uremic encephalopathy

04/12/23 Dr. Abrar Ali Katpar 1

UremicUremicEncephalopathyEncephalopathy

Dr. Abrar Ali KatparDr. Abrar Ali KatparResident NephrologyResident Nephrology

King Khalid Hospital, Hail, K.S.AKing Khalid Hospital, Hail, K.S.A

04/12/2304/12/23 44Dr. Abrar Ali KatparDr. Abrar Ali Katpar

BackgroundBackground

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

• It results from accumulating metabolites of It results from accumulating metabolites of proteins & amino acids & concomitant proteins & amino acids & concomitant failure of renal catabolic, metabolic, and failure of renal catabolic, metabolic, and endocrinologic processes. endocrinologic processes.

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

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


IntroductionIntroduction• Uremic encephalopathyUremic encephalopathy is an organic is an organic

brain disorder. brain disorder. • 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 & remain creatinine clearance levels fall & remain below 15 mL/min.below 15 mL/min.

• Manifestations vary from Manifestations vary from • Mild symptoms (eg, lassitude, fatigue) to Mild symptoms (eg, lassitude, fatigue) to • Severe symptoms (eg, seizures, coma). Severe symptoms (eg, seizures, coma).


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

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


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.


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.


In terminal renal failureIn terminal renal failure• Increase levels in various regions of brain with Increase levels in various regions of brain with

uremia uremia • Guanidinosuccinic acid & guanidineGuanidinosuccinic acid & guanidine >100-fold >100-fold • MethylguanidineMethylguanidine >20- >20-

fold. fold. • CreatinineCreatinine >5-fold >5-fold

• Disturbance in kynurenic pathway occurs, Disturbance in kynurenic pathway occurs, • Tryptophan is converted to neuroactive kynurenines. Tryptophan is converted to neuroactive kynurenines.

• Elevation of kynurenine, 2 kynurenines, 3-Elevation of kynurenine, 2 kynurenines, 3-hydroxykynurenine, with chronic renal hydroxykynurenine, with chronic renal insufficiency.insufficiency. Leads to alterations in cellular metabolismLeads to alterations in cellular metabolism

cellular damage, and eventually cell death.cellular damage, and eventually cell death.• Kynurenine can induce convultions.Kynurenine can induce convultions.


Study shows In rats brain with RF

• Increased levelIncreased level• CP = Creatine Phosphate.CP = Creatine Phosphate.• ATP = adinosine triphosphate ATP = adinosine triphosphate • Glucose.Glucose.

• Decreased levelsDecreased levels• ADP = Adinosine Diaphosphate ADP = Adinosine Diaphosphate • AMP = Adinosine Monophosphate AMP = Adinosine Monophosphate • Lactate.Lactate.

• This suggest that uremic brain less uses ATP and This suggest that uremic brain less uses ATP and produce less ADP and AMP and lactate then normal produce less ADP and AMP and lactate then normal brain.brain.

• And is consistent of generalized decrease in metabolic And is consistent of generalized decrease in metabolic brain function. brain function.


TransketolasTransketolasee• Transketolase is a thiamine-

dependent enzyme of pentose phosphate pathway.

• Found mainly in myelinated neurons.

• it maintains axon-cylinder myelin sheaths.

• Guanidinosuccinic acid can inhibit transketolase resulting demylination.

• It also inhibit excitatory synaptic transmission in CA1 region of hippocampus, contributing to cognitive syndrome in UE.


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.


Hormones Hormones • Increased levels.Increased levels.

• PTHPTH• InsulinInsulin• Growth hormoneGrowth hormone• GlucagonGlucagon• ThyrotropinThyrotropin• ProlectinProlectin• Luteinizing hormoneLuteinizing hormone• Gastrin Gastrin

• PTH is thought to promote the entry of Ca PTH is thought to promote the entry of Ca into neurons specially in cerebral cortex, into neurons specially in cerebral cortex, which leads to many changes observed.which leads to many changes observed.


Leads to distorted balance of excitatory & inhibitory effects, contributes to systemic changes in UE. These changes in CSF may be response of early phase of disorder. Alterations occur in metabolism of dopamine & serotonin in brain, which may lead to early symptoms eg, sensorial clouding.

• 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


• 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.


Abnormalities may be Abnormalities may be associated with UEassociated with UE

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


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.


Mortality/MorbidityMortality/Morbidity

• Symptoms include :-Symptoms include :-• Somnolence & decreased mentation. Somnolence & decreased mentation. • Asterixis usually present. Asterixis usually present. • Symptoms are reversible following Symptoms are reversible following

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

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

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


• RaceRace• No racial predilection exists.No racial predilection exists.

