Figure 78.1. Algorithm for the unresponsive patient.
* Tests for metabolic disorder: EEG, laboratory, cultures.
The general examination should be performed systematically. Vital signs can be helpful, e.g., fever (usually an inflammatory process that is systemic or in the central nervous system) or severe hypertension (raising the possibility of a hypertensive encephalopathy or pointing to underlying renal disease or drugs). Marked hypothermia in itself can produce coma, but can also be found in some septic patients and in myxedema coma, some with Wernicke’s encephalopathy and intoxications. Severe hypotension may relate to septic shock or adrenal failure/crisis. Examining the respiratory pattern, coupled with blood gas determination, can help narrow the diagnostic possibilities. For example, hyperventilation due to a metabolic acidosis limits the possibilities to renal failure, diabetic ketoacidosis, lactic acidosis, exogenous agents (e.g., methanol, ethylene glycol, and salicylates). Hyperventilation with respiratory alkalosis can occur with early sepsis or the initial phase of salicylate intoxication, acute pulmonary disease or hepatic failure. The general examination may also reveal the stigmata of chronic liver disease; needle tracks suggest drug intoxication or infection. Cherry-red lips imply carbon monoxide intoxication; fever and a cardiac murmur suggest bacterial endocarditis. A tongue bitten on its lateral aspect suggests a convulsive seizure. Purpuric lesions may be found in meningococcemia or thrombotic thrombocytopenic purpura.
Psychogenic unresponsiveness or pseudoseizures may also mimic acute encephalopathies. One looks for inconsistencies and normal findings on exam to help. A history of psychiatric illness also raises, but does not in itself establish, the possibility of non-organic brain disease.
Laboratory tests are helpful, but should be guided by the history and examination findings. As mentioned, blood gas determination is invaluable in cases of hyperventilation. For apparent diffuse encephalopathies the following are indicated: hemoglobin, white blood count and platelet count in the peripheral blood, serum electrolytes, calcium, magnesium, glucose, urea, creatinine and a screen for drugs (often guided by toxidromes). When indicated, liver function tests, blood cultures, thyroid and adrenal function, carboxyhemoglobin, and special hematological tests (screening for disseminated intravascular coagulation or TTP) should be conducted. Electroencephalography can be of great help in diagnosing nonconvulsive status epilepticus, which could mimic metabolic coma, as well as in helping to confirm the latter (e.g., trochaic waves are most commonly seen in hepatic of renal failure or with sepsis-associated encephalopathy). Periodic epileptiform discharges from the temporal lobes in the context of an acute febrile encephalopathy favors herpes simplex encephalitis. Lumbar puncture is indicated for meningitis and encephalitis and to confirm subarachnoid hemorrhage if the diagnosis is in doubt after neuroimaging. Neuroimaging with CT or MRI is helpful in ruling in or out structural brain lesions. TA classification of metabolic encephalopathies is provided in Table 78.1, which lists principal metabolic encephalopathies, along with some distinguishing clinical and laboratory features.
Encephalopathy | Distinguishing clinical features | Laboratory features |
Hepatic encephalopathy | Hyperventilation, jaundice, ascites | Abnormal liver function tests, increased INR (with acute liver failure), respiratory alkalosis, triphasic waves on EEG |
Hypoglycemia | Seizures, myoclonus, sweating, agitation progressing to stupor or coma | Serum glucose <2.5 mmol/l, MRI may show DWI changes in cerebral cortex, hypocampus, but sparing of thalamus and cerebellum |
Hyperglycemia | Often seizures and fluctuating signs in nonketotic hyperglycemia, hyperventilation in DKA | Serum glucose usually >20 mmol/l for coma |
Hyponatremia | Vomiting, seizures, focal signs (occasionally) | Cerebral edema, serum sodium often <120 mmol/l for severe encephalopathy; CPM if overly rapid correction |
Hypernatremia | Preceding dehydration (e.g., gastroenteritis), seizures | Serum Na usually >160 mmol/l for severe encephalopathy; brain shrinkage; subdural hematomas |
Hypermagnesemia | Profound weakness, parasympathetic paralysis | Serum Mg usually >2.5 mmol/l for severe encephalopathy |
Hypomagnesemia | Preceding muscle cramps, hyper-reflexia, seizures | Serum Mg usually <0.5 mmol/l for coma |
Hypophosphatemia | Seizures, myoclonus, profound weakness, coma often after refeeding nutritionally deprived individuals | Encephalopathy usually with serum PO4 <0.5 mmol/l |
Hypercarbia | May have papilledema with raised ICP, tremor, asterixis and myoclonus | PaCO2 usually >60 mmHg; pH <7.2 with acute respiratory failure with coma. |
Hypercalcemia | Preceding renal stones, bone pains | Serum Ca usually >3 mmol/l; findings associated with underlying cause, e.g., malignancies, hyperparathyroidism |
Hypocalcemia | Hyperexcitability, tremor, chorea, seizures | Symptomatic when serum Ca <0.5mmol/l |
Hyperthyroidism | Tachycardia, sweating; warm skin; tremor; goiter; ophthalmoparesis (e.g., inferior rectus deposits lead to impaired upgaze) | Elevated free T4 and T3, reduced TSH in serum |
Hypothyroidism | Hypothermia and bradycardia, thick tongue; pale, puffy skin, slow relaxation of DTRs | With primary thyroid failure: elevated TSH, low T4 and T3, elevated PaCO2, EEG is suppressed in voltage and slow in frequency |
Adrenal insufficiency | Hypotension, hyperpigmentation of gingivae and palmar creases | Hyperkalemia, hypoglycemia, low serum cortisol |
Septic encephalopathy | Paratonic rigidity, features of systemic inflammatory response syndrome, e.g. fever or hypothermia, tachycardia. | Increased WBC, evidence of infection or systemic inflammation; slowing or triphasic waves on EEG |
Uremic encephalopathy | With acute uremia, hyperexcitability, multifocal myoclonus, seizures | Elevated serum urea and creatinine |
Table 78.1. Principal metabolic encephalopathies.
