Initial observation of the patient’s level of arousal, posture in bed, breathing pattern, vital signs, and behavioral fluctuations is highly suggestive of a metabolic disturbance in many cases. Waxing and waning levels of activity are the hallmark of metabolic encephalopathy and may occur over hours to days. Often signs of sympathetic overactivity (tachycardia, elevated blood pressure, tremulousness) and abnormal sleep patterns or “sun-downing” are present.

Mild behavioral changes are the earliest manifestations, such as lack of attentiveness to surroundings or a paucity of spontaneous speech, which may give the patient an apathetic or withdrawn appearance. The Mini-Mental State Examination easily reveals mild confusion and can be used to grade the patient’s level of cognitive performance sequentially [1]. When there is impaired consciousness, however, this test is unreliable.

The cranial nerve examination is focused on pupillary responses, oculomotor function, and respiratory patterns (Table 170.3). As a rule, pupils are small, symmetric, and responsive to light in metabolic causes of obtundation or coma. Noteworthy exceptions to this are anticholinergic poisoning (e.g., atropine, scopolamine), which produces dilated sluggish pupils, and glutethimide (Doriden) poisoning, which results in mid- to large-sized sluggish or fixed pupils [2]. Ocular movements are usually unaffected initially, with eyes in midline position or slightly deviated outward and upward at rest (Bell’s phenomenon). Doll’s eye maneuvers produce conjugate deviation of the eyes opposite to the direction of head rotation. As the level of brainstem suppression progresses to coma, these responses may disappear completely, especially with an overdose of sedative drugs. In the face of hyperpnea and decerebrate
rigidity, the preservation of doll’s eyes is a useful sign pointing to a metabolic, rather than anatomic, cause of coma.

Changes in the respiratory pattern are the next most important findings for the diagnosis of metabolic encephalopathy, also providing a clue as to its etiology. In the mildly confused patient, breathing may be normal, but lethargic or mildly obtunded patients tend to hyperventilate, with brief spells of apnea. This is due to transient lowering of the partial pressure of carbon dioxide (PCO₂) below 15 mm Hg without the appropriate CNS drive to breathe more rapidly at a lower tidal volume. After 12 to 30 seconds of apnea, the cycle of hyperventilation appears again, resulting in a pattern of “periodic respirations” [3]. Hypoventilation is usually seen with depressant drug overdoses, chronic pulmonary failure, and metabolic alkalosis of any cause. Cheyne-Stokes respiration, a rhythmic cycle of waxing and waning hyperpnea/apnea, is another pattern that is occasionally seen in metabolic encephalopathy caused by uremia or hypoxia, but more commonly this indicates bilateral structural lesions of the cortex. Other neurogenic respiratory patterns, such as constant or “central” neurogenic hyperventilation, cluster breathing, and ataxic breathing, are signs of brainstem dysfunction due to structural damage or suppression by barbiturates. These changes are seen only when the patient is stuporous or comatose. Abnormal motor activity is characteristic of many metabolic encephalopathies and is quite varied in appearance; tremors, myoclonus, asterixis, rigidity, and choreoathetosis may be seen. Tremors are rhythmic, involuntary oscillatory movements seen in all limbs and often exaggerated during voluntary movement. Tremors occur most often in early hypoglycemic encephalopathy, thyrotoxicosis, acute uremia, chronic dialysis encephalopathy, hypercapnia, and drug intoxication, especially with sympathomimetic agents.

Myoclonus is multifocal, appearing as brief shock-like contractions of large muscle groups. Synchronous myoclonic jerks in all limbs can be seen in any patient who is slipping in and out of a drowsy sleep—also known as sleep-onset myoclonus. This is often seen in patients who are receiving large doses of narcotics. Multifocal myoclonus, in contrast, is seen in hypoxic–ischemic encephalopathy, chronic hepatic failure of all types, uremia, pulmonary failure, and intoxication with methaqualone and psychedelic agents [4].

Asterixis is a flapping movement produced by unsustained muscle contraction against gravity. Rhythmic extension and flexion of the outstretched limb is present, which disappears at rest. The most common setting for this is in hepatic encephalopathy of any cause, frequently with flapping of the hands, feet, jaw, and tongue. Subacute uremia and pulmonary failure produce asterixis accompanied by myoclonus, which presents a picture of almost constant muscular jerking movements.

Rigidity or generalized muscle spasms are states of constant muscle contraction that are seen when the degree of metabolic encephalopathy is more severe and leads to stupor or coma. This can be the result of end-stage hepatic failure, hypoglycemia (< 25 mg glucose per dL) lasting more than a few minutes, acute renal failure, hyperthermia, and hypothermia below 92°F rectally. Rigidity with dystonic posturing is a clue to amphetamine or phenothiazine poisoning. Choreoathetosis, on the other hand, occurs in chronic hepatic failure, subacute bacterial endocarditis, post-hypoxic insult, Reye’s syndrome, chronic dialysis, chronic hypoglycemia, and chronic hyperparathyroidism, appearing as a nonpatterned sequence of twisting or dance-like limb movements.

