Many drugs can cause confusional states, especially when taken in greater than customary doses, in combination with other drugs, by patients with altered drug metabolism from hepatic or renal failure, by the elderly, or in those with preexisting cognitive impairment. Evaluation of any patient with a confusional state should always include a thorough review of prescribed and over-the-counter medications. Recreational and psychotherapeutic drugs are the most likely to produce altered consciousness (Table 4-6).
Table 4-6.Drug-Induced Confusional States. ||Download (.pdf) Table 4-6. Drug-Induced Confusional States.
|Drug Class ||Examples ||Mechanism of Action ||Intoxication Syndrome1 ||Antidote |
|Level of Consciousness ||Respiratory Depression ||Pupils ||Eye Movements |
|Alcohols ||Ethanol ||GABAA receptor potentiator ||Depressed ||± ||Normal ||Nystagmus ||None |
|Sedatives || |
|GABAA receptor agonists ||Depressed or comatose ||+ ||Normal ||Impaired ||Flumazenil (benzodiazepines) |
|Opiates || |
|μ-Opiate receptor agonists ||Depressed or comatose ||+ ||Constricted ||Normal ||Naloxone |
|Anticholinergics ||Tricyclic antidepressants ||Muscarinic acetylcholine receptor antagonists ||Agitated ||— ||Dilated ||Normal ||Physostigmine |
|Sympathomimetics || |
|Catecholamine reuptake inhibitors and releasers ||Agitated ||— ||Dilated ||Normal || |
|Hallucinogens ||LSD ||Serotonin receptor agonists ||Agitated ||— ||Normal or dilated ||Normal ||None |
|Dissociative anesthetics || |
|NMDA receptor antagonists ||Euphoric, agitated, depressed, or comatose ||— ||Normal ||Nystagmus ||None |
|Entactogens ||MDMA (Ecstasy) ||Serotonin and dopamine reuptake inhibitors and releasers ||Euphoric ||— ||Dilated ||Nystagmus ||None |
|Synthetic cathinones (bath salts) || |
|Catecholamine reuptake inhibitors and releasers ||Agitated ||— ||Dilated ||Normal ||None |
|γ-Hydroxybutyrate and prodrugs || |
|γ-Hydroxybutyrate and GABAB receptor agonists ||Euphoric, agitated, depressed or comatose ||— ||Normal ||Normal ||None |
|Inhalants || |
|Unknown ||Euphoric, depressed, or comatose ||— ||Normal ||Normal ||None |
|Synthetic cannabinoids (Spice, K2) || |
|CB1 cannabinoid receptor agonists ||Agitated or depressed ||— ||Normal ||Normal ||None |
Ethyl alcohol (ethanol) intoxication produces a confusional state with nystagmus, dysarthria, and limb and gait ataxia. In nonalcoholics, signs correlate roughly with blood alcohol levels, but chronic alcoholics, who have developed tolerance, may have very high levels without appearing intoxicated. Laboratory studies useful in confirming the diagnosis include blood alcohol levels and serum osmolality, which exceeds the calculated osmolality (2 × serum sodium + 1/20 serum glucose + 1/3 serum urea nitrogen) by 22 mOsm/L for every 100 mg/dL of alcohol. Intoxicated patients are at high risk for head trauma and hypoglycemia, and chronic alcoholism increases the risk of bacterial meningitis. Alcohol intoxication requires no treatment unless a withdrawal syndrome ensues, but thiamine (200-500 mg three times daily by the intravenous route, for 3 days or until a normal diet is restored) should be given to prevent malnutrition-related Wernicke encephalopathy (discussed later in this chapter).
Three common withdrawal syndromes are recognized (Figure 4-1). Patients with these syndromes are also at risk for Wernicke encephalopathy and should be given thiamine.
Alcohol withdrawal syndromes in relation to the time since cessation of drinking. (Data from Victor M, Adams RD. The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis. 1952;32: 526-573.)
Tremulousness & Hallucinations
This self-limited condition occurs within 2 days after cessation of drinking and is characterized by tremulousness, agitation, anorexia, nausea, insomnia, tachycardia, and hypertension. Confusion, if present, is mild. Illusions and hallucinations, usually visual, occur in approximately 25% of patients. Lorazepam (1-4 mg) or diazepam (5-20 mg), given intravenously every 5-15 minutes until calm and hourly thereafter to maintain light sedation, will terminate the syndrome and prevent more serious consequences of withdrawal.
Alcohol withdrawal seizures occur within 48 hours of abstinence and within 7-24 hours in approximately two-thirds of cases. Roughly 40% of patients who experience seizures have a single seizure; more than 90% have between one and six seizures. In approximately 85% of cases, the interval between the first and last seizures is 6 hours or less. Treatment is not usually required, as seizures cease spontaneously in most cases, but lorazepam 2 mg intravenously may reduce the number of seizures that occur. Unusual features such as focal seizures, prolonged duration of seizures (>6-12 hours), more than six seizures, status epilepticus, or a prolonged postictal state should prompt a search for other causes or complicating factors, such as head trauma or infection. The patient should be observed for 6-12 hours after the onset of seizures to make certain that atypical features suggesting another cause do not develop.
This most serious ethanol withdrawal syndrome typically begins 3-5 days after cessation of drinking and lasts for up to 72 hours. It is characterized by confusion, agitation, fever, sweating, tachycardia, hypertension, and hallucinations. Death may result from concomitant infection, pancreatitis, cardiovascular collapse, or trauma. Treatment consists of lorazepam or diazepam as described previously for tremulousness and hallucinations and correction of fluid and electrolyte abnormalities and hypoglycemia, if present. β-adrenergic receptor blockade with atenolol (50-100 mg/d) may be useful for patients with persistent hypertension or tachycardia.
SEDATIVE DRUG INTOXICATION
Sedative drugs include barbiturates, benzodiazepines, propofol, methaqualone, glutethimide, and chloral hydrate. The distinctive clinical features of sedative drug intoxication are a confusional state or coma with respiratory depression, reactive pupils, and impaired eye movements. Other common findings include hypotension, hypothermia, nystagmus, ataxia, dysarthria, and hyporeflexia; decerebrate or decorticate posturing can also occur. The differential diagnosis of altered consciousness with impaired eye movements includes structural brainstem lesions, but these usually affect the pupils as well. Sedative drug ingestion can be confirmed by toxicologic analysis of blood, urine, or gastric aspirate, but blood levels of short-acting sedatives do not correlate with clinical severity.
Management is directed at supporting respiratory and circulatory function while the drug is being cleared, primarily by hepatic metabolism. Patients with benzodiazepine intoxication can also be treated with flumazenil, 1 to 5 mg intravenously over 2 to 10 minutes, repeated every 20 to 30 minutes as needed.
Complications of sedative drug intoxication include aspiration pneumonia, hypotension, and renal failure. However, barring such complications, patients who arrive at the hospital with adequate cardiopulmonary function should survive without sequelae.
Sedative drug withdrawal can produce confusional states, seizures, or a syndrome resembling delirium tremens. The likelihood and severity of these complications depend on the duration of drug intake and the dose and half-life of the drug, and are greatest in patients taking large doses of intermediate- or short-acting drugs for at least several weeks. Withdrawal syndromes typically develop 1 to 3 days after cessation of short-acting sedatives but may not appear until 1 week or more with longer-acting drugs. Sedative drug withdrawal can be confirmed by the failure of a normally sedating or hypnotic dose to produce signs of sedative drug intoxication (sedation, nystagmus, dysarthria, or ataxia). Symptoms and signs of withdrawal are usually self-limited, but myoclonus and seizures—most common in patients taking several times a drug’s sedative dose daily—may require treatment.
Opiates (narcotics) include morphine, heroin, codeine, hydromorphone, oxycodone, hydrocodone, meperidine, fentanyl, and methadone. These drugs can produce analgesia, mood changes, confusional states, coma, respiratory depression, pulmonary edema, nausea and vomiting, pupillary constriction, hypotension, urinary retention, and reduced gastrointestinal motility. Chronic use is associated with tolerance and physical dependence.
The cardinal features of opiate overdose are pinpoint pupils, which usually constrict in bright light, and respiratory depression. Pinpoint pupils can also occur in pontine hemorrhage, but opiate overdose can be distinguished by the patient’s response to the opiate antagonist naloxone and the preservation of horizontal eye movements. After administration of naloxone, pupillary dilation and full recovery of consciousness usually occur promptly. When large doses of opiates or multiple drug ingestions are involved, however, slight dilation of the pupils may be the only observable effect.
Treatment consists of intravenous administration of naloxone, 0.4-2.0 mg every 2-3 minutes, to a maximum of 10 mg. Ventilatory support is sometimes also required. An intranasal naloxone preparation is available but its effect is slower in onset. Because the action of naloxone may be as short as 1 hour—and many opiates are longer-acting—naloxone should be readministered as the patient’s condition dictates. With appropriate treatment, patients should recover uneventfully.
Muscarinic anticholinergic drugs are used to treat parkinsonism (eg, trihexyphenidyl), motion sickness (eg, dimenhydrinate), allergies (eg, diphenhydramine), gastrointestinal disturbances (eg, dicyclomine), and psychiatric disease (eg, antipsychotics, tricyclic antidepressants). Overdose with any of these agents can produce a confusional state with agitation, hallucinations, fixed and dilated pupils, blurred vision, dry skin and mucous membranes, flushing, fever, urinary retention, and tachycardia (Figure 4-2). In some cases, the diagnosis can be confirmed by toxicologic analysis of blood or urine. Symptoms usually resolve spontaneously, but treatment with the cholinesterase inhibitor physostigmine may be required if life-threatening cardiac arrhythmias occur. However, because physostigmine may produce bradycardia and seizures, it is rarely used.
Pupillary dilation and facial flushing in anticholinergic drug overdose. (Used with permission from Dodt C: Iatrogenic anticholinergic overdose. Dtsch Arztebl Int 2017; 114: 167.)
Sympathomimetics include cocaine, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, phentermine, fenfluramine, ephedrine, and antidepressants. Sympathomimetic intoxication can produce a confusional state with hallucinations, motor hyperactivity, stereotypic behavior, and paranoid psychosis. Examination shows tachycardia, hypertension, and dilated pupils. Hyperthermia, tremor, seizures, and cardiac arrhythmias may also occur, and cocaine or amphetamine use can be associated with stroke. Agitation is treated with benzodiazepines, psychosis with haloperidol, and hypertension with sodium nitroprusside or phentolamine.