• SexSex• No association No association

• AgeAge• Any age, mostly after 65 years as Any age, mostly after 65 years as

general.general.


ClinicalClinical

• HistoryHistory• Symptoms 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.


• Changes in Changes in sensorium sensorium include:- include:-

• Loss of memory, Loss of memory, • Impaired Impaired

concentration, concentration, • Depression, Depression, • Delusions, Delusions, • Lethargy, Lethargy, • Irritability, Irritability, • Fatigue, Fatigue, • Insomnia, Insomnia, • Psychosis,Psychosis,• Stupor,Stupor,• Catatonia, &Catatonia, &• Coma. Coma.

• Patients may Patients may complain of:complain of:

• Slurred speech, Slurred speech, • Pruritus, Pruritus, • Muscle Muscle

twitches, or twitches, or • Restless legs.Restless legs.


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


HistoryHistory

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


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

of encephalopathy. of 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.


Findings• Include : Include :

• Myoclonic jerks, twitches, or Myoclonic jerks, twitches, or fasciculations (ie, fasciculations (ie, uremic twitch-convulsive syndrome postulated by postulated by Adams et al in 1997) Adams et al in 1997)

• Asterixis Asterixis • Dysarthria Dysarthria • Agitation Agitation • Tetany Tetany • Seizures, usually generalized tonic-clonic Seizures, usually generalized tonic-clonic


DDDD1. Encephalopathy, Hepatic2. Hyperparathyroidism3. Encephalopathy,

Hypertensive4. Hypoglycemia5. Hypercalcemia6. Hyponatremia7. Hypermagnesemia8. Hypophosphatemia9. Hypernatremia10. Subdural Hematoma11. Hyperosmolar Coma 12. Wernicke-Korsakoff

Syndrome13.13. Alzheimer DiseaseAlzheimer Disease14.14. Alzheimer Disease in Alzheimer Disease in

Individuals With Down Individuals With Down SyndromeSyndrome

15.15. AphasiaAphasia

15. Apraxia and Related Syndromes16. Complex Partial Seizures17. Dementia in Motor Neuron

Disease18. Dementia With Lewy Bodies19. EEG in Dementia and

Encephalopathy20. EEG in Status Epilepticus21. Frontal and Temporal Lobe

Dementia22. Generalized EEG Waveform

Abnormalities23. Huntington Disease24. Intracranial Hemorrhage25. Normal Pressure Hydrocephalus26. Pick Disease27. Status Epilepticus28. Subdural Hematoma29. Tonic-Clonic Seizures30. Transient Global Amnesia


• Other Problems to Be ConsideredOther Problems to Be Considered• Drug intoxicationDrug intoxication• CVACVA• Encephalopathy from drugs normally excreted or Encephalopathy from drugs normally excreted or

metabolized by the kidney (ie, meperidine, metabolized by the kidney (ie, meperidine, cimetidine)cimetidine)

• DementiaDementia• Complex partial status epilepticusComplex partial status epilepticus• Dementia in Huntington diseaseDementia in Huntington disease• Dementia in Parkinson diseaseDementia in Parkinson disease• Dementia in progressive supranuclear palsyDementia in progressive supranuclear palsy• Epileptic encephalopathiesEpileptic encephalopathies• Vascular dementiaVascular dementia• EEG in comaEEG in coma• Tonic seizuresTonic seizures


WorkupWorkup


Laboratory StudiesLaboratory Studies

1.1. Electrolytes, BUN, creat, & Electrolytes, BUN, creat, & glucose glucose A-A- Markedly elevated BUN & Markedly elevated BUN &

creatinine levels indicate UE. creatinine levels indicate UE.

B-B- Obtain serum electrolyte & Obtain serum electrolyte & glucose measurements to rule out glucose measurements to rule out other causes:-other causes:-

-hyponatremia, -hypernatremia, -hyponatremia, -hypernatremia,

- hyperglycemia & - hyperglycemia &

-hyperosmolar syndromes-hyperosmolar syndromes


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

3.3.Obtain serum calcium, phosphate, and PTH Obtain serum calcium, phosphate, and PTH levels to determine the presence of levels to determine the presence of hypercalcemia, hypophosphatemia, and hypercalcemia, hypophosphatemia, and severe hyperparathyroidism, which cause severe hyperparathyroidism, which cause metabolic encephalopathy. metabolic encephalopathy.

4.4.Serum magnesium levels may be elevated Serum magnesium levels may be elevated in a patient with renal insufficiency, in a patient with renal insufficiency, particularly if the patient is ingesting particularly if the patient is ingesting magnesium-containing antacids. magnesium-containing antacids. Hypermagnesemia may manifest as encephalopathy.

