WELCOME WELCOME TO TO ALLALL

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UremicUremicEncephalopathyEncephalopathy

DR. MD REZUAN ULLAHDR. MD REZUAN ULLAHResident Phase AResident Phase A

NINSHNINSH

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IntroductioinIntroductioin• Uremic Encephalopathy is an organic Uremic Encephalopathy is an organic

brain disorder. brain disorder.

• Uremia is final stage of progressive Uremia is final stage of progressive renal insufficiency & resultant renal insufficiency & resultant multiorgan failure.multiorgan failure.

• It results from accumulating metabolites It results from accumulating metabolites of proteins & amino acidsof proteins & amino acids

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• No single metabolite has been No single metabolite has been identified as the sole cause of identified as the sole cause of uremia.uremia.

• Uremic encephalopathy (UE) is one Uremic encephalopathy (UE) is one of many manifestations of renal of many manifestations of renal failure (RF).failure (RF).

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• Occurs due to build up of toxins which Occurs due to build up of toxins which are normally cleared by kidneys. are normally cleared by kidneys.

• It develops in pts with RF, usually when It develops in pts with RF, usually when creatinine clearance levels fall & creatinine clearance levels fall & remain below 15 mL/min.remain below 15 mL/min.

• Manifestations vary from Manifestations vary from • Mild symptoms (eg, lassitude, Mild symptoms (eg, lassitude,

fatigue) to fatigue) to • Severe symptoms (eg, Severe symptoms (eg,

seizures,coma). seizures,coma).

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• Severity & progression depend on rate Severity & progression depend on rate of decline in renal function.of decline in renal function.•Symptoms are usually worse in ARF. Symptoms are usually worse in ARF.

• Prompt identification of uremia as the Prompt identification of uremia as the cause of encephalopathy is essential cause of encephalopathy is essential because symptoms are readily because symptoms are readily reversible following initiation of reversible following initiation of dialysis.dialysis.

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Patho-physiologyPatho-physiology• It has a complex pathophysiology.It has a complex pathophysiology.• With unknown exact cause.With unknown exact cause.• Endogenous guanidino compounds Endogenous guanidino compounds

are neurotoxic.are neurotoxic.

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Accumulating metabolites of proteins & amino acids affect the

entire neuraxis. Several organic

substances accumulate• Urea, • Guanidine compounds, • Uric acid, • Hippuric acid, • Various amino acids,• Polypeptides, • Polyamines, • Phenols & conjugates

of phenols,

• Phenolic and indolic acids,

• Acetoin, • Glucuronic acid, • Carnitine, • Myoinositol, • Sulfates, • Phosphates, and

middle molecules.

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Accumulation of diamethylarginine

• It’s a NOS ( nitric oxide synthase) It’s a NOS ( nitric oxide synthase) inhibitor.inhibitor.

• Observed in uremic Pts leads to Observed in uremic Pts leads to vasoconstriction.vasoconstriction.

• Induces hypertension.Induces hypertension.• Increases ischemia & vulnerability Increases ischemia & vulnerability

to uremic brain.to uremic brain.

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Hormones Hormones • Increased levels.Increased levels.

• PTHPTH• InsulinInsulin• Growth hormoneGrowth hormone• GlucagonGlucagon• ThyrotrophinThyrotrophin• ProlactinProlactin• Luteinizing hormoneLuteinizing hormone• Gastrin Gastrin

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• Increased levelsIncreased levels• Ca activityCa activity• Organic acidsOrganic acids• Free tryptophanFree tryptophan

• Decrease levelsDecrease levels• GABA (gamma-GABA (gamma-

aminobutyric acid)aminobutyric acid)• Glutamine Glutamine • Glycin activityGlycin activity

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• As uremia progresses As uremia progresses accumulation of guanidino compounds accumulation of guanidino compounds

results in results in activation of excitatory N-methyl-D-activation of excitatory N-methyl-D-

aspartate (NMDA) receptors & aspartate (NMDA) receptors & inhibition of inhibitory GABA receptors, inhibition of inhibitory GABA receptors,

which may cause which may cause myoclonus & seizures..• The encephalopathy correlates roughly with

BUN level, urea itself is not thought to be causative.

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Abnormalities may be Abnormalities may be associated with UEassociated with UE

• AcidosisAcidosis• HyponatremiaHyponatremia• HyperkalemiaHyperkalemia• HypocalcaemiaHypocalcaemia• HypermagnacemiaHypermagnacemia• Over hydration Over hydration • Dehydration.Dehydration.

