Renal transplantation
 Recovery from neuropathy through remyelinisation

 Supplementation with biotin, pyridoxine, cobalamin a

nd thiamine
 stimulation of nerve metabolism and encouragement of rege
neration

 Symptomatic therapy
 tricyclic antidepressants and anticonvulsants