78.3 Hepatic Encephalopathy
Hepatic encephalopathy can be divided into acute and chronic, two quite different disorders in terms of their underlying liver disease, clinical presentations and treatment. They will be discussed separately.
78.3.1 Acute Hepatic Encephalopathy
Acute liver failure is due to impaired hepatocellular function and develops within 6 months from onset; a subset, acute fulminant liver failure, develops over 8 weeks.
Acute liver failure is commonly due to acetaminophen poisoning, viral and auto-immune hepatitis, ecstasy and other toxins, liver infarction, Wilson’s disease, Bud-Chiari syndrome, acute fatty liver of pregnancy, lymphomatous infiltration, heat stroke and malignant hyperthermia are other causes.
Ammonia is still thought to play a key role in the pathogenesis of both acute and chronic hepatic encephalopathy, even though serum ammonia concentrations show at best only a crude correlation with the severity of brain dysfunction [1]. Glial swelling, related to increased glutamine production and mitochondrial toxicity, account for most of the cerebral edema. As a corollary, one should not be overly pessimistic when diffusion-weighted MRI scans show marked signal change in the cerebral cortex (Figure 78.2).
Acute hepatic failure most often presents in a dramatic fashion with rapid development of delirium or organic psychosis (Grade 1 hepatic encephalopathy is associated with an agitated delirium; Grade 2 is associated with blunting of consciousness) that can quickly progress to stupor (Grade 3 encephalopathy) and coma (Grade 4). Seizures can accompany severe or rapidly progressive disease. These features may occur so abruptly that they may precede the usual signs associated with liver failure, e.g., jaundice.
Cerebral edema is common with acute hepatic failure (most commonly the acute fulminant type). This can be life-threatening and needs to be detected and managed aggressively. We have found serial CT head scans to be an effective means of monitoring cerebral edema, especially if “baseline” CT head scans are done when the patient presents (before established encephalopathy) [2]. This is probably more practical and safer than intracranial pressure (ICP) monitoring, which shows rises only when compensatory mechanisms are exhausted. The main advantage of ICP monitoring is that allows for adjustment of blood pressure to allow a mean cerebral perfusion pressure of at least 60 mmHg. Intermittent hypertonic saline (rather than mannitol) with hypothermia are sometimes helpful, but hepatic transplantation should be considered in severe, rapidly progressive cases.
78.3.2 Chronic Hepatic Encephalopathy
Chronic hepatic failure, which takes over 8 months to become manifest, almost always relates to shunting of blood from the portal to the systemic circulation, bypassing the detoxifying effect of the liver on blood from the gut. Urea cycle abnormalities constitute a rare cause of chronic ammonia intoxication.
Chronic hepatic encephalopathy most often relates to varices (allowing portal-systemic shunting) associated with alcoholic and viral hepatitis, Wilson’s disease and transjugular intraheptic shunts (TIPS). Rarely urea cycle abnormalities produce hyperammonemia, which can produce a syndrome indistinguishable from encephalopathy due to liver dysfunction.
Cerebral edema is not as common with chronic hepatic encephalopathy as with the acute form, as the brain can compensate in the former. Severe exacerbations may be accompanied by seizures, coma and brain swelling, however.
Management consists of reducing ammonia production in the gut by limiting protein in the diet and the use of lactulose, detecting and treating precipitants (including gastrointestinal bleeding, intercurrent infections and electrolyte disturbances), using nonabsorbable antibiotics to kill bacteria in the gut and, in severe cases, hepatic transplantation. Sedative drugs should be avoided. Seizures are managed symptomatically; we have used various agents, but those without clearance by the liver, e.g., levetiracetam or gabapentin, have some advantages.
78.4 Uremic Encephalopathy
Central nervous system complications of uremia can be divided into direct effects of acute and chronic renal failure as well as side effects/complications of therapy (Table 78.2).