Hallucinogens include lysergic acid diethylamide (LSD), psilocybin, mescaline, ibogaine, and bufotenin. They do not usually produce confusional states that come to medical attention, but may cause anxiety, panic, hypertension, hyperthermia, and seizures. Benzodiazepines can be used to treat anxiety.
Dissociative anesthetics include phencyclidine (PCP) and ketamine. Intoxication can produce drowsiness, agitation, disorientation, amnesia, hallucinations, paranoia, and violent behavior. Neurologic examination may show large or small pupils, horizontal and vertical nystagmus, ataxia, increased muscle tone, analgesia, hyperreflexia, and myoclonus. In severe cases, complications include hypertension, malignant hyperthermia, status epilepticus, coma, and death. Benzodiazepines may be useful for sedation and for treating muscle spasms, and antihypertensives, anticonvulsants, and dantrolene (for malignant hyperthermia) may be required. Symptoms and signs usually resolve within 24 hours.
Entactogens (also termed empathogens) are recreational drugs that evoke sensations of connectedness or empathy. Most, including MDMA (ecstasy), are amphetamine derivatives. Altered consciousness requiring medical attention is unusual, but jaw clenching, bruxism, and nystagmus are common, and adverse effects similar to those of hallucinogens (discussed previously) can occur. In addition, hyponatremia may result from a combination of drug-induced antidiuretic hormone release and polydipsia. Rhabdomyolysis and acute kidney injury are reported, and imaging studies are consistent with MDMA-induced damage to serotonergic nerve terminals in the brain.
Synthetic cathinones are analogs of a stimulant alkaloid found in the khat plant. They are related to amphetamines and found in preparations sold as “bath salts”. Clinical manifestations of cathinone intoxication include agitation, tachycardia, hypertension, and seizures. Psychosis and bizarre or violent behavior can occur.
γ-Hydroxybutyrate and its prodrugs (eg, γ-butyrolactone and 1,4-butanediol) are so-called date-rape drugs, sometimes used to induce rapid somnolence or unconsciousness in prospective victims. Bradycardia and myoclonus may occur. In addition to assault, adverse effects include vomiting with aspiration and depressed respiration.
These include volatile solvents (eg, glue), volatile nitrites (eg, amyl nitrite), anesthetics (eg, ether, chloroform, nitrous oxide), and propellants. Their pharmacologic actions are diverse, but most can produce euphoria followed by depression, and sometimes respiratory compromise. Withdrawal may be associated with irritability, anxiety, tremor, and seizures. There is no specific treatment.
Synthetic cannabinoids (eg, Spice, K2) are analogs of Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of marijuana, with more potent and purer agonist effects on CB1 cannabinoid receptors. As a consequence, they are much more likely than marijuana to produce adverse effects, including tachycardia, agitation, drowsiness, nausea, vomiting, and hallucinations.
ENDOCRINE & Metabolic DISORDERS
Hypoglycemia is an especially important cause of a confusional state, because its prompt recognition and treatment can prevent rapid progression from a reversible to an irreversible stage.
The most common cause of hypoglycemia is insulin overdose in diabetic patients (Table 4-7), but oral hypoglycemic drugs, alcoholism, malnutrition, hepatic failure, insulinoma, and non–insulin-secreting fibromas, sarcomas, or fibrosarcomas may also be responsible. Neurologic symptoms develop over minutes to hours. Although no strict correlation between blood glucose levels and the severity of neurologic dysfunction can be demonstrated, prolonged hypoglycemia at levels of 30 mg/dL or lower invariably leads to irreversible brain damage.
Table 4-7.Features of Hypo- and Hyperglycemic Encephalopathies. ||Download (.pdf) Table 4-7. Features of Hypo- and Hyperglycemic Encephalopathies.
| ||Hypoglycemia ||Diabetic Ketoacidosis ||Hyperosmolar Nonketotic State |
|Precipitating factors || |
|Blood glucose (mg/dL) ||<60 ||>250 ||>600 |
|Serum osmolality (mOsm/L) ||<300 ||<320 ||>320 |
|Ketosis ||– ||+ ||– |
|Metabolic acidosis ||– ||+ ||– |
|Confusion ||Common ||Uncommon ||Common |
|Focal neurologic signs ||+ ||– ||+ |
|Seizures ||+ ||– ||+ |
Early signs of hypoglycemia include tachycardia, sweating, and pupillary dilation, which may be followed by a confusional state with somnolence or agitation at blood glucose levels less than ~50 mg/dL and by coma at under ~30 mg/dL. Neurologic dysfunction progresses in a rostral-caudal fashion (see Chapter 3, Coma) and may mimic a mass lesion causing transtentorial herniation. Coma ensues with spasticity, extensor plantar responses, and decorticate or decerebrate posturing. Signs of brainstem dysfunction then appear, including abnormal eye movements and loss of pupillary reflexes. Respiratory depression, bradycardia, hypotonia, and hyporeflexia signal that irreversible brain damage is imminent. Hypoglycemic coma may be associated with focal neurologic signs and focal or generalized seizures.
The diagnosis is confirmed by measuring blood glucose levels, but intravenous glucose (50 mL of 50% dextrose) should be given immediately, without waiting for the blood glucose level to be measured. Improvement in the level of consciousness occurs within minutes after glucose administration in patients with reversible hypoglycemic encephalopathy. In hypoglycemia caused by sulfonylurea antidiabetic drugs (eg, tolbutamide, glipizide, or glyburide), administration of glucose may stimulate insulin secretion, antagonizing the therapeutic effect. In such cases, octreotide (50-75 μg subcutaneously or intravenously) should be given to inhibit insulin release. Doubt as to whether encephalopathy in a diabetic is due to hypoglycemia or hyperglycemia should never delay dextrose administration, since the consequences of worsening hyperglycemia are less dire than those of failing to treat hypoglycemia.
Two hyperglycemic syndromes, diabetic ketoacidosis (hyperglycemia, ketosis, and metabolic acidosis) and hyperosmolar nonketotic hyperglycemia (hyperglycemia and hyperosmolarity) (Table 4-7), can produce encephalopathy or coma, and may be the presenting manifestation of diabetes. Impaired cerebral metabolism, intravascular coagulation, and brain edema contribute to pathogenesis. Whereas the severity of hyperosmolarity correlates well with depression of consciousness, the degree of systemic acidosis does not.
Symptoms include blurred vision, dry skin, anorexia, polyuria, and polydipsia. Physical examination may show hypotension and other signs of dehydration, especially in hyperosmolar nonketotic hyperglycemia. Deep, rapid (Kussmaul) respiration characterizes diabetic ketoacidosis. Impairment of consciousness varies from mild confusion to coma. Focal neurologic signs and generalized or focal seizures are common in hyperosmolar nonketotic hyperglycemia. Laboratory findings are summarized in Table 4-7.
Treatment is with intravenous fluids, regular insulin, potassium (if <5 mmol/L in blood), and bicarbonate (if arterial blood pH < 6.9); antibiotics are added for concurrent infection. Fluids should be given as 0.9% saline (1-2 L over 1-2 hours), followed by 0.9% or 0.45% saline (250-500 mL/hour) until blood glucose reaches ~200 mg/dL, and then 5% dextrose in 0.9% saline. Regular insulin is administered as a bolus of 0.1 U/kg, followed by continuous infusion at 0.1 U/kg/h; this is reduced to 0.05 U/kg/h when blood glucose reaches ~250 mg/dL and adjusted thereafter to maintain blood glucose at ~200 mg/dL. Blood glucose, electrolytes, urea nitrogen, and pH should be followed closely. Mortality is <1% in diabetic ketoacidosis but 5-16% in hyperosmolar nonketotic hyperglycemia; causes include delayed treatment due to misdiagnosis, sepsis, cardiovascular complications, and renal failure.
The most common cause of hypothyroidism is Hashimoto thyroiditis. Symptoms and signs include fatigue, depression, weight gain, constipation, bradycardia, dry skin, and hair loss (Figure 4-3). Cognitive disturbances include flat affect, psychomotor retardation, agitation, and psychosis (myxedema madness); profound hypothyroidism can produce a confusional state, coma, or dementia. Findings on examination include hypothermia, dysarthria, deafness, and ataxia, but the most characteristic neurologic abnormality is delayed relaxation of the tendon reflexes. Untreated, hypothyroidism can progress to seizures, coma, and death.
Clinical features of hypothyroidism. The patient shows a lack of facial expression, together with pallor, dry skin, loss of hair in the lateral eyebrows, facial puffiness, and broadening of the nose. (Used with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill; 2007.)
Blood-test abnormalities include elevated thyroid-stimulating hormone (TSH) levels, low serum free tetraiodothyronine (T4) levels, and antithyroglobulin and antithyroperoxidase antibodies. Hypoglycemia, hyponatremia, and respiratory acidosis may be present. CSF protein is typically elevated, and CSF pressure is occasionally increased. Treatment is of the underlying thyroid disorder. With severe myxedema madness or coma (myxedema crisis), this involves administration of levothyroxine (T4; 500 μg, then 50-100 μg intravenously daily) and sometimes liothyronine (T3; 10-20 μg, then 10 μg intravenously every 4-6 hours for 48 hours), with hydrocortisone (100 mg, then 25-50 mg intravenously every 8 hours) for adrenal insufficiency, which often coexists.
Hyperthyroidism (thyrotoxicosis) is most often due to Graves disease and produces anxiety, palpitations, sweating, and weight loss. Physical examination may show goiter, warm moist skin, and pretibial myxedema. Acute exacerbation of hyperthyroidism (Figure 4-4) may cause a confusional state, coma, or death. In younger patients, agitation, hallucinations, and psychosis are common (activated thyrotoxic crisis), whereas those older than age 50 tend to be apathetic and depressed (apathetic thyrotoxic crisis). Seizures may occur. Neurologic examination shows exophthalmos, restricted eye movements, exaggerated physiologic action tremor, and hyperreflexia; ankle clonus and extensor plantar responses are rare. The diagnosis is confirmed by low serum TSH, elevated free T3, antithyroglobulin and antithyroperoxidase antibodies, and increased 123I uptake on thyroid scan. Treatments include propranolol 60 mg orally once or twice daily, increasing gradually to 320 mg daily; methimazole 30-60 mg orally daily or propylthiouracil 75-150 mg orally four times daily; iodinated contrast agents; radioactive iodine (unless ophthalmopathy is present); and thyroidectomy. Adjustments to treatment must be made for pregnant or lactating patients. Factors precipitating thyrotoxic crisis (eg, medications or tumors) should also be investigated and corrected.
