AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

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.

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 with acute renal failure. Prompt identification of uremia as the cause of encephalopathy is essential because symptoms are readily reversible following initiation of dialysis.

Pathophysiology

Uremic encephalopathy has a complex pathophysiology, and many toxins that accumulate in renal failure may be contributive. Parathyroid hormone (PTH) likely contributes to uremic encephalopathy.

Secondary hyperparathyroidism, which occurs in renal 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. In uremic 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.

Numerous other uremic toxins may contribute to uremic encephalopathy, but the lack of research in this area in recent years is notable. Although the encephalopathy correlates roughly with BUN level, urea itself is not thought to be causative.

Frequency

United States

Most patients with a CrCl level less than 10% of normal probably develop some degree of encephalopathy; however, they may not be clearly symptomatic. In one pediatric study, encephalopathy occurred in 40% of the children with a BUN level greater than 90 mg/dL. As the BUN level increased, the likelihood of these children developing convulsions increased.

Mortality/Morbidity

Symptoms include somnolence and decreased mentation. Asterixis is usually present. These findings are reversible following initiation of dialysis and recovery of renal function in patients with acute renal failure. Symptoms are also reversible following the institution of dialysis or renal transplantation in patients with chronic renal insufficiency. The severe complications (ie, seizures, coma) can lead to death. Early recognition of encephalopathy in the setting of decreased renal function is crucial to prevent morbidity or mortality.

Race

No racial predilection exists.

Sex

No significant association between sex and incidence exists.

Age

Uremic encephalopathy may develop at any age.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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.

Causes

Uremic encephalopathy may occur in a patient affected with acute or chronic renal failure of any etiology.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Drug intoxication
Cerebrovascular accident
Encephalopathy from drugs normally excreted or metabolized by the kidney (ie, meperidine, cimetidine)

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• Electrolytes, BUN, creatinine, and glucose
• • Markedly elevated BUN and creatinine levels indicate uremic encephalopathy.
  
  
  • Obtain serum electrolyte and glucose measurements to rule out hyponatremia, 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 of hypercalcemia, 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 renal 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 renal 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.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

No medications are specific to the treatment of encephalopathy.

• The presence of uremic encephalopathy in a patient with either acute renal failure or chronic renal 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:
• • 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.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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.

In/Out Patient Meds

• 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 renal insufficiency 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.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize renal failure as the cause of encephalopathy in a patient who presents with altered mental status
• Failure to promptly initiate dialysis in a patient with uremic encephalopathy

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

• Biasioli S, D'Andrea G, Feriani M, Chiaramonte S, Fabris A, Ronco C, et al. Uremic encephalopathy: an updating. Clin Nephrol. Feb 1986;25(2):57-63. [Medline].
• Biasioli S. Neurologic aspects of dialysis. In: Nissenson A, Fine R, eds. Clinical Dialysis. 2005:855-876.
• Bolton CF, Young GB. Encephalopathy of chronic renal failure. In: Neurological Complications of Renal Disease. 1990:49-74.
• Brouns R, De Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg. Dec 2004;107(1):1-16. [Medline].
• Deguchi T, Isozaki K, Yousuke K, Terasaki T, Otagiri M. Involvement of organic anion transporters in the efflux of uremic toxins across the blood-brain barrier. J Neurochem. Feb 2006;96(4):1051-9. [Medline].
• Fraser CL, Arieff AI. Nervous system manifestations of renal failure. In: Schrier RW, ed. Diseases of the Kidney. 2001:2769-2794.
• Moe SM, Sprague SM. Uremic encephalopathy. Clin Nephrol. Oct 1994;42(4):251-6. [Medline].

Article Last Updated: May 8, 2007