The reflex examination often reveals diffuse hyperreflexia, symmetric except in limbs that were previously affected by a structural lesion. Plantar responses, also known as the Babinski reflex, are typically extensor in both feet and can be elicited easily. In contrast, the sensory examination is usually not affected, but is unreliable if the patient is agitated or obtunded. Response to pinprick, painful pinch/pressure, or a cold stimulus on the limbs is the most useful in demonstrating a grossly intact sensory arc.

Abnormal autonomic responses in metabolic encephalopathy may demand intervention and can cause significant morbidity and mortality. Hypotension, unresponsive to volume expansion, points to intoxication with barbiturates or opiates, myxedema, or Addisonian crisis. In this setting, occult sepsis must always be ruled out before treating for specific metabolic derangements. Fever and leukocytosis may be absent in very debilitated patients. Examination of urine, blood cell counts and coagulation factors, blood and sputum cultures, chest x-ray, and a lumbar puncture are essential to rule out infection. If there remains any doubt about the cause of hypotension, empiric antibiotics, naloxone hydrochloride (Narcan) for possible opiate overdose, intravenous (IV) glucose (1 ampoule), and pressor agents should be added to other supportive measures acutely while the cause is being investigated. Seizures are another significant symptom of metabolic encephalopathy, especially in uremia, hypoglycemia, pancreatic failure, and various types of metabolic acidosis (e.g., ethylene glycol, salicylates, and so forth). They occur most often at the onset of the metabolic disturbance, for example, as the blood urea nitrogen (BUN) is climbing acutely, and as a preterminal expression of severe neuronal injury in a comatose patient. Management of the seizures is typically ineffective until the underlying cause is corrected. In renal failure, however, one third to half of the standard loading doses of phenytoin or phenobarbital may be all that is needed to control seizures. The interictal electroencephalogram (EEG) serves as a guideline to the need for continued treatment once the encephalopathy has cleared or has become chronic and stable. A persistent focus of epileptiform activity warrants further investigation and anticonvulsant therapy.

The laboratory investigation of patients with delirium or coma is crucial in defining the cause of a metabolic encephalopathy. Blood tests for glucose, electrolytes, and blood gases should be drawn immediately along with a panel of hepatic function tests [ratio of serum alanine aminotransferase to serum aspartate aminotransferase, lactate dehydrogenase, ammonium ion (NH₄⁺)], BUN, and creatinine. Serum and urine osmolality, cerebrospinal fluid (CSF) analysis, serum magnesium and phosphate levels, and specific hormone levels may be needed to define the cause of encephalopathy further. Careful review of all medications taken before and during hospitalization may direct attention to toxicology screens of blood and urine. The general toxicology screen should be sensitive to opiates, benzodiazepines, caffeine and salicylates, theophylline, barbiturates, and alcohol. Additional drug levels should be ordered if their use is known or suspected (e.g., digoxin, cocaine, phenytoin, and so forth). If there has been a sudden change in mental status, a bolus of 25 g glucose should be administered intravenously without hesitation to avoid prolonged hypoglycemia.

In general, the EEG in metabolic encephalopathy is abnormal; background slowing is the most common pattern found (< 9 Hz) [5]. Other patterns can also be useful in identifying or corroborating the cause of the encephalopathy. Slow activity that is prominent frontally, with deep triphasic waves (in the 2- to 4-Hz range), is characteristic of hepatic encephalopathy but can be seen in renal failure too [6]. This has also been reported in levetiracetam toxicity [7], hyperammonemic states due to gastroplasty [8] and ureterosigmoidostomy [9], and rare metabolic disorders such as ornithine transcarbamylase deficiency [10]. Spreading of the slow activity toward the occipital leads is a sign of deepening coma in this setting. Bursts of high-voltage activity amidst normal background frequencies are also a sign of diffuse metabolic disturbance. More importantly, the EEG in a patient with an acute encephalopathy of unknown cause may reveal subclinical (electrical) status epilepticus,
warranting urgent and aggressive anticonvulsant treatment. This is particularly common in the case of alcoholics and diabetics, who are at risk for multiple CNS insults.