Clinical features of hyperthyroidism. The patient shows (A) ophthalmopathy with exophthalmos (proptosis), and (B) pretibial myxedema. (Used with permission from Brunicardi CF, Andersen DK, Billiar TR, et al. Schwartz’s Principles of Surgery. 9th ed. New York: McGraw Hill, 2009.)
Causes of adrenocortical insufficiency include autoimmunity (Addison disease), tuberculosis, adrenal hemorrhage (Waterhouse–Friderichsen syndrome), and withdrawal from corticosteroids. Hypoadrenalism produces fatigue, weakness, weight loss, anorexia, hyperpigmentation of the skin, hypotension, nausea and vomiting, abdominal pain, and diarrhea or constipation. Neurologic manifestations include confusional states, seizures, or coma. Blood tests show decreased cortisol, sodium, glucose, and bicarbonate; increased potassium; and eosinophilia. Treatment of acute adrenocortical insufficiency is with hydrocortisone (100–300 mg intravenously in 0.9% saline, followed by 50–100 mg every 6 hours until oral replacement is possible), and correction of hypovolemia, hypoglycemia, electrolyte disturbances, and any precipitating illness.
Hyperadrenalism (Cushing syndrome) usually results from administration of exogenous glucocorticoids, but may also be due to ACTH-secreting pituitary adenomas (Cushing disease) or adrenal tumors. Clinical features include moon facies with facial flushing (Figure 4-5), truncal obesity, hirsutism, menstrual irregularities, hypertension, weakness, cutaneous striae, acne, and ecchymoses. Neuropsychiatric disturbances are common and include depression or euphoria, anxiety, irritability, memory impairment, psychosis, delusions, and hallucinations. The diagnosis can be confirmed by a dexamethasone suppression test, 24-hour urinary free cortisol, late night salivary cortisol assay, or midnight serum cortisol level. Measurement of serum adrenocorticotropic hormone (ACTH) distinguishes adrenal from pituitary causes of hyperadrenalism, and magnetic resonance imaging (MRI) is used to localize pituitary or other ACTH-secreting tumors. Treatment depends on the cause and includes tapering of exogenous corticosteroids, transphenoidal resection or stereotactic radiotherapy of pituitary adenomas, and laparoscopic resection of cortisol-secreting adrenal neoplasms or ectopic ACTH-secreting tumors.
Moon (round, full, puffy) facies and facial flushing in Cushing syndrome. (Used with permission from Wolff K, Johnson RA, Saavedra A, Roh E. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. 8th ed. New York, NY: McGraw-Hill; 2017.)
Hyponatremia (serum sodium <135 mEq/L), particularly when acute, produces brain swelling from hypoosmolality of the extracellular fluid and resulting water influx into cells. If uncorrected this can lead to brain herniation and death. Causes of acute (evolving over 24-48 hours) hyponatremia include psychogenic polydipsia, exercise-associated hyponatremia, and entactogen drugs (eg, ecstasy). Hyponatremia produces headache, lethargy, confusion, weakness, muscle cramps, nausea, and vomiting. Neurologic signs include confusional state or coma, papilledema, tremor, asterixis, rigidity, extensor plantar responses, focal or generalized seizures, and occasionally focal neurologic deficits. Neurologic complications are usually associated with serum sodium levels less than 120 mEq/L (Figure 4-6), but may be seen after a rapid fall to 130 mEq/L; conversely, chronic hyponatremia with levels as low as 110 mEq/L may be asymptomatic.
Relationship between serum sodium concentration and neurologic manifestations of hyponatremia. (Adapted with permission from Arieff AI, Llach F, Massry SG. Neurologic manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine. 1976;55:121-129.)
Treatment includes correction of the underlying cause of hyponatremia and administration of hypertonic (3%) saline to raise the serum sodium concentration to 125-130 mmol/L, at a rate not exceeding 4-6 mmol/L/d. Serum sodium should be monitored at ~2-h intervals. Furosemide (20 mg intravenously) may be added, but vasopressin receptor antagonists (eg, tolvaptan, conivaptan) have no established role in the treatment of acute or severe symptomatic hyponatremia. Excessively rapid correction of hyponatremia may lead to osmotic demyelination syndrome (formerly central pontine myelinolysis), a disorder of white matter characterized by a confusional state, paraparesis or quadriparesis, dysarthria, dysphagia, hyper- or hyporeflexia, and extensor plantar responses. Severe cases can result in the locked-in syndrome (see Chapter 3, Coma), coma, or death. MRI may show pontine and extrapontine white matter lesions. There is no treatment for osmotic demyelination syndrome, so prevention is essential and may best be achieved by adhering to the guidelines given above for gradual correction of hyponatremia.
Hypercalcemia may result from primary hyperparathyroidism (serum calcium ≥10.5 mg/dL or 2.6 mmol/L) or from neoplasms associated with bone metastases, especially lung cancer, breast cancer, or multiple myeloma (serum calcium ≥14 mg/dL or 3.5 mmol/L). Symptoms include thirst, polyuria, constipation, nausea and vomiting, abdominal pain, anorexia, and flank pain from nephrolithiasis. Neurologic symptoms are always present with serum calcium levels higher than ~17 mg/dL (8.5 mEq/L) and include headache, weakness, and lethargy.
Physical examination may show dehydration, abdominal distention, focal neurologic signs, myopathic weakness, and a confusional state that can progress to coma. Seizures are rare. The myopathy spares bulbar muscles, and tendon reflexes are usually normal. The diagnosis is confirmed by an elevated serum calcium level and sometimes by increased parathyroid hormone levels and a shortened QT interval on the electrocardiogram (ECG). Severe hypercalcemia in patients with normal cardiac and renal function is treated by vigorous intravenous hydration with 0.45% or 0.9% saline and usually requires central venous pressure monitoring. Bisphosphonates (eg, zoledronic acid) are added to treat hypercalcemia associated with malignancy.
Hypocalcemia (total serum calcium <8.5 mg/dL or 2.1 mmol/L; ionized calcium <4.6 mg/dL or 1.15 mmol/L) can be due to chronic kidney disease, hypoparathyroidism, hypomagnesemia, pancreatitis, or vitamin D deficiency. Symptoms include irritability, delirium, psychosis with hallucinations, depression, nausea and vomiting, abdominal pain, and paresthesias of the circumoral region and distal extremities. The most characteristic physical signs are those of overt or latent tetany. These include contraction of facial muscles in response to percussion of the facial (VII) nerve anterior to the ear (Chvostek sign) and carpopedal spasm (Figure 4-7), which may occur spontaneously or after tourniquet-induced limb ischemia (Trousseau sign). Cataracts and papilledema are sometimes present, and chorea is reported. Seizures or laryngospasm can be life threatening. The ECG may show a prolonged QT interval. Treatment of severe symptomatic hypocalcemia is with intravenous calcium gluconate, 10-15 mg/kg of elemental calcium over 4-6 hours followed by infusion to maintain serum calcium at 7-8.5 mg/dL. Concomitant magnesium deficiency should also be corrected. Seizures are sometimes treated acutely with phenytoin or phenobarbital, but long-term anticonvulsant therapy is not indicated.
Carpal spasm, a sign of tetany (neuronal hyperexcitability) in hypocalcemia. (Used with permission from Gardner DG, Shoback D. Greenspan’s Basic & Clinical Endocrinology, 8th ed. New York, NY: McGraw-Hill, 2007.)
Wernicke encephalopathy is usually a complication of chronic alcoholism, but can also result from gastrointestinal tract disease, hyperemesis gravidarum, malnutrition, bariatric surgery, cancer, or intravenous feeding. It is caused by deficiency of thiamine (vitamin B1). Pathologic features include neuronal loss, demyelination, and gliosis in periventricular gray matter. Proliferation of small blood vessels and petechial hemorrhages may be seen. The areas most commonly involved are the medial thalamus, mammillary bodies, periaqueductal gray matter, cerebellar vermis, and oculomotor, abducens, and vestibular nuclei.
The classic syndrome comprises the triad of ophthalmoplegia, ataxia, and confusional state. The most common ocular abnormalities are nystagmus, abducens (VI) nerve palsy, and horizontal or combined horizontal–vertical gaze palsy. Ataxia affects gait primarily, with ataxia of the arms and dysarthria uncommon. The mental status examination reveals global confusion with a prominent disorder of immediate recall and recent memory. The confusional state progresses to coma in a small percentage of patients. Most patients have associated neuropathy with absent ankle jerks. Hypothermia and hypotension may occur. Pupillary abnormalities, including mild anisocoria, or a sluggish reaction to light, are occasionally seen. The peripheral blood smear may show macrocytic anemia, and MRI may show atrophy of the mammillary bodies (Figure 4-8).
Coronal T1-weighted MRI with contrast showing abnormal enhancement of the mammillary bodies (arrows) in a patient with Wernicke encephalopathy. (Used with permission from Fauci A, Braunwald E, Kasper D, et al. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill, 2008.)
Treatment is prompt administration of thiamine, 500 mg intravenously, before or with dextrose (which, if given alone, can exacerbate the disorder). Parenteral thiamine is continued for several days. The maintenance requirement for thiamine, approximately 1 mg/d, is usually available in the diet, although enteric absorption of thiamine is impaired in alcoholics.
After treatment, ocular abnormalities usually begin to improve within 1 day and ataxia and confusion within 1 week. Ophthalmoplegia, vertical nystagmus, and acute confusion are entirely reversible, usually within 1 month. Horizontal nystagmus and ataxia, however, resolve completely in only approximately 40% of cases. The major long-term complication of Wernicke encephalopathy is Korsakoff syndrome (see Chapter 5, Dementia & Amnestic Disorders).
