http://emedicine.medscape.

com/article/239191-overview#a0104

Uremic Encephalopathy
Author: James W Lohr, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN

Uremic encephalopathy is an organic brain disorder. It develops in patients with acute or chronic renal failure, usually when creatinine clearance (CrCl) levels fall and remain below 15 mL/min.[1,
2, 3, 4]

Manifestations of this syndrome vary from mild symptoms (eg, lassitude, fatigue) to severe symptoms (eg, seizures, coma). Severity and progression depend on the rate of decline in renal function; thus, symptoms are usually worse in patients withacute renal failure. Prompt identification of uremia as the cause of encephalopathyis essential because symptoms are readily reversible following initiation ofdialysis.[5, 6]

Pathophysiology
Uremic encephalopathy has a complex pathophysiology, and many toxins that accumulate in kidney failure may be contributive. Parathyroid hormone (PTH) likely contributes to uremic encephalopathy.[7] Secondary hyperparathyroidism, which occurs in kidney failure, causes an increase in calcium content in the cerebral cortex. In animal models with uremia, EEG changes were typical of those observed in patients with renal failure. Inuremic patients with secondary hyperparathyroidism, EEG changes have been shown to improve after medical suppression of PTH or parathyroidectomy. The specific mechanism by which PTH causes disturbance in brain function is unclear, but it may be caused by increases in intracellular concentration of calcium in brain cells. However, since the encephalopathy improves with dialysis, which does not have a marked effect on PTH levels, hyperparathyroidism is not thought to be the main cause. Another theory about the etiology of uremic encephalopathy suggests imbalances of neurotransmitter amino acids within the brain. During the early phase of uremic encephalopathy, plasma and cerebrospinal fluid (CSF) determinations indicate that levels of glycine increase and levels of glutamine and GABA decrease; additionally, alterations occur in metabolism of dopamine and serotonin in the brain, which may lead to early symptoms (eg, sensorial clouding). As uremia progresses, it has been proposed that the accumulation of guanidino compounds results in activation of excitatory N-methyl-D-aspartate (NMDA) receptors and inhibition of inhibitory GABA receptors, which may cause myoclonus and seizures.[5, 8, 9] A study of acute kidney injury in mice found evidence of a blood-brain barrier disruption from such injury, with increased neuronal pyknosis and microgliosis. In addition, proinflammatory chemokines were increased in brain tissue.[10] Numerous other uremic toxins may contribute to uremic encephalopathy, but there has been a notable lack of research in this area. Although the encephalopathy correlates roughly with BUN level, urea is not itself thought to be causative.

History

Early symptoms Anorexia Nausea Restlessness Drowsiness Diminished ability to concentrate Slowed cognitive functions More severe symptoms Vomiting Emotional volatility Decreased cognitive function Disorientation Confusion Bizarre behavior As uremic encephalopathy progresses, patients may develop myoclonus, asterixis, seizures, stupor, and coma.

Physical

Altered mental status (confusion) Cranial nerve signs (nystagmus) Papilledema Hyperreflexia, clonus, asterixis Stupor Coma occurs only if uremia remains untreated and progresses. Penyebab GGA dan CKD

Laboratory Studies

Electrolytes, BUN, creatinine, and glucose[12] Markedly elevated BUN and creatinine levels are seen in uremic encephalopathy. Obtain serum electrolyte and glucose measurements to rule outhyponatremia, hypernatremia, hyperglycemia, and hyperosmolar syndromes as the cause of encephalopathy. Obtain a complete blood cell count to detect leukocytosis, which may suggest an infectious cause and determine whether anemia is present. (Anemia may contribute to the severity of mental alterations.) Obtain serum calcium, phosphate, and PTH levels to determine the presence ofhypercalcemia, hypophosphatemia, and severe hyperparathyroidism, which cause metabolic encephalopathy. Serum magnesium levels may be elevated in a patient with renal insufficiency, particularly if the patient is ingesting magnesium-containing antacids.Hypermagnesemia may manifest as encephalopathy. Order a toxicology screen in all patients. Medication levels Determine drug levels because medications may accumulate in patients with kidney failure and contribute to encephalopathy (eg, digoxin, lithium).

Some medications cannot be detected and are excreted by the kidney. These may also accumulate in patients with kidney failure, resulting in encephalopathy (eg, penicillin, cimetidine, meperidine, baclofen).

Imaging Studies

Severe symptoms Obtain an MRI or head CT scan for a uremic patient who presents with severe neurologic symptoms to rule out structural abnormalities (eg, cerebrovascular accident, intracranial mass). A CT scan does not demonstrate any characteristic findings for uremic encephalopathy. With milder symptoms, initially treat the patient with dialysis and observe for neurologic improvement.

Other Tests

Electroencephalogram An EEG is commonly performed on patients with metabolic encephalopathy. Findings typically include the following: (1) slowing and loss of alpha frequency waves, (2) disorganization, and (3) intermittent bursts of theta and delta waves with slow background activity. Reduction in frequency of EEG waves correlates with the decrease in renal function and the alterations in cerebral function. After the initial period of dialysis, clinical stabilization may occur while the EEG findings do not improve. Eventually, EEG results move toward normal. Aside from the routine EEG, evoked potentials (EPs) (ie, EEG signals that occur at a reproducible time after the brain receives a sensory stimulus [eg, visual, auditory, somatosensory]) may be helpful in evaluating uremic encephalopathy. Chronic renal failure prolongs latency of the cortical visual-evoked response. Auditory-evoked responses are generally not altered in uremia, but delays in the cortical potential of the somatosensory-evoked response do occur. Cognitive function tests: Several cognitive function tests are used to evaluate uremic encephalopathy. Uremia may result in worse performance on the trail-making test, which measures psychomotor speed; the continuous memory test, which measures short-term recognition; and the choice reaction time test, which measures simple decision making. Alterations in choice reaction time appear to correlate best with renal failure.

Procedures
Lumbar puncture Lumbar puncture is not routinely performed; however, it may be indicated to find other causes of encephalopathy if a patient's mental status does not improve after initiation of dialysis. No specific CSF finding indicates uremic encephalopathy.

Medical Care
No medications are specific to the treatment of encephalopathy.

The presence of uremic encephalopathy in a patient with either acute kidney failure or chronic kidney failure is an indication for the initiation of dialytic therapy (ie, hemodialysis, peritoneal dialysis, continuous renal replacement therapy). After beginning dialysis, the patient generally improves clinically, although EEG findings may not improve immediately. In patients with end-stage renal disease (ESRD), EEG abnormalities generally improve after several months but may not completely normalize. Address the following factors when treating uremic encephalopathy, which are also included in the standard care of any patient with ESRD:

o o o

Adequacy of dialysis Correction of anemia Regulation of calcium and phosphate metabolism

Consultations
Consult a neurologist if symptoms do not improve upon initiation of dialysis therapy. Consult a vascular surgeon for placement of vascular access in patients with ESRD. Refer patients with ESRD to a dietitian familiar with renal diseases.

Diet
To avoid malnutrition in patients with ESRD, maintain adequate protein intake (>1 g/kg/d) and initiate dialysis (despite the presence of encephalopathy).

Activity
Instruct patients with significant symptoms to continue bed rest.

Further Inpatient Care

Admit patients for dialysis and further workup.

Further Outpatient Care

Schedule maintenance hemodialysis for patients who have 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
Patients may require transfer to a facility that can provide emergent hemodialysis.

Deterrence/Prevention
Refer patients with chronic kidney disease to a nephrologist for regular monitoring of CrCl so that dialysis may be initiated before encephalopathy develops.

Complications

Seizures Coma Death

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