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FrequencyFrequency• United StatesUnited States

• CrCl level < 10% of normal probably CrCl level < 10% of normal probably develop some degree of develop some degree of encephalopathy.encephalopathy.

• In one pediatric study, In one pediatric study, encephalopathy occurred in 40%, encephalopathy occurred in 40%, with a BUN level > 90 mg/dL. with a BUN level > 90 mg/dL.

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Mortality/MorbidityMortality/Morbidity• Symptoms include :-Symptoms include :-

• Somnolence & decreased Somnolence & decreased mentation. mentation.

• Asterixis usually present. Asterixis usually present. • Symptoms are reversible Symptoms are reversible

following following •Institution of dialysis Institution of dialysis •Renal transplantation .Renal transplantation .

•The severe complications The severe complications seizuresseizurescomacoma leads to leads to death. death.

•Early recognition is crucial to Early recognition is crucial to prevent morbidity or prevent morbidity or mortality.mortality.

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ClinicalClinicalSymptoms begin insidiously Symptoms begin insidiously

•Not noticed by patients but by family Not noticed by patients but by family members/caregivers. members/caregivers.

•In many cases, CNS impairment provides first indication of metabolic derangements.

•Symptoms may progress slowly or rapidly.

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• Changes in Changes in sensorium sensorium include:- include:- • Loss of memoryLoss of memory• Impaired Impaired

concentrationconcentration• DepressionDepression• DelusionsDelusions• LethargyLethargy• IrritabilityIrritability• FatigueFatigue• InsomniaInsomnia• PsychosisPsychosis• StuporStupor• Catatonia &Catatonia &• Coma. Coma.

• Patients may Patients may complain of:complain of:• Slurred speechSlurred speech• Pruritus Pruritus • Muscle twitchesMuscle twitches• Restless legs.Restless legs.

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HistoryHistory• Early symptoms

1. Anorexia 2. Nausea 3. Restlessness 4. Drowsiness 5. Diminished ability to

concentrate 6. Slowed cognitive

functions

• More severe symptoms 1. Vomiting 2. Emotional volatility 3. Decreased cognitive

function 4. Disorientation 5. Confusion 6. Bizarre behavior

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• As uremic encephalopathy progresses, patients may develop:-• Myoclonus• Asterixis• Seizures• Stupor & • Coma.

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Physical examPhysical exam• Variable & depending on severity of Variable & depending on severity of

encephalopathy. encephalopathy. • Neurologic findings range from Neurologic findings range from

normal to a comatose state. normal to a comatose state. • Altered mental status (confusion) • Cranial nerve signs (nystagmus) • Papilledema • Hyperreflexia, clonus, asterixis • Stupor • Coma occurs only if uremia

remains untreated & progresses.

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• Myoclonic jerks, twitches, or Myoclonic jerks, twitches, or fasciculationsfasciculations

• Asterixis Asterixis • Dysarthria Dysarthria • Agitation Agitation • Tetany Tetany • Seizures, usually generalized Seizures, usually generalized

tonic-clonic tonic-clonic

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Differential DiagnosisDifferential Diagnosis1. Hepatic

Encephalopathy 2. Hypertensive

Encephalopathy, 3. Hypoglycemia4. Hyponatremia5. Hypernatremia6. Subdural Hematoma7. Hyperosmolar Coma 8.8. Alzheimer DiseaseAlzheimer Disease9. Status Epilepticus10.Intracranial

haemorrhage

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Laboratory StudiesLaboratory Studies11.. Electrolytes, BUN, creatinine, & Electrolytes, BUN, creatinine, &

glucose glucose A-A- Markedly elevated BUN & Markedly elevated BUN &

creatinine levels indicate UE. creatinine levels indicate UE. B-B- Obtain serum electrolyte & glucose Obtain serum electrolyte & glucose

measurements to rule out other measurements to rule out other causes:-causes:--hyponatremia, -hypernatremia, -hyponatremia, -hypernatremia, - hyperglycemia & - hyperglycemia & -hyperosmolar syndromes-hyperosmolar syndromes

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2.2.Obtain CBC to detect leukocytosis, Obtain CBC to detect leukocytosis, which may suggest an infectious which may suggest an infectious cause and determine whether cause and determine whether anemia is present. anemia is present. (Anemia may contribute to the severity of mental alterations.)