Vitamin B12 deficiency usually results from autoimmune destruction of gastric parietal cells leading to defective secretion of intrinsic factor (pernicious anemia); malabsorption due to achlorhydria, gastritis, gastrectomy, proton pump inhibitors, or H2 antihistamines; or dietary inadequacy in vegans or vegetarians. Neurologic abnormalities include polyneuropathy, subacute combined degeneration of the corticospinal tracts and dorsal columns of the spinal cord (combined systems disease), optic neuropathy, and cognitive dysfunction ranging from mild confusion to dementia or psychosis (megaloblastic madness).
The presentation is usually with macrocytic anemia or orthostatic lightheadedness but may also be neurologic. Distal paresthesias, gait ataxia, a bandlike sensation of tightness around the trunk or limbs, and Lhermitte sign (an electric shock-like sensation along the spine precipitated by neck flexion) may be present. Physical examination may show low-grade fever, glossitis, lemon-yellow discoloration of the skin, and cutaneous hyperpigmentation. Cerebral involvement produces confusion, depression, agitation, or psychosis with hallucinations. Spinal cord involvement causes impaired vibratory and joint position sense, sensory gait ataxia, and spastic paraparesis with extensor plantar responses. Associated peripheral nerve involvement may lead to loss of tendon reflexes in the legs and urinary retention.
Hematologic abnormalities in vitamin B12 deficiency (Figure 4-9) include macrocytic anemia, leukopenia with hypersegmented neutrophils, and thrombocytopenia with giant platelets. The diagnosis is based on detecting a serum cobalamin level <148 pmol/L or 200 ng/L, but folate levels must also be determined, because folate deficiency can confound vitamin B12 measurement and mimic hematologic features of vitamin B12 deficiency. Pernicious anemia can be distinguished from other causes of vitamin B12 deficiency by testing blood for anti-intrinsic factor antibodies, which are highly specific but insensitive; anti-parietal cell antibodies are too nonspecific to be diagnostically useful. T1-weighted MRI may show gadolinium enhancement of the posterior spinal cord in B12 myelopathy (discussed in Chapter 10, Sensory Disorders) and deep T2-signal abnormalities in B12 encephalopathy, which resolve with treatment.
Peripheral blood smear from a patient with vitamin B12 deficiency showing oval macrocytes (A) and hypersegmented neutrophil (B). (Used with permission from Kaushansky K, Lichtman M, Beutler E, Kipps T. Williams Hematology. 8th ed. New York, NY: McGraw-Hill, 2010.)
Treatment should begin as soon as blood is drawn to determine the vitamin B12 level. Cyanocobalamin is given by either the intramuscular route (1,000 μg immediately, then 8-10 times over the following 1-2 weeks, and then monthly for life) or orally (1,000-2,000 μg immediately, then daily for life), unless a correctable underlying cause is found. The reversibility of neurologic complications depends on their duration, and abnormalities present for more than 1 year are less likely to resolve with treatment. Encephalopathy may begin to clear within 24 hours after the first vitamin B12 dose, but full neurologic recovery, when it occurs, may take several months.
Hepatic encephalopathy occurs as a complication of alcoholic cirrhosis, portosystemic shunting, chronic active hepatitis, or fulminant hepatic necrosis after viral hepatitis. The syndrome may be chronic and progressive or acute in onset; in the latter case, gastrointestinal hemorrhage, systemic infection, dehydration, and sedative drugs are frequent precipitating factors. Liver disease impairs hepatocellular detoxifying mechanisms and causes portosystemic shunting of venous blood, leading to hyperammonemia. Cerebral symptoms may result from ammonia toxicity, cytotoxic edema, altered GABAergic neurotransmission, and inflammation.
Physical examination shows systemic signs of liver disease, such as jaundice, ascites, fetor hepaticus, gynecomastia, palmar erythema, spider angiomas, and caput medusae. Cognitive disturbances include somnolence, agitation, and coma. Ocular reflexes are usually brisk. Nystagmus, tonic downward ocular deviation, or disconjugate eye movements may be seen. A helpful indicator of metabolic disturbance (including, but not limited to, liver disease) is asterixis (Figure 4-10)—a flapping tremor of the outstretched, dorsiflexed hands or feet that results from impaired postural control. Other motor abnormalities in hepatic encephalopathy include tremor, myoclonus, paratonic rigidity, spasticity, decorticate or decerebrate posturing, and extensor plantar responses. Focal neurologic signs and focal or generalized seizures may occur.
Asterixis, a flapping tremor of the outstretched hands or feet, is often associated with hepatic encephalopathy, but can be seen in a variety of metabolic disorders.
Laboratory studies may show elevated serum bilirubin, transaminases, ammonia, prothrombin time (PT) and partial thromboplastin time (PTT); respiratory alkalosis; and elevated CSF glutamine. The electroencephalogram (EEG) may be diffusely slow with triphasic waves.
Underlying factors that may have precipitated acute decompensation should be corrected, and, when indicated, coagulopathy should be reversed with fresh-frozen plasma or vitamin K. Encephalopathy is treated with lactulose, a nonabsorbable disaccharide that decreases colonic pH and ammonia absorption (20-30 g orally 2-4 times daily, or 200 g in 1 L of saline rectally for 30-60 min every 4-6 hours), and rifaximin, a poorly absorbed antibiotic that reduces ammonia-forming bacteria in the colon (550 mg orally, twice daily). Dietary protein should not be severely restricted. Liver transplantation is required in some cases. Prognosis in hepatic encephalopathy correlates best with the severity of hepatocellular rather than neurologic dysfunction.
Renal failure, particularly when acute or rapidly progressive, may produce encephalopathy or coma with hyperventilation and prominent motor manifestations, including tremor, asterixis, myoclonus, and tetany. Focal or generalized seizures, focal neurologic signs, and decorticate or decerebrate posturing may occur. Laboratory abnormalities include elevated serum urea nitrogen, creatinine, and potassium and metabolic acidosis, but their severity correlates poorly with symptoms. The EEG is diffusely slow and may show triphasic waves or paroxysmal spikes or sharp waves.
Acute management includes relief of urinary tract obstruction if present, hydration, protein and salt restriction, and treatment of complications such as seizures. Long-term management includes dialysis or kidney transplantation. Although dialysis reverses the encephalopathy, clinical improvement often lags behind normalization of serum urea nitrogen and creatinine. Dialysis itself can produce an encephalopathy (dialysis disequilibrium syndrome) that is thought to result from hypo-osmolality leading to brain edema. This can be avoided by more gradual correction of uremia.
Patients with lung disease or brainstem or neurologic disorders that affect respiratory function may develop encephalopathy related to hypoventilation. Symptoms include headache, confusion, and somnolence. Examination shows papilledema, asterixis or myoclonus, and a confusional state or coma. Tendon reflexes are often decreased, but pyramidal signs may be present, and seizures occur occasionally. Arterial blood gases show respiratory acidosis. Treatment involves ventilatory support to decrease hypercapnia and maintain adequate oxygenation.
Bone-marrow or solid-organ transplantation may be associated with an acute confusional state related to surgical complications, immunosuppressive drug treatment, stroke, opportunistic infection, reconstitution of the immune system, lymphoproliferative disorders, or transplant rejection. The problems encountered depend on the time in relation to transplantation and on the organ transplanted.
Surgical complications that may produce encephalopathy include hypotension, hypoxia, thromboembolism, and air embolism, which are most common with heart and liver transplants.
Drugs used for pretransplantation conditioning or preventing transplant rejection can cause acute confusional states by direct effects on the nervous system or as a consequence of immunologic impairment. Calcineurin inhibitors (eg, cyclosporine, tacrolimus) produce encephalopathy that may be associated with seizures, tremor, visual disturbances, weakness, sensory symptoms, or ataxia. MRI may show abnormalities in the occipital and posterior parietal white matter (posterior reversible encephalopathy syndrome). Symptoms are often associated with excessively high drug levels in the blood and may improve with dosage reduction or substitution of mycophenolate mofetil or an mTOR inhibitor (eg, sirolimus, everolimus). Corticosteroids can produce psychosis, and corticosteroid withdrawal is sometimes associated with lethargy, headache, myalgia, and arthralgia. The monoclonal antibody muromonab-CD3 may cause encephalopathy, aseptic meningitis, and seizures. Busulfan can produce encephalopathy and seizures. Gabapentin, valproate, and leviracetam are recommended to treat seizures in transplant recipients because of their relative lack of pharmacokinetic interaction with other drugs typically given to these patients.
Infections causing confusional states are most prominent after bone marrow transplantation but are also common after transplantation of other organs. They are comparatively rare in the first month after transplantation and, when they occur, usually reflect preexisting infection in the recipient or in the donor organ, or a perioperative complication. Within this period, the most frequent organisms are gram-negative bacteria, herpes simplex virus, and fungi. Opportunistic infections are more common between 1 and 6 months after transplant and include acute Listeria meningitis or encephalitis, human herpes virus 6 limbic encephalitis, chronic meningitis from Cryptococcus or Mycobacterium tuberculosis, and brain abscesses related to infection with Aspergillus, Nocardia, or Toxoplasma. Past 6 months, varicella-zoster virus, progressive multifocal leukoencephalopathy, Toxoplasma, Cryptococcus, Listeria, or Nocardia infection may be seen.
Immune reconstitution inflammatory syndrome (IRIS) related to transplantation is typically seen following reduction of immunosuppressive therapy and institution of antibiotics for an opportunistic infection. Neurologic involvement may produce headache, increased intracranial pressure, and CSF pleocytosis. Treatment is with corticosteroids. A similar syndrome occurs in patients with human immunodeficiency virus infection receiving combination antiretroviral therapy.
Posttransplant lymphoproliferative disorder is related to immunosuppression and may be associated with primary central nervous system (CNS) lymphoma.
Transplant rejection may also produce encephalopathy, especially in recipients of kidney transplants.
MENINGITIS, ENCEPHALITIS, & SEPSIS
ACUTE BACTERIAL MENINGITIS
Acute bacterial meningitis is a leading cause of confusional states and one in which early diagnosis is crucial to a good outcome. Predisposing conditions include systemic (especially respiratory) or parameningeal infection, head trauma, anatomic meningeal defects, prior neurosurgery, cancer, alcoholism, and immunodeficiency states. The great majority of cases in adults are due to Streptococcus pneumoniae or Neisseria meningitidis infection, but the etiologic organism varies with age and with the presence of predisposing conditions (Table 4-8).
