Uremic Encephalopathy

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INTRODUCTION Uremia the final stage of progressive renal insufficiency the resultant multiorgan failureaccumulating metabolites of proteins and amino acids and concomitant failure of renal catabolic, metabolic, and endocrinologic processesUremic encephalopathy (UE) is one of many manifestations of renal failure (RF).

Neurological complications in renal failureThe 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 encephalopathyComplex and poorly understoodAccumulation of metabolitesDisturbance of the intermediary metabolismImbalance in excitatory and inhibitory neurotransmitters Hormonal disturbance

Pathophysiology of uremic encephalopathyAccumulation of numerous organic substancesUremic neurotoxinsurea, 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 encephalopathyGuanidino compounds guanidinosuccinic acid, methylguanidine, guanidine and creatinine : highly increased in serum, CSF and brainInhibited responses to GABA and glycine (inhibitory amino acids) Guanidinosuccinic acid : inhibits transketolase, a thiamine-dependent enzyme of the pentose phosphate pathwayInhibition of transketolase : demyelinative changes to both central and peripheral nervous systemMethylguanidine : seizures and uremic twitch-convulsive syndrome

Patients with terminal RF have >100-fold increases in levels of guanidinosuccinic acid and guanidine, 20-fold increases in levels of methylguanidine, and 5-fold increase in levels of creatinine in various regions of the brain It is postulated that these compounds may contribute to the epileptic and cognitive symptoms accompanying uremic encephalopathya thiamine-dependent enzyme of the pentose phosphate pathway that is important for the maintenance of myelin

Pathophysiology of uremic encephalopathyDecrease in brain metabolic functionIncreased levels of creatine phosphate, adenosine triphosphat(ATP) and glucoseDecreased 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

Animal model brain .

Pathophysiology of uremic encephalopathyHormonal disturbancesparathyroid hormone, insulin, growth hormone, glucagon, thyrotropin, prolactin, luteinizing hormone and gastrin are elevatedPTH : promote the entry of calcium into neuronsCalcium : 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.

A combination of factors, including increased calcium and decreased GABA and glycine activity, leads to a distorted balance of excitatory and inhibitory effects that contributes to systemic changes associated with UE.

Incidence The prevalence of UE is difficult to determine. Depends on the number of ESRD patientsIn 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 signsSymptoms 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)DysarthriaAgitationTetanySeizures, usually generalized tonic-clonicConfusion, stupor, and coma

Imaging studiesBrain 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 progressGeneralized slow wave : more severe as the condition worsensIn 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 wavesBilateral spike discharge : myoclonic jerksAfter 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 spike-wave 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 improvesSeizures may be treated with anticonvulsants

Uremic polyneuropathy

Clinical Neurology and Neurosurgery 107 (2004) 116

Uremic polyneuropathyUremic polyneuropathy is the most common neurologic complication of RF : 60% Affect motor, sensory, autonomic and cranial nervesMale predominanceGFR< 12 ml/min : nerve conduction studies become abnormal< 6 ml/min : Clinical signs of peripheral nerve dysfunction

Clinical manifestationsThe neuropathy usually evolves over several months Distal, symmetrical, mixed sensorimotor neuropathyInjury is directly related to axon lengthLonger axons : first ( more prominent in the lower extremities)Sensory symptoms (paresthesias, burning sensation, pain) tend to precede the motor symptoms

The neuropathy usually evolves over several months but rarely an acute or subacute course is seen

Clinical manifestationsEarly finding Elevation of the vibratory threshold and impaired temperature sensibilityParadoxical heat sensation, paresthesias or painLater findingAscending hypesthesia to pinprick or touch, areflexia, restless legs, muscle weakness, cramps and atrophy

Sensory syndromesThe restless leg syndromes Persistent and extremely uncomfortable sensation in the lower extremitiesRelieved by movement of the legsMore prominent at night and interfere with sleepThe burning foot syndromeSevere pain and a burning sensation in the distal lower extremitiesEarly days of dialysis : acquired thiamine deficiencyParadoxical heat sensationApplication of low temperature sensation of high temperature

Motor symptomsMotor involvement : more advanced diseaseLoss of motor functionMuscle atrophy, myoclonus, paralysis

Autonomic neuropathy Intradialytic and orthostatic hypotension, incontinence, diarrhea, constipation, esophageal dysfunction, hyperhydrosis and impotenceCardiovascular autonomic testNeuropathy of cranial nervesoptic, trigeminal, facial and vestibulocochlear neuropathy

Cardiovascular autonomic testing should include Tilt-table test and measurement of the beat-to-beat variation in heart ratein the supine position, during deep breathing and Valsalva

Diagnosis Electrophysiologic studiesMost sensitive studyImpaired nerve function : 80% of patentsF-wave parameters from the lower limbs, vibration detection thresholds on the foot, the sural nerve sensory action potential amplitude and decreased nerve conduction velocity

PathogenesisAxonal degeneration secondary segmental demyelinationMost severe distalDemelination of the posterior columns and other CNSMetabolic and chemical causeThiamine deficiencyDecreased transketolase activityReduced of biotin and zincAccumulation of uremic toxins

inhibits transketolase, a thiamine-dependent enzyme of the pentose phosphate pathwayInhibition of transketolase : demyelinative changes to both central and peripheral nervous system

Treatment Dialysis Stabilize or improve symptomsParathesia : rapidly improve once hemodialysisOther symptoms mostly persist.Complete resolution may occur only mild symptoms.

Earlier and more dialysis for the decline in the incidence of uremic neuropathy

Before irreversible nerve damage has occured

Treatment Renal transplantationRecovery from neuropathy through remyelinisation

Supplementation with biotin, pyridoxine, cobalamin and thiaminestimulation of nerve metabolism and encouragement of regeneration

Symptomatic therapy tricyclic antidepressants and anticonvulsants

Before irreversible nerve damage has occured

Patients with terminal RF have >100-fold increases in levels of guanidinosuccinic acid and guanidine, 20-fold increases in levels of methylguanidine, and 5-fold increase in levels of creatinine in various regions of the brain It is postulated that these compounds may contribute to the epileptic and cognitive symptoms accompanying uremic encephalopathya thiamine-dependent enzyme of the pentose phosphate pathway that is important for the maintenance of myelin

Animal model brain .A combination of factors, including increased calcium and decreased GABA and glycine activity, leads to a distorted balance of excitatory and inhibitory effects that contributes to systemic changes associated with UE.The neuropathy usually evolves over several months but rarely an acute or subacute course is seen

Cardiovascular autonomic testing should include Tilt-table test and measurement of the beat-to-beat variation in heart ratein the supine position, during deep breathing and Valsalvainhibits transketolase, a thiamine-dependent enzyme of the pentose phosphate pathwayInhibition of transketolase : demyelinative changes to both central and peripheral nervous systemBefore irreversible nerve damage has occuredBefore irreversible nerve damage has occured