Anoxic, Metabolic, and Toxic Encephalopathies

Michael J. Aminoff, M.D., D.Sc.
University of California, San Francisco, School of Medicine

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Diffuse cerebral dysfunction
• Alterations in cortical function and disturbances of consciousness ranging from mild confusional states to coma
• Onset is often insidious
• Neurologic findings are symmetrical or multifocal in distribution
• Tremor, asterixis, and myoclonus are common
• Seizures, usually generalized but may be focal
• Focal or lateralizing signs are absent or inconsistent
• Usually caused by a systemic disorder that affects the brain diffusely

Anoxic Encephalopathies

• Circulatory arrest
• Disorders associated with cardiac procedures (e.g., cardiac catheterization, PTCA, CABG, cardiac transplantation)

• Respiratory diseases
  • Hypoxia
  • Hypercapnia
  • Hypocapnia
• Sepsis
• Liver diseases
  • Portosystemic encephalopathy
  • Chronic non-Wilsonian hepatocerebral degeneration
  • Liver transplantation
• Pancreatic encephalopathy
• Gastrointestinal diseases
• Renal failure
  • Dialysis disequilibrium syndrome
  • Dialysis dementia
  • Renal transplantation
• Electrolyte disturbances
  • Sodium: hyponatremia and hypernatremia
  • Potassium: hyperkalemia
  • Calcium: hypercalcemia, hypocalcemia
  • Magnesium: hypomagnesemia, hypermagnesemia
• Pituitary disease
  • Cushing disease
  • Hypopituitarism
  • Diabetes insipidus
• Thyroid disease: hyperthyroidism, hypothyroidism, Hashimoto disease
• Diabetes mellitus
• Hypoglycemia
• Nutritional deficiencies
  • Wernicke encephalopathy
  • Korsakoff encephalopathy
  • Subacute necrotizing encephalomyelopathy
  • Pellagra
  • Central pontine myelinolysis
  • Vitamin B₁₂ deficiency
  • Hyperalimentation

Toxic Encephalopathies

• Iatrogenic disorders
  • Drug overdose, as from hypnotics, sedatives, neuroleptics, antidepressants, anticonvulsants, analgesics
  • Complications of immunosuppressive and chemotherapeutic agents
  • Complications of transcatheter embolization and allogeneic bone marrow transplantation
  • Side effects of glucocorticoids, lidocaine, calcium channel blockers, beta blockers, digoxin, thiazide diuretics
• Alcohol-related disorders

Miscellaneous Encephalopathies

• Disseminated intravascular coagulation
• Connective tissue diseases and vasculitides
  • Polyarteritis nodosa
  • Allergic granulomatous angiitis (Churg-Strauss syndrome)
  • Overlap syndrome
  • Giant cell (temporal) arteritis
  • Wegener granulomatosis
  • Angiitis of the CNS
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Sjögren syndrome
  • Antiphospholipid antibodies

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Differential Diagnosis

• Neoplasm
• Infection
• Cerebrovascular disease
• Other disorders

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Best Tests

• History
  • Onset of neurologic symptoms—abrupt or gradual
  • Progression of symptoms since onset
  • Other symptoms and signs
  • Seizures
  • Diabetes mellitus
  • Alcoholism
• Physical examination
  • Jaundice, petechial hemorrhages, GI bleeding, ascites, or hypothermia may indicate hepatic dysfunction
  • Coarse facies, dry hair, or bradycardia suggests hypothyroidism
  • Acne, obesity, and hypertension suggest Cushing syndrome
  • Needle tracks in the skin suggest toxic encephalopathy
  • Hypertension suggests metabolic or ischemic disorder
  • Hypothermia suggests metabolic or toxic cause
• Neurologic examination
  • Signs of meningeal irritation suggest meningitis or subarachnoid hemorrhage
  • Focal neurologic deficit or increased intracranial pressure necessitates exclusion of intracranial mass lesion
  • Focal or lateralizing neurologic signs do not exclude metabolic or toxic encephalopathies
  • Evaluate mental status, including level of consciousness, orientation, behavior, language function, mood and affect, thought content, and memory
  • Evaluate cranial nerves, especially pupillary responses, and sensorimotor functions in the limbs, including tendon reflexes and plantar responses
    • Fixed dilated or poorly responsive pupils may indicate acute cerebral anoxia, intoxication with anticholinergic or sympathomimetic agents, or herniating intracranial mass lesion
    • Pinpoint pupils indicate opioid toxicity, organophosphate poisoning, use of miotic eyedrops, or pontine damage
    • Abnormal asymmetry of pupil size or responsiveness suggests structural brain stem (or cranial nerve) lesion; such symptoms are unlikely in metabolic and toxic encephalopathies
    • Preserved pupillary responses with impaired brain stem function strongly suggest metabolic or toxic disorders
    • In comatose patients, loss of oculovestibular responses may occur with structural pontine lesion or sedative intoxication; downward deviation of one or both eyes with unilateral cold-water stimulation strongly suggests sedative intoxication
• Laboratory tests
  • Serum glucose and electrolytes
  • Complete blood count and sedimentation rate
  • Liver and kidney function studies
  • Toxicity screen
  • Lumbar puncture (if meningitis or subarachnoid hemorrhage is suspected)
  • Arterial blood gas determinations (to distinguish among causes of metabolic encephalopathy)
• Imaging
  • CT scan of the head if focal intracranial lesion suspected
  • Chest radiography

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Best Therapy

• For all patients with encephalopathy of uncertain cause
  • Maintain adequacy of respiration and circulation
• For coma of acute onset and unknown cause
  • Dextrose, 25 g I.V. (to treat possible hypoglycemia)
  • Thiamine, 100 mg I.V. (to prevent or treat Wernicke encephalopathy)
  • Naloxone, 1 mg I.V. (to treat possible opiate overdose)
• Further investigation and treatment, depending on results of initial studies

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Best References

Ferenci P, et al: Hepatology 35:716, 2002 PMID 11870389

Giacino J, et al: J Head Trauma Rehabil 20:30, 2005 PMID 15668569

Wijdicks EF, et al: Mayo Clin Proc 80:1037, 2005 PMID 16092583

Wilson JX, et al: Can J Neurol Sci 30:98, 2003 PMID 12774948