Table 4-8.Causes and Empirical Antibiotic Treatment of Acute Bacterial Meningitis. ||Download (.pdf) Table 4-8. Causes and Empirical Antibiotic Treatment of Acute Bacterial Meningitis.
|Age or Condition ||Etiologic Agents ||Antibiotics of Choice |
|Neonate || |
Ceftriaxone2 or cefotaxime3
|Child || |
Ceftriaxone2 or cefotaxime3
|Adult <50 y || |
Ceftriaxone5 or cefotaxime6
|Adult >50 y || |
Ceftriaxone5 or cefotaxime6
|Immunosuppression || |
Ceftriaxone5 or cefotaxime6
|Head trauma, neurosurgery, or CSF shunt || |
Bacteria typically gain access to the CNS by colonizing the mucous membranes of the nasopharynx, leading to local tissue invasion, bacteremia, and hematogenous seeding of the subarachnoid space. Listeria is an exception in that it is ingested. Bacteria can also spread to the meninges directly, through anatomic defects in the skull or from parameningeal sites such as the paranasal sinuses or middle ear. The low levels of antibody and complement present in the cerebrospinal fluid are inadequate to contain the infection. The resulting inflammatory response is associated with release of inflammatory cytokines that promote blood–brain barrier permeability, vasogenic cerebral edema, changes in cerebral blood flow, and perhaps direct neurocellular toxicity.
Acute bacterial meningitis is characterized by leptomeningeal and perivascular infiltration with polymorphonuclear leukocytes and an inflammatory exudate (Figure 4-11). These tend to be most prominent over the cerebral convexities in Streptococcus pneumoniae and Haemophilus infection and over the base of the brain with Neisseria meningitidis. Brain edema, hydrocephalus, and cerebral infarction may occur, although bacterial invasion of the brain parenchyma is rare.
Acute bacterial meningitis showing purulent exudate over the cerebral convexities. (Used with permission from Kemp WL, Burns DK, Brown TG. Pathology: The Big Picture. New York, NY: McGraw-Hill; 2008. Fig. 11-23A.)
At presentation, most patients have had symptoms for 1 to 7 days. These include fever, confusion, vomiting, headache, and neck stiffness, but the full syndrome is not usually present (Table 4-9).
Table 4-9.Findings in Acute Bacterial Meningitis. ||Download (.pdf) Table 4-9. Findings in Acute Bacterial Meningitis.
|Feature ||Percentage of Patients |
|Clinical findings |
|Headache1 ||87 |
|Neck stiffness1 ||83 |
|Fever (≥38°C)1 ||77 |
|Altered mental status1 ||69 |
|Focal neurologic deficit ||33 |
|Skin rash ||26 |
|Papilledema ||3 |
|At least 2 of classic tetrad (1above) ||95 |
|Neck stiffness + fever + altered mental status ||44 |
|Laboratory findings |
|CSF pressure >200 mm water ||82 |
|CSF WBC ≥100/μL ||92 |
|CSF WBC ≥1,000/μL ||78 |
|Positive blood culture ||66 |
|Abnormal head CT scan2 ||34 |
Physical examination may show fever and signs of systemic or parameningeal infection, such as skin abscess or otitis. A petechial rash is seen in 50% to 60% of patients with N. meningitidis meningitis (Figure 4-12). Signs of meningeal irritation (meningismus) are seen in approximately 80% of cases, but are often absent in the very young and very old, or with immunosuppression or profoundly impaired consciousness. These signs include neck stiffness on passive flexion, thigh flexion on flexion of the neck (Brudzinski sign), and resistance to passive extension of the knee with the hip flexed (Kernig sign) (see Figure 1-5). The level of consciousness, when altered, ranges from mild confusion to coma. Focal neurologic signs, seizures, and cranial nerve palsies may occur. Papilledema is rare.
Petechial skin rash in meningococcemia with meningococcal meningitis.
Peripheral blood may show polymorphonuclear leukocytosis from systemic infection or leukopenia caused by immunosuppression. The causative organism can be cultured from the blood in approximately two-thirds of cases. Images of the chest, sinuses, or mastoid bones may indicate a primary site of infection. A brain CT or MRI scan may show contrast enhancement of the cerebral convexities, the base of the brain, or the ventricular ependyma. The EEG is usually diffusely slow.
Prompt lumbar puncture and CSF examination are critical in all cases of suspected meningitis. CSF pressure is elevated in approximately 90% of cases, and the appearance of the fluid ranges from slightly turbid to grossly purulent. CSF white cell counts of 1,000 to 10,000/μL are usual, consisting chiefly of polymorphonuclear leukocytes, although mononuclear cells may predominate in Listeria monocytogenes meningitis. Protein concentrations of 100 to 500 mg/dL are most common. The CSF glucose level is lower than 40 mg/dL in approximately 80% of cases and may be too low to measure. Gram-stained smears of CSF identify the causative organism in 70% to 80% of cases. CSF culture, which is positive in approximately 80% of cases, provides a definitive diagnosis and allows determination of antibiotic sensitivity. The polymerase chain reaction is also useful, including for culture-negative or partially treated bacterial meningitis.
Signs of meningeal irritation may also be seen with nonbacterial meningitis and subarachnoid hemorrhage. However, the combination of an acute to subacute course (days rather than weeks), polymorphonuclear pleocytosis, and low CSF glucose point to a bacterial cause. Early viral meningitis can produce polymorphonuclear pleocytosis and symptoms identical to those of bacterial meningitis, but a repeat lumbar puncture after 6 to 12 hours should demonstrate a shift to lymphocytic predominance in viral meningitis, and the CSF glucose level is normal. Subarachnoid hemorrhage is distinctive in that lumbar puncture yields bloody CSF, which does not clear as increasing amounts of CSF are removed.
Vaccines are available for three bacteria that can cause meningitis: H. influenzae type b, N. meningitidis, and S. pneumoniae. Current recommendations for vaccination are listed in Table 4-10. The risk of contracting H. influenzae or N. meningitidis meningitis can be reduced in household and other close contacts of affected patients by prophylactic administration of rifampin 20 mg/kg/d orally given as a single daily dose for 4 days (H. influenzae) or as two divided doses for 2 days (N. meningitidis).
Table 4-10.Vaccines Against Acute Bacterial Meningitis. ||Download (.pdf) Table 4-10. Vaccines Against Acute Bacterial Meningitis.
|Agent ||Recommended Vaccination Schedule |
|H. influenzae type b ||Ages 2, 4, 6, and 12-15 months |
|N. meningitidis (serogroups A,C,W135,Y) ||Age 11-12 years |
|N. meningitidis (serogroup B) ||Age 16-18 years |
|S. pneumoniae || |
Ages 2, 4, 6, and 12-15 months
Age ≥ 65 years
Unless the physical examination shows focal neurologic abnormalities or papilledema, suggesting a mass lesion, lumbar puncture should be performed immediately; if the CSF is not clear and colorless, antibiotic treatment (see next paragraph) is started without delay. When focal signs or papilledema are present, blood and urine should be taken for culture, antibiotics begun, and a brain CT scan obtained. If the scan shows no focal lesion that would contraindicate lumbar puncture, the puncture is then performed.
The initial choice of antibiotics is empirical, based on the patient’s age and predisposing factors (see Table 4-8). Therapy is adjusted as indicated when the Gram stain, PCR, or culture and sensitivity results become available (Table 4-11). Lumbar puncture can be repeated to assess the response to therapy. CSF should be sterile after 24 hours, and a decrease in pleocytosis and in the proportion of polymorphonuclear leukocytes should occur within 3 days.
Table 4-11.Treatment of Acute Bacterial Meningitis of Known Cause. ||Download (.pdf) Table 4-11. Treatment of Acute Bacterial Meningitis of Known Cause.
|Etiologic Agents ||Antibiotics of Choice ||Treatment Duration |
|CSF Gram stain |
|Gram-positive cocci || |
Ceftriaxone2 or cefotaxime3
|Gram-negative cocci ||Penicillin G5 ||4 |
|Gram-positive bacilli || |
Ampicillinf or penicillin G5
|Gram-negative bacilli || |
Ceftriaxone,2 cefotaxime,3 or ceftazidime,8
|CSF culture or PCR |
|S. pneumoniae || |
Ceftriaxone2 or cefotaxime3
|10-14 days |
|H. influenzae ||Ceftriaxone2 ||7 days |
|N. meningitidis ||Penicillin G5 ||7 days |
|L. monocytogenes || |
|21 days |
|S. agalactiae ||Penicillin G5 ||14-21 days |
|Gram-negative enteric bacilli || |
Ceftriaxone2 or cefotaxime3
|21-28 days |
|Pseudomonas aeruginosa, Acinetobacter || |
|21-28 days |
|Actinomyces israelii ||Penicillin G9 ||6-12 months |
|Nocardia species || |
|12 months |
Dexamethasone, given immediately before the onset of antibiotic treatment and continued for 4 days, may improve outcome and decrease mortality in immunocompetent patients with confirmed bacterial meningitis.
Complications of acute bacterial meningitis include headache, seizures, hydrocephalus, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), residual neurologic deficits (including cognitive disturbances and cranial—especially VIII—nerve abnormalities), and death. A CT or MRI scan will confirm suspected hydrocephalus, and fluid and electrolyte status should be carefully monitored to detect SIADH. N. meningitidis infections may be complicated by adrenal hemorrhage related to meningococcemia (Waterhouse–Friderichsen syndrome), resulting in hypotension and often death.
Morbidity and mortality from acute bacterial meningitis are high. Fatalities occur in approximately 20% of affected adults, and more often in low-income countries and with some pathogens (eg, S. pneumoniae, gram-negative bacilli) compared to others (eg, H. influenzae, N. meningitidis). Factors that worsen prognosis include extremes of age, delay in diagnosis and treatment, complicating illness, stupor or coma, seizures, and focal neurologic signs.
Tuberculous meningitis should be considered in patients who present with a confusional state, especially if there is a history of pulmonary tuberculosis, alcoholism, corticosteroid treatment, HIV infection, or other conditions associated with impaired immune responses. It should also be considered in patients from regions (eg, Asia, Africa) or groups (eg, the homeless and inner-city drug users) with a high incidence of tuberculosis.