5.5.Order a toxicology screen in all patients.Order a toxicology screen in all patients.


6. Contributing to encephalopathy Medication levels A- Determine detectabale drugs

• digoxin, • lithium etc.

B- Some medications cannot be detected & are excreted by kidney. eg,

• penicillin,• cimetidine, • meperidine, • Baclofen etc.


Imaging StudiesImaging Studies• Brain imaging is of limited value. Brain imaging is of limited value. • CT and MRI studies typically show cerebral CT and MRI studies typically show cerebral

atrophy & secondary ventricular dilatation. atrophy & secondary ventricular dilatation. • These studies are valuable for excluding intracranial These studies are valuable for excluding intracranial

hemorrhage & subdural hematoma when patients hemorrhage & subdural hematoma when patients have an acute change in mental status. have an acute change in mental status.

• Case reports have documented increased signal Case reports have documented increased signal intensity in the cortical and subcortical areas of the intensity in the cortical and subcortical areas of the parietal and occipital lobes. parietal and occipital lobes.

• These findings are thought to reflect local edema These findings are thought to reflect local edema that resolved after dialysis treatments. that resolved after dialysis treatments.

• Improvement on MRI has been correlated with Improvement on MRI has been correlated with improved serum creatinine and BUN levels.improved serum creatinine and BUN levels.


Imaging StudiesImaging Studies

• Severe symptoms • Obtain an 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.

• With milder symptoms• initially treat with dialysis & • observe for neurologic improvement.


ROI placement. Axial FLAIR-prepped echo-planar T2-weighed images (TR/TE/TI, 10,000/91.7/2200; FOV, 40; b = 0 s/mm2) in a patient with PRES secondary to uremic encephalopathy. Nineteen ROIs were systemically placed in 22 patients with PRES and 18 control subjects, as shown. The images were coregistered to the ADC map, on which measurements were taken. Typical ROI sizes varied with brain region, as follows: cerebellum, 400 mm2; pons, 240 mm2; lenticular nucleus, 250 mm2; corticospinal tract, 60 mm2; posterior temporal lobe, 360 mm2; caudate head, 60 mm2; thalamus, 220 mm2; occipital lobe, 360 mm2; parietal lobe, 400 mm2; frontal lobe, 500 mm2.


• AA, MR image in a case of uremic , MR image in a case of uremic encephalopathy shows marked frontal encephalopathy shows marked frontal lobe involvement. lobe involvement.


Other TestsOther Tests

• Electroencephalogram Electroencephalogram • An EEG is commonly performed on An EEG is commonly performed on

patients with metabolic patients with metabolic encephalopathy. encephalopathy.

• Findings typically include the following: Findings typically include the following: • (1) slowing and loss of alpha frequency (1) slowing and loss of alpha frequency

waves, waves, • (2) disorganization, (2) disorganization, • (3) intermittent bursts of theta and delta (3) intermittent bursts of theta and delta

waves with slow background activity. waves with slow background activity.


• EEG in a 56-year-old man EEG in a 56-year-old man with uremic with uremic encephalopathy. encephalopathy.

• He became increasingly He became increasingly lethargic, requiring lethargic, requiring intubation. intubation.

• EEG shows absence of a EEG shows absence of a posterior dominant alpha posterior dominant alpha rhythm and diffuse bilateral rhythm and diffuse bilateral slowing with mixed theta- slowing with mixed theta- and delta-frequency signal. and delta-frequency signal.

• A single sharp wave is A single sharp wave is present in the left occipital present in the left occipital region, phase reversing at region, phase reversing at O1. O1.

• From top to bottom: Fp1-F7, From top to bottom: Fp1-F7, F7-T3, T3-T5, T5-O1, O1-O2, F7-T3, T3-T5, T5-O1, O1-O2, O2-T6, T6-T4, T4-F8, F8-Fp2, O2-T6, T6-T4, T4-F8, F8-Fp2, Fp2-Fp1, F3-C3, C3-P3, P3-Fp2-Fp1, F3-C3, C3-P3, P3-O1, F4-C4, C4-P4, P4-O2, Fz-O1, F4-C4, C4-P4, P4-O2, Fz-Cz.Cz.


• Reduction in frequency of EEG waves correlates with Reduction in frequency of EEG waves correlates with the decrease in renal function and the alterations in the decrease in renal function and the alterations in cerebral function. cerebral function.

• After the initial period of dialysis, clinical After the initial period of dialysis, clinical stabilization may occur while the EEG findings do stabilization may occur while the EEG findings do not improve. Eventually, EEG results move toward not improve. Eventually, EEG results move toward normal. normal.