33.. Serum calcium, phosphate and Serum calcium, phosphate and PTH levels to determine the PTH levels to determine the presence of hypercalcaemia, presence of hypercalcaemia, hypophosphatemia, and severe hypophosphatemia, and severe hyperparathyroidism, which cause hyperparathyroidism, which cause metabolic encephalopathy. metabolic encephalopathy.

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Imaging StudiesImaging Studies• Brain imaging is of limited value Brain imaging is of limited value

•MRI or head CT with severe neurologic symptoms to rule out structural abnormalities (eg, CVA, Intracranial mass).

•CT does not demonstrate any characteristic findings for UE.

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Other TestsOther Tests• Electroencephalogram:Electroencephalogram:

An EEG is commonly performed on An EEG is commonly performed on patients with metabolic encephalopathy. patients with metabolic encephalopathy.

Findings typically include the following: Findings typically include the following: (1) slowing and loss of alpha (1) slowing and loss of alpha frequency wavesfrequency waves(2) disorganization(2) disorganization(3) intermittent bursts of theta and (3) intermittent bursts of theta and delta waves with slow background delta waves with slow background activity. activity.

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Cognitive function testsCognitive function testsSeveral cognitive function tests are used to Several cognitive function tests are used to evaluate UE. evaluate UE.

• Uremia may result in worse performance on Uremia may result in worse performance on •The trail-making test:- which measures

psychomotor speed.•The continuous memory test:- which

measures short-term recognition.•The choice reaction time test:- which

measures simple decision making. •Alterations in choice reaction time appear

to correlate best with renal failure.

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Histologic FindingsHistologic FindingsBrain histologic findings include:-

• Meningeal fibrosis• Glial changes• Edema• Vascular degeneration• Focal & diffuse neuronal degeneration • Focal demyelination• Small infarcts are also seen & are

probably due to HTN or focal necrosis

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ProceduresProceduresLumbar puncture:

•Not routinely performed, however •It is indicated to find other causes if a patient's mental status does not improve after initiation of dialysis.

•No specific CSF finding indicates UE.

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TreatmentTreatment

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Medical CareMedical Care• No medications are specific.No medications are specific.• Care includes correcting metabolic Care includes correcting metabolic

disturbance disturbance •In ARF or CRF indication for early

initiation of :-•Hemodialysis•Peritoneal dialysis•Continuous renal replacement therapy.

After beginning dialysis, patient generally improves clinically.

EEG findings may not improve immediately.•In ESRD, EEG improve after several months but may not completely normalize.

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CONT…

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Address the following factors:

1. Adequacy of dialysis 2. Correction of anemia 3. Regulation of calcium & phosphate

metabolism.4. Medical parathyroidectomy.5. Infections need to be treated

appropriately.

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Seizures Seizures May be treated with anticonvulsants.

• These drugs should be administered at lower-than-usual doses.

• Low albumin levels can lead to higher levels of unbound anticonvulsant.

• The unbound drug is therapeutically active fraction.

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ConsultationsConsultations1. Nephrologist 2. Vascular surgeon for placement of vascular

access in patients with ESRD. 3. Neurologist if symptoms do not improve upon

initiation of dialysis therapy.4. Dietitian the one familiar with renal diseases.5. Specialist in critical care medicine 6. Neurosurgeon Neurosurgical intervention for

intracranial hemorrhage or subdural hematoma.7. Infectious disease specialist: Bacterial

meningitis remains a high cause of mortality in hemodialyzed patients, often because of delay in treatment.

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Diet:Diet:•To mainitain adequate nutrition•Low-salt

Activity:Activity:•Instruct patients with significant

symptoms to continue bed rest.

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Follow-upFollow-up

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•Patients need close follow-up in acute stage of uremic encephalopathy.

•After underlying problem is treated properly, the symptoms should resolve.

•Levels of anticonvulsant drugs must be closely monitored to prevent toxicity.

CONT…CONT…Further Outpatient Care:

•Schedule maintenance HD for ESRD.

•Carefully monitor mental status.•Administer medications (eg, iron,

erythropoietin, phosphate binders, vitamin D analogues) for patients with ESRD to optimize their quality of life.

•Avoid sedatives.

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Complications

If untreated:• Seizures • Coma • Death

PrognosisPrognosis

•The prognosis is generally favorable if treatment is successful.

•With prompt dialytic therapy, the mortality rate is low.

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Patient EducationPatient Education

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To ensure that treatment is initiated early, instruct patients & their family members & caregivers about the need for prompt medical evaluation when mental status changes occur.

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Thank YouThank You