Tuberculous meningitis usually results from reactivation of latent infection with Mycobacterium tuberculosis. Primary infection, typically acquired by inhaling bacillus-containing droplets, may be associated with metastatic dissemination of blood-borne bacilli from the lungs to the meninges and the surface of the brain. Here the organisms remain in a dormant state in tubercles that can rupture into the subarachnoid space at a later time, resulting in tuberculous meningitis.
The main pathologic finding is a basal meningeal exudate containing primarily mononuclear cells (Figure 4-13). Tubercles may be seen on the meninges and surface of the brain. The ventricles may be enlarged as a result of hydrocephalus, and their surfaces may show ependymal exudate or granular ependymitis. Arteritis can result in cerebral infarction, and basal inflammation and fibrosis can compress cranial nerves.
Basilar meningitis showing inflammatory exudate surrounding cranial nerves and blood vessels at the base of the brain, as seen in tuberculous or fungal meningitis. (Used with permission from Kemp WL, Burns DK, Brown TG. Pathology: The Big Picture. New York, NY: McGraw-Hill; 2008. Fig 11-25.)
Symptoms usually have been present for less than 4 weeks at the time of presentation and include headache, fever, neck stiffness, vomiting, and lethargy or confusion. Weight loss, visual impairment, diplopia, focal weakness, and seizures may also occur. A history of contact with known cases of tuberculosis is usually absent.
Fever, signs of meningeal irritation, and a confusional state are the most common findings on physical examination, but all may be absent. Papilledema, ocular palsies, and hemiparesis or paraparesis are sometimes seen. Complications include hyponatremia, hydrocephalus, brain edema, visual loss, cranial nerve (especially III, IV, and VI) palsies, spinal subarachnoid block, and stroke, which usually affects the internal capsule, basal ganglia, or thalamus.
Only one-half to two-thirds of patients show a positive skin test for tuberculosis or evidence of active or healed tubercular infection on chest X-ray; chest CT is more sensitive. The diagnosis is established by CSF analysis. CSF pressure is usually increased, and the fluid is typically clear and colorless. Lymphocytic and mononuclear cell pleocytosis of 50 to 500 cells/mL is most often seen, but polymorphonuclear pleocytosis can occur early and may give an erroneous impression of bacterial meningitis. CSF protein is usually more than 100 mg/dL and may exceed 500 mg/dL, particularly in patients with spinal subarachnoid block. The glucose level is usually decreased and may be less than 20 mg/dL. Acid-fast bacillus (AFB) smears of CSF (Figure 4-14) should be performed in all cases of suspected tuberculous meningitis, but they are positive in only a minority of cases. PCR of CSF is diagnostically helpful. Culturing M. tuberculosis from the CSF usually takes several weeks and requires large quantities of spinal fluid for maximum yield, so it is useful in confirming a presumptive diagnosis of tuberculous meningitis, but not in deciding to begin treatment. A CT or MRI scan may show enhancement of the basal cisterns and cortical meninges or hydrocephalus.
Acid-fast bacillus (AFB) stain showing Mycobacterium tuberculosis bacilli (red rods).
Many other conditions can cause a subacute to chronic confusional state with mononuclear cell pleocytosis (Table 4-12). These can usually be distinguished based on the history, associated physical findings, and appropriate laboratory studies.
Table 4-12.Causes of Chronic Meningitis. ||Download (.pdf) Table 4-12. Causes of Chronic Meningitis.
|Cause ||Features |
|Bacteria || |
| Partially treated acute bacterial meningitis ||History of antibiotic treatment |
| Tuberculosis ||Positive CSF acid-fast stain and AFB culture |
| Syphilis ||Positive CSF VDRL |
| Lyme disease ||History of tick bite, erythema migrans, facial (VII) nerve palsy, painful polyradiculopathy, positive serology |
| Leptospirosis ||Myalgia, conjunctival reddening, positive serology |
| Brucellosis ||Exposure to livestock, enzootic areas |
| Mycoplasma ||Cough, abnormal chest X-ray |
|Viruses (HIV, EBV, HSV2) ||Positive HIV or EBV serology, Mollaret cells in CSF (HSV2) |
|Fungi ||Positive CSF India ink stain, cryptococcal antigen, or CSF culture |
|Parasites ||Blood smear (malaria), peripheral or CSF eosinophilia, CT or MRI scan (toxoplasmosis, cysticercosis), positive serology |
|Parameningeal infection ||Sinusitis, otitis, dental infection, CSF leak |
|Neoplastic meningitis ||Low CSF glucose, positive cytology |
|Chemical meningitis || |
| Subarachnoid hemorrhage ||CSF xanthochromia |
| Drugs (NSAIDs, antimicrobials, IVIG, immunosuppressants, allopurinol, lamotrigine, intrathecal agents, vaccination) ||History of treatment |
|Uveomeningitis1 || |
| Sarcoidosis ||Erythema nodosum, dyspnea, facial (VII) nerve palsy, hilar adenopathy, positive biopsy |
| Behçet syndrome ||Painful orogenital ulcers, erythema nodosum-like skin lesions, abducens (VI) nerve palsy, ataxia, corticospinal signs |
| Wegener granulomatosis ||Upper and lower respiratory tract disease, glomerulonephritis, cranial neuropathy, mononeuritis multiplex |
| Vogt–Koyanagi–Harada syndrome ||Deafness, tinnitus, alopecia, poliosis, vitiligo |
| Sjögren syndrome ||Xerostomia, xerophthalmia, trigeminal (V) neuropathy, positive Schirmer test, positive ANA (SSB/La), lip biopsy |
|Fabry disease ||Exercise-induced neuropathic pain, periumbilical angiokeratomas, stroke |
|Hypertrophic pachymeningitis ||Cranial neuropathies |
Treatment should be started as early as possible; it should not be withheld while awaiting culture results. The decision to treat is based on the CSF findings described previously; lymphocytic pleocytosis and decreased glucose are particularly suggestive, even if AFB smears are negative.
Four antituberculous drugs are used for the 2-month initiation phase of therapy: isoniazid 300 mg, rifampin 600 mg, pyrazinamide 1,500 mg, and ethambutol 1,200 mg, each given orally once daily. During the subsequent, 7- to 12-month continuation phase, only isoniazid and rifampin are used, at the same doses. Adverse drug effects, drug resistance, concurrent HIV infection, and pregnancy may necessitate modifying the treatment regimen. Pyridoxine 50 mg/d can decrease the likelihood of isoniazid-induced polyneuropathy or seizures.
Corticosteroids (eg, prednisone, 60 mg/d orally, tapered gradually over 3-4 weeks) reduce mortality from tuberculous meningitis. Aspirin 75-150 mg/d may confer an additional anti-inflammatory effect. Antifungal therapy (see later) should be added unless fungal meningitis has been excluded. Ventriculoperitoneal shunting or endoscopic third ventriculostomy can be useful to relieve hydrocephalus. Treatment of tuberculous meningitis in patients with HIV infection is similar except that the benefit of corticosteroids is less clearly established. Delaying the onset of retroviral therapy for 2 months after beginning treatment of tuberculous meningitis in patients with HIV infection yields a similar rate of survival with fewer adverse effects.
Even with appropriate treatment, approximately one-third of patients with tuberculous meningitis succumb. Adverse prognostic factors include age less than 5 or more than 50 years, coma, seizures, and concomitant HIV infection. Neurologic sequelae include cognitive disturbances, visual loss, motor deficits, and cranial nerve palsies.
Syphilitic meningitis usually occurs within 2 years after primary syphilitic infection. It is most common in young adults, and patients with HIV infection are at particular risk for developing this and other forms of neurosyphilis.
In approximately one-fourth of patients with Treponema pallidum infection, treponemes gain access to the CNS, where they produce meningitis that is usually asymptomatic. Asymptomatic neurosyphilis is associated with CSF pleocytosis, elevated protein, and positive serologic tests for syphilis.
In a few patients, syphilitic meningitis is a clinically apparent acute or subacute disorder. At presentation, symptoms such as headache, nausea and vomiting, stiff neck, mental disturbances, focal weakness, seizures, deafness, and visual impairment usually have been present for up to 2 months.
Physical examination may show signs of meningeal irritation, confusion or delirium, papilledema, hemiparesis, and aphasia. The cranial nerves most frequently affected are (in order) the facial (VII), acoustic (VIII), oculomotor (III), trigeminal (V), abducens (VI), and optic (II) nerves, but other nerves may be involved as well. Fever is typically absent.
The diagnosis is established by CSF findings. Opening pressure is normal or slightly elevated. Pleocytosis is lymphocytic or mononuclear in character, with white blood cell counts usually in the range of 100 to 1,000/mL. Protein level may be mildly or moderately elevated (<200 mg/dL) and glucose mildly decreased. CSF Venereal Disease Research Laboratory (VDRL) and serum fluorescent treponemal antibody (FTA) or microhemagglutination-Treponema pallidum (MHA-TP) tests are usually positive. Protein electrophoretograms of CSF may show discrete γ-globulin bands (oligoclonal bands) not visible in normal CSF.
Syphilitic meningitis is usually a self-limited disorder, but treatment is required to avoid more advanced vascular and parenchymatous neurosyphilis (tabes dorsalis, general paresis, optic neuritis, myelitis). Treatment is with aqueous penicillin G 2 to 4 × 106 units intravenously every 4 hours for 10 to 14 days. For penicillin-allergic patients, ceftriaxone 2 g intravenously daily for 14 days or doxycycline 200 mg orally twice daily for 21 to 28 days can be substituted. The CSF should be examined every 6 months until all findings are normal. Another course of therapy must be given if the CSF cell count or protein remains elevated.
Lyme disease is a tick-borne disorder due to infection with the spirochete Borrelia burgdorferi (or, outside the United States, other Borrelia species). Most cases occur during the summer. Primary infection may be manifested by an expanding erythematous annular skin lesion (erythema migrans) (Figure 4-15), which usually appears 1-2 weeks after detachment of the tick (Ixodes scapularis or Ixodes pacificus). Less distinctive symptoms include fatigue, headache, fever, neck stiffness, joint or muscle pain, anorexia, sore throat, and nausea. Neurologic involvement (neuroborreliosis), which occurs in 10-15% of cases, may be delayed for up to 10 weeks. It is characterized by meningitis or meningoencephalitis and disorders of the cranial or peripheral nerves or nerve roots; bilateral facial weakness from involvement of cranial nerve VII is particularly common. Cardiac abnormalities (conduction defects, myocarditis, pericarditis, cardiomegaly, or heart failure) can also occur at this stage. Lyme meningitis produces prominent headache accompanied by signs of meningeal irritation, photophobia, pain when moving the eyes, nausea, and vomiting. When encephalitis is present, it is usually mild and characterized by insomnia, emotional lability, or impaired concentration and memory. European Lyme disease differs clinically from that seen in the United States in that the infective organism is Borrelia garinii or Borrelia afzelii, erythema migrans is not a feature, and painful radiculopathy (Bannwarth syndrome) is common.