• Aside from the routine EEG, evoked potentials (EPs) Aside from the routine EEG, evoked potentials (EPs) (ie, EEG signals that occur at a reproducible time (ie, EEG signals that occur at a reproducible time after the brain receives a sensory stimulus [eg, after the brain receives a sensory stimulus [eg, visual, auditory, somatosensory]) may be helpful in visual, auditory, somatosensory]) may be helpful in evaluating uremic encephalopathy. evaluating uremic encephalopathy.

• CRF prolongs latency of the cortical visual-evoked CRF prolongs latency of the cortical visual-evoked response. response.

• Auditory-evoked responses are generally not altered Auditory-evoked responses are generally not altered in uremia, but delays in the cortical potential of the in uremia, but delays in the cortical potential of the somatosensory-evoked response do occur.somatosensory-evoked response do occur.


Cognitive function testsCognitive function tests

• Several cognitive function tests are Several cognitive function tests are used to evaluate UE. used to evaluate UE. • Uremia may result in worse performance Uremia may result in worse performance

on 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.


Histologic FindingsHistologic Findings• Brain histologic findings include:-

• Meningeal fibrosis, • Glial changes, • Edema, • Vascular degeneration, • Focal & diffuse neuronal degeneration,

and • Focal demyelination. • Small infarcts are also seen & are

probably due to HTN or focal necrosis. • Cerebellar acute granule cell necrosis is

observed.


Inflammatory ischemia and fibrosisDevelop.Hematoxylin/eosin staining reveals meningeal fibrosis (A) and inflammation (B) in the spinal cord. (C) Inflammation and fibrosis are shown also in the medulla oblongata. (D) CNPase immunoreactivity at the perivascular area shows that myelin is largely preserved.

Necrotic lesions form around the inflamed perivascular areas (E, hematoxylin/eosin) and show secondary myelin loss (F, CNPase immunostaining). Serial cerebellar brain sections stained with Bielschowsky silver staining (G), which stains neurons and axons, and luxol fast blue/periodic acid Schiff (H), which stains myelin, show an ischemic lesion where both axons and myelin are damaged.


ProceduresProcedures

• Lumbar 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.


Lumbar Lumbar puncturepuncture


TreatmentTreatment


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.

Note: EEG findings may not improve immediately. • In ESRD, EEG improve after several months but may

not completely normalize.


• 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.


Seizures Seizures

• May be treated with anticonvulsants. • These drugs should be administered at

lower-than-usual doses to accommodate the low albumin levels observed in CRF.

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

• The unbound drug is therapeutically active fraction.


ConsultationsConsultationsyour patient needsyour patient needs

1. 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.


• DietDiet• To avoid malnutrition, • Maintain adequate protein intake (>1

g/kg/d).• Low-salt, low-protein (ie, renal) diet..

• ActivityActivity• Instruct pts with significant symptoms

to continue bed rest.


Follow-upFollow-up


• Further Inpatient Care:-• Admit for dialysis & further workup. • 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. • In cases of intracranial hemorrhage, serial head

neuroimaging may be necessary. • Further Outpatient Care

• Schedule maintenance HD for ESRD. • Carefully monitor mental status.

• Inpatient & Outpatient Medications• Administer medications (eg, iron, erythropoietin,

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

• Avoid sedatives.


Transfer& Deterrence/Prevention

• Transfer• Patients may require transfer to a facility that

can provide emergent hemodialysis. • Transfer to a facility with staff & equipment for

further evaluation & care may be necessary. • As always, trained personnel with appropriate

monitoring should perform the transfer.• Deterrence/Prevention

• Refer patients with chronic renal insufficiency to a Nephrologist for regular monitoring of CrCl so that dialysis may be initiated before encephalopathy develops.


ComplicationsPrognosis

Patient Education• Complications

• If untreated• Seizures • Coma • Death

• Prognosis• The prognosis is

generally favorable if treatment is successful.

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

• Patient Education• 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.


Medicolegal Pitfalls

1. Failure to recognize RF as the cause of encephalopathy in a patient who presents with altered mental status.

2. Failure to promptly initiate dialysis in a patient with UE.

3. Failure to adequately monitor drug levels may lead to toxicity & further complications.

4. Accidental falls may occur & can lead to litigation.

5. The slow onset of symptoms may lead to complications that might be grounds for litigation.


Thank YouThank You

uremic encephalopathy

Education

uremic brain

early symptoms

severe symptoms

uremic encephalopathy

normal brain

mild symptoms

mortalitymorbidity symptoms

renal function