Neuroimaging [computed tomography (CT) or magnetic resonance imaging (MRI)] scans are often crucial in situations in which there is rapid deterioration of mental status without focal signs or an obvious metabolic cause such as hypoglycemia. Most mass lesions, such as subdural hematomas or brain tumors, are evidenced clinically by a rostrocaudal progression of neurologic signs. The initial picture may be nonfocal with obtundation, but this is followed sequentially by flexor or extensor posturing on one or both sides and then the loss of pupillary or caloric responses. Later, medullary respiratory patterns or bradycardia appear. A noncontrast head CT or MRI is definitive in many cases but does not always distinguish a brainstem stroke. Early consultation by a neurologist is crucial, especially when the cause of impaired consciousness is not clearly due to a metabolic disorder. Transient changes in vascular permeability associated with Wernicke’s encephalopathy can manifest as vasogenic edema in the brainstem periaqueductal and fourth ventricular areas along with contrast enhancement of the mammillary bodies [11].

Lumbar puncture is also indicated when there is a rapid onset of encephalopathy, especially with a fever, headache, or meningismus. Occult subarachnoid hemorrhage, infection, or elevated intracranial pressure may be found in the absence of funduscopic changes or clear-cut clinical history. Ideally, the lumbar puncture should be performed atraumatically with a small (22-gauge) spinal needle and a simultaneous sample of serum obtained to compare glucose and protein levels in the blood and CSF.

The clinical onset of hepatic encephalopathy may be subtle, with a blunting of affect and lethargy, or dramatic in 10% to 20%, with mania or an agitated delirium [12]. It is easy to recognize hepatic encephalopathy in an individual with the obvious stigmata of chronic liver disease, such as ascites, varices, or jaundice. In those without apparent liver disease, the mental changes may only appear after an additional metabolic demand on the liver. Such stressors are a high-protein meal, gastrointestinal bleeding with increased blood absorption from the gut, or hepatically metabolized drugs [13]. Sedatives and acetazolamide are particularly offensive in this situation.

Asterixis is the next most common clinical sign, appearing in all limbs, the jaw, and the tongue. As the patient progresses into a coma, it may be replaced by muscle spasticity and decorticate or decerebrate posturing to stimulation. The Babinski responses are present (extensor plantar reflexes), and gaze-evoked ocular movements are variable at this stage; pupillary responses are always preserved. Oculocephalic and vestibulo-ocular (caloric) responses remain until the patient is moribund. Hyperventilation is another consistent sign of hepatic encephalopathy and results in respiratory alkalosis. The ocular, pupillary, and respiratory patterns above help to distinguish severe hepatic encephalopathy from space-occupying lesions of the cortex and brainstem.

The pathophysiology of hepatic coma is not certain, but it is thought to be caused by portacaval shunting of neurotoxic substances. These putative toxins include excess ammonia, large molecules normally excluded by the blood–brain barrier [14], increased water, and the “false” neurotransmitter octopamine [15]. Hypoglycemia, as a result of decreased glycogen stores in the liver, may complicate the CNS picture.

The serum transaminases are usually elevated two- to threefold, and serum ammonia is at least in the high normal range once the patient is lethargic—with a linear correlation thereafter between higher laboratory values and lower cognitive state. The CSF remains normal until the serum bilirubin exceeds approximately 5 mg per dL, which tints the fluid yellow. The EEG characteristically shows progressive slowing from the frontal to the occipital leads as coma deepens. Triphasic waves are seen in most cases but are not pathognomonic.

Therapy for hepatic encephalopathy is directed toward decreasing the amount of toxic substances that are being shunted to the brain. Neomycin and lactulose help to sterilize and flush the gut. A protein-restricted diet and the exclusion of hepatically cleared drugs decrease the metabolic load, and IV glucose effectively maintains the serum glucose level. Neurologic recovery then depends on the capacity of the liver to regenerate at least 25% of its full function. With prolonged or repeated bouts of hepatic coma, there may be persistent, irreversible signs of basal ganglia dysfunction evidenced by chorea, postural tremors, or a parkinsonian picture (acquired hepatocerebral degeneration) [16].

Reye’s syndrome is a unique and quite morbid form of acute hepatic encephalopathy seen in children, usually between ages 1 and 10 years. It occurs in the clinical setting of an acute viral infection, for example, chickenpox or influenza A or B, plus aspirin therapy [17]. Approximately 4 to 7 days after the viral symptoms start, the child becomes irritable, with vomiting and sometimes with headache or blurred vision. An agitated delirium, combativeness, and progressive obtundation rapidly ensue over hours, followed by hyperventilation, pupillary dilatation, and generalized seizures. Later in the course decerebrate rigidity, Babinski responses, and papilledema may develop as well.

The pathology of Reye’s syndrome includes infiltration of the liver and other visceral organs with small fat droplets and diffuse cerebral edema. In cases that are complicated by severe hypoglycemia and seizures, anoxic damage with laminar necrosis of the cerebral cortex is also found. The cause of these changes is presumed to be mitochondrial poisoning, but the pathogenic agent has not yet been identified. Acetylsalicylic acid has consistently been implicated in this cellular damage. This has led to the standard practice of prescribing acetaminophen instead of aspirin for viral symptoms in children, thereby reducing the incidence of Reye’s syndrome [18].