Erythema migrans due to Borrelia burgdorferi (Lyme disease). (Used with permission from James Gathany, Public Health Image Library, US Centers for Disease Control and Prevention.)
The CSF usually shows a lymphocytic pleocytosis with 100 to 200 cells/mL, slightly elevated protein, and normal glucose. Oligoclonal immunoglobulin G (IgG) bands may be detected. Definitive diagnosis is usually made by serologic testing for B. burgdorferi, using enzyme-linked immunosorbent assay (ELISA) for screening followed by western blot to confirm positive ELISA results.
Preventive measures include avoiding tick-infested areas and using insect repellents and protective clothing when avoidance is impossible. Treatment of Lyme disease with neurologic involvement is with ceftriaxone (2 g/d intravenously) or doxycycline (100 mg/d orally) for 2 to 3 weeks.
Symptoms of acute Lyme disease typically resolve within 10 days in treated cases. Untreated or inadequately treated infections may lead to recurrent oligoarthritis; memory, language, and other cognitive disturbances; focal weakness; and ataxia. In such cases, a CT scan or MRI may show hydrocephalus, lesions in white matter resembling those seen in multiple sclerosis, or abnormalities suggestive of cerebral infarction. Subtle chronic cognitive or behavioral symptoms should not be attributed to Lyme encephalitis in the absence of serologic evidence of B. burgdorferi exposure, CSF abnormalities, or focal neurologic signs. The peripheral neurologic manifestations of Lyme disease are discussed in Chapter 10, Sensory Disorders.
VIRAL MENINGITIS & ENCEPHALITIS
Viral infections of the meninges (meningitis), brain parenchyma (encephalitis), or both (meningoencephalitis) often present as acute confusional states. The most common causative agents are listed in Table 4-13. Clues in the history that suggest a specific virus or virus family include the time of year, recent travel, contact with insects or other animals, sexual contacts, and immunosuppression. Some viruses (eg, herpesviruses) can cause either meningitis or encephalitis, but others preferentially affect the meninges (eg, enteroviruses) or brain parenchyma (eg, many arthropod-borne—or arbo—viruses). Herpes simplex and human immunodeficiency virus infections have special features that merit distinct consideration, and are therefore discussed separately.
Table 4-13.Causes of Viral Meningitis and Encephalitis. ||Download (.pdf) Table 4-13. Causes of Viral Meningitis and Encephalitis.
| ||Virus ||Season or Geography ||Vector ||Features |
|Enterovirus ||Echo, coxsackie, enterovirus 71 ||Summer, fall ||Human ||Rash, gastroenteritis, carditis |
|Herpesvirus ||Herpes simplex type 2 (HSV2) ||— ||Human ||Neonates |
| ||Varicella-zoster virus (VZV) ||— ||Human ||Immunosuppression; rash |
| ||Epstein–Barr virus (EBV) ||— ||Human ||Teenagers; infectious mononucleosis syndrome |
|Arbovirus ||West Nile ||Summer ||Mosquito ||May also cause encephalitis, flaccid paralysis |
| ||Toscana ||Southern Europe ||Sandfly ||May also cause encephalitis |
| ||Tick-borne ||Eurasia ||Tick ||May also cause encephalitis |
|Other ||Human immunodeficiency virus (HIV) ||— ||Human ||Immunosuppression |
| ||Mumps ||Winter, spring ||Human ||Especially boys; parotitis, orchitis, oophoritis, pancreatitis |
| ||Lymphocytic choriomeningitis ||Fall, winter ||Mouse ||Pharyngitis, pneumonia; marked CSF pleocytosis, low CSF glucose; transmissible by organ transplantation |
|Herpesvirus ||Herpes simplex type 1 (HSV1) ||— ||Human ||Focal (especially temporal lobe); treatable with acyclovir |
| ||Varicella-zoster virus (VZV) ||— ||Human ||Immunosuppression; rash |
| ||Epstein–Barr virus (EBV) ||— ||Human ||Teenagers; infectious mononucleosis syndrome |
|Arbovirus ||Japanese ||Asia ||Mosquito ||Common; vaccine available; high mortality |
| ||St. Louis ||Western hemisphere ||Mosquito ||Common in US |
| ||California ||North America ||Mosquito ||Common in US; includes La Crosse encephalitis |
| ||Western equine ||Western hemisphere ||Mosquito ||Children |
| ||Eastern equine ||Western hemisphere ||Mosquito ||Children |
| ||Venezuelan equine ||Western hemisphere ||Mosquito ||Children |
| ||Powassan ||Northeast US ||Tick ||Seizures (in children), focal neurologic signs |
| ||Dengue ||Southeast Asia, Western Pacific ||Mosquito ||May cause hemorrhagic fever |
| ||Chikungunya ||Africa ||Mosquito ||Arthralgia |
| ||Zika ||Pacific Islands, Americas ||Mosquito ||May also cause microcephaly & Guillain–Barré syndrome; can be sexually transmitted |
|Other ||Rabies ||— ||Dog, bat, raccoon, skunk, fox ||Postexposure prophylaxis available; fatal once symptoms (hyperexcitability, autonomic dysfunction, hydrophobia) appear |
| ||Ebola ||West Africa ||Human, bat ||Vomiting, diarrhea, hemorrhage, persistent neurologic deficits |
Viral infections can affect the CNS in three ways—hematogenous dissemination of a systemic viral infection (eg, arthropod-borne viruses), neuronal spread of the virus by axonal transport (eg, herpes simplex, rabies), and autoimmune postinfectious demyelination (eg, varicella, influenza). Pathologic changes in viral meningitis consist of an inflammatory meningeal reaction mediated by lymphocytes. Encephalitis is characterized by perivascular cuffing, lymphocytic infiltration, and microglial proliferation mainly involving subcortical gray matter regions. Intranuclear or intracytoplasmic inclusions are often seen.
Clinical manifestations of viral meningitis include fever, headache, neck stiffness, photophobia, pain with eye movement, and mild impairment of consciousness. Patients usually do not appear as ill as those with bacterial meningitis. Systemic manifestations of viral infection, including skin rash, pharyngitis, lymphadenopathy, pleuritis, carditis, jaundice, organomegaly, diarrhea, or orchitis, may suggest a particular etiologic agent. Viral encephalitis, which involves the brain directly, causes more marked alteration of consciousness than viral meningitis, and may also produce seizures and focal neurologic signs.
CSF analysis is the most important laboratory test. CSF pressure is normal or increased, and a lymphocytic or monocytic pleocytosis is present, with cell counts usually less than 1,000/mL. Higher counts can be seen in lymphocytic choriomeningitis or herpes simplex encephalitis. A polymorphonuclear pleocytosis can occur early in viral meningitis, whereas red blood cells may be seen with herpes simplex encephalitis. Protein level is normal or slightly increased (usually 80-200 mg/dL). Glucose is usually normal, but may be decreased in mumps, herpes zoster, or herpes simplex encephalitis. Gram stains and other tests for bacterial, tuberculous, syphilitic and fungal infection are negative. Oligoclonal bands and CSF protein electrophoresis abnormalities may be present. An etiologic diagnosis often can be made from CSF by virus isolation, polymerase chain reaction, or detection of antiviral antibodies.
Blood counts may show a normal white cell count, leukopenia, or mild leukocytosis. Atypical lymphocytes in blood smears and a positive heterophile test suggest infectious mononucleosis. Serum amylase is frequently elevated in mumps; abnormal liver function tests are associated with both hepatitis viruses and infectious mononucleosis. The EEG is diffusely slow, especially if there is direct cerebral involvement.
The differential diagnosis of meningitis with mononuclear cell pleocytosis includes partially treated bacterial meningitis; syphilitic, tuberculous, fungal, parasitic, and neoplastic meningitis; and acute disseminated encephalomyelitis after infections (see later). Evidence of systemic viral infection and CSF wet mounts, stained smears, cultures, and cytology can distinguish among these possibilities. When suspected early viral meningitis is associated with a polymorphonuclear pleocytosis of less than 1,000 white blood cells/mL and normal CSF glucose, one of two strategies can be used. The patient can be treated for bacterial meningitis until the results of CSF cultures are known, or treatment can be withheld and lumbar puncture repeated in 6 to 12 hours. If the meningitis is viral in origin, the second sample should show a mononuclear cell pleocytosis.
Vaccines are available against varicella-zoster virus and Japanese encephalitis, and postexposure prophylaxis against rabies can be achieved through active immunization by vaccine combined with passive immunization using human rabies-immune globulin. No specific treatment is available for most causes of viral meningitis or encephalitis. Exceptions include herpes simplex and human immunodeficiency viruses (discussed in the following sections); varicella-zoster, which responds to acyclovir (10-15 mg/kg intravenously every 8 hours for 14 days); and cytomegalovirus, which is treated with a 21-day course of ganciclovir (5 mg/kg intravenously twice daily) and foscarnet (60 mg/kg intravenously every 8 hours), followed by maintenance therapy for 3 to 6 weeks with either drug. Corticosteroids are of no proven benefit except in immune-mediated postinfectious syndromes. Headache and fever can be treated with acetaminophen or nonsteroidal anti-inflammatory drugs. Seizures usually respond to phenytoin or phenobarbital. Supportive measures in comatose patients include mechanical ventilation and intravenous or nasogastric feeding.
Symptoms of viral meningitis usually resolve spontaneously within 2 weeks regardless of the causative agent, although residual deficits may be seen. The outcome of viral encephalitis varies with the specific virus—for example, eastern equine and HSV infections are associated with severe morbidity and high mortality rates. Mortality rates as high as 20% have also been reported in immune-mediated encephalomyelitis after measles infections.
HERPES SIMPLEX VIRUS ENCEPHALITIS
Herpes simplex virus (HSV) type 1 (oral herpes) is the most common cause of sporadic fatal encephalitis in the United States. Most cases involve patients <3 or >50 years of age. The virus migrates along nerve axons to sensory ganglia, where it persists in a latent form and may be subsequently reactivated. HSV type 1 encephalitis can result from either primary infection or reactivation of latent infection. Neonatal HSV encephalitis usually results from acquisition of HSV type 2 (genital herpes) during passage through the birth canal of a mother with active genital lesions. CNS involvement by HSV type 2 in adults usually causes meningitis, rather than encephalitis.
HSV type 1 encephalitis is an acute, necrotizing, asymmetric hemorrhagic process with lymphocytic and plasma cell reaction and usually involves the medial temporal and inferior frontal lobes. Intranuclear inclusions may be seen in neurons and glia. Patients who recover may show cystic necrosis of the involved regions.
The clinical syndrome may include headache, stiff neck, vomiting, behavioral disorders, memory loss, anosmia, aphasia, hemiparesis, and focal or generalized seizures. Active herpes labialis is seen occasionally, but does not reliably implicate HSV as the cause of encephalitis. HSV encephalitis is usually rapidly progressive over several days and may result in coma or death. The most common sequelae in patients who survive are memory and behavior disturbances, reflecting the predilection of HSV for limbic structures.
The CSF in HSV type 1 encephalitis most often shows increased pressure, lymphocytic or mixed lymphocytic and polymorphonuclear pleocytosis (50-100 white blood cells/mL), mild protein elevation, and normal glucose; red blood cells, xanthochromia, and decreased glucose are seen in some cases. However, CSF pleocytosis may not be found in immunocompromised patients. The virus generally cannot be isolated from the CSF, but can be detected by the polymerase chain reaction and serologic testing. The EEG may show periodic slow-wave complexes arising from one or both temporal lobes. MRI is more sensitive than CT for early detection of edema and mass effect in one or both temporal lobes and cingulate gyrus (Figure 4-16). However, imaging studies may also be normal, especially early in the course.
MRI in herpes simplex encephalitis. FLAIR I (A) and T2 (B) sequences show mild mass effect, loss of gray-white differentiation caused by edema, and characteristic involvement of the temporal lobe (arrow). T2 image shows involvement on the other side as well. (Used with permission from Jason Handwerker.)
The symptoms and signs are not specific for herpes virus infection, and may also be observed with brain abscess, tuberculosis, varicella-zoster virus encephalitis, and autoimmune limbic encephalitis. Detection of viral DNA in CSF using PCR is highly sensitive and specific, so brain biopsy is no longer required for definitive diagnosis of HSV encephalitis.
Treatment is with acyclovir, 10 mg/kg intravenously every 8 hours for 14 to 21 days. Complications include erythema at the infusion site, gastrointestinal disturbances, headache, skin rash, tremor, seizures, and encephalopathy or coma. Treatment is started as early as possible, without waiting for laboratory confirmation of the diagnosis, because outcome is greatly influenced by the severity of dysfunction at the time treatment is initiated.
Patients younger than age 30 and those who are only lethargic at the onset of treatment are more likely to survive than are older or comatose patients. With acyclovir treatment, mortality is <10% in immunocompetent but >30% in immunocompromised patients.
HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Acquired immune deficiency syndrome (AIDS) is caused by human immunodeficiency virus type 1 (HIV-1) and is characterized by opportunistic infections, malignant neoplasms (eg, non-Hodgkin lymphoma, Kaposi sarcoma), and a variety of neurologic disturbances. Transmission occurs through sexual activity or transfer of virus-contaminated blood or blood products, such as by intravenous drug users who share needles. HIV enters the brain and spinal cord directly or in circulating HIV-infected lymphocytes or monocytes, yielding detectable levels of HIV RNA in CSF within ~1 week of viral exposure. Within the CNS, the virus infects microglia, perivascular macrophages, astrocytes and endothelial cells, and increases blood-brain barrier permeability. Neurotoxicity is an indirect result of these alterations.
Neurologic complications of HIV infection per se include meningitis, dementia (see Chapter 5, Dementia & Amnestic Disorders), myelopathy (see Chapter 10, Sensory Disorders), neuropathy (see Chapter 10), myopathy (see Chapter 9, Motor Disorders), and stroke (see Chapter 13, Stroke). Patients with systemic HIV infection are also at increased risk of neurologic involvement from opportunistic infections and tumors. Moreover, antiretroviral treatment of HIV may cause paradoxical clinical worsening of (or unmask) opportunistic infections, especially cryptococcal meningitis, tuberculous meningitis, and progressive multifocal leukoencephalopathy (immune reconstitution inflammatory syndrome; see Organ Transplantation earlier in this chapter).
Around the time of HIV-1 seroconversion, patients can develop a syndrome characterized by headache, fever, signs of meningeal irritation, cranial nerve (especially VII) palsies, other focal neurologic abnormalities, or seizures. An acute confusional state with impaired concentration and memory disturbance may also be present. HIV-1 meningitis is associated with mononuclear CSF pleocytosis of up to approximately 200 cells/μL with normal or slightly elevated protein and normal glucose levels. HIV may be detectable in CSF by polymerase chain reaction. Symptoms usually resolve spontaneously within about 1 month. Other causes of pleocytosis associated with HIV infection, including cryptococcal meningitis and cerebral toxoplasmosis, must be excluded. Treatment of newly diagnosed HIV disease, including meningitis, should include a combination of two nucleoside reverse transcriptase inhibitors plus a third drug from one of the following categories: integrase strand transfer inhibitor, non-nucleoside reverse transcriptase inhibitor, or protease inhibitor with pharmacokinetic enhancer. Recommended regimens for specific clinical situations can be found at https://aidsinfo.nih.gov/guidelines.
B. Cryptococcal Meningitis or Meningoencephalitis
Cryptococcus neoformans causes subacute meningitis or meningoencephalitis in patients with HIV infection. Clinical features include headache, confusion, stiff neck, fever, nausea and vomiting, seizures, and cranial nerve palsies. CSF cell counts, protein, and glucose may be normal, so CSF India ink staining and cryptococcal antigen titers should always be obtained. CT or MRI scans may show meningeal enhancement, intraventricular or intraparenchymal cryptococcomas, gelatinous pseudocysts, abscesses, hydrocephalus, or small vessel ischemic infarcts. Treatment consists of induction for at least 2 weeks with liposomal amphotericin B (0.7-1 mg/kg intravenously 4 times daily) and flucytosine (25 mg/kg orally 4 times daily), followed upon clinical improvement and negative CSF culture by consolidation with fluconazole (400 mg orally daily for 8 weeks), and then maintenance with fluconazole (200 mg orally daily) until the patient is asymptomatic with CD4 cell counts >100/μL. Increased intracranial pressure should be managed by daily lumbar puncture or ventriculoperitoneal shunting. Corticosteroids are not recommended. Survival is improved by delaying antiretroviral therapy until 5 weeks after the start of treatment for cryptococcal meningitis.
C. Cerebral Toxoplasmosis
In patients with HIV infection, cerebral toxoplasmosis produces cerebral abscesses and, less commonly, diffuse encephalitis or chorioretinitis. Presenting symptoms include fever, headache, altered mental status, focal neurologic abnormalities, and seizures. Movement disorders may also occur due to the predilection of Toxoplasma abscesses for the basal ganglia. Blood and CSF serology and PCR can be diagnostically helpful, but lumbar puncture may be inadvisable in the presence of mass lesions. Thus, imaging studies are typically relied upon for presumptive diagnosis of cerebral toxoplasmosis. MRI is more sensitive than CT scanning and typically reveals one or more ring-enhancing supratentorial lesions at cortical gray-white matter junctions or in the basal ganglia. Because intracerebral mass lesions in HIV-infected patients are typically due to toxoplasmosis or primary central nervous system lymphoma (see later), and since toxoplasmosis is more readily treatable, patients with HIV infection and intracerebral mass lesions should be treated for toxoplasmosis. Treatment is with pyrimethamine (200 mg then 75-100 mg orally daily), sulfadiazine (1-1.5 g orally four times daily), and folinic acid (10-50 mg orally daily), continued until 1-2 weeks after clinical resolution. In patients with CD4+ cell counts <100/μL, maintenance therapy should then be instituted with pyrimethamine (25-50 mg orally daily), sulfadiazine (0.5-1 g orally four times daily), and folinic acid (10-50 mg orally daily). Absence of a response to treatment for toxoplasmosis should prompt brain biopsy for diagnosis of possible lymphoma.
D. Cytomegalovirus Encephalitis
Cytomegalovirus infection can result in encephalitis, myelitis, polyradiculitis, or retinitis in patients with HIV infection. Clinical features of encephalitis include fever, headache, confusion, seizures, cranial nerve palsies, and ataxia. CSF cell count, protein, and glucose are variable; diagnosis is by PCR testing of CSF. Treatment is with ganciclovir (5 mg/kg) and foscarnet (90 mg/kg), both given intravenously twice daily until improvement occurs (~3-6 weeks).
E. Progressive Multifocal Leukoencephalopathy
This demyelinating disorder is caused by infection with JC virus. Altered mental status may be accompanied by focal neurologic signs, including hemianopsia, ataxia, or hemiparesis, and seizures. Headache and fever are usually absent. CT or MRI scan shows one or more white matter lesions, which may be bilateral. The CSF typically shows mild lymphocytic pleocytosis, elevated protein, and normal glucose, and polymerase chain reaction may provide evidence for JC virus infection. There is no proven effective treatment.
Primary CNS lymphoma is the most common brain tumor associated with HIV infection. Clinical features include confusion, hemiparesis, aphasia, seizures, cranial nerve palsies, and headache; signs of meningeal irritation are uncommon. CSF commonly shows elevated protein and mild mononuclear pleocytosis, and glucose may be low; cytology is rarely positive. MRI is more sensitive than CT scanning and shows single or multiple contrast-enhancing lesions, which may not be distinguishable from those seen in toxoplasmosis. Patients with HIV infection and one or more intracerebral mass lesions that fail to respond to treatment for toxoplasmosis within 3 weeks should undergo brain biopsy for diagnosis of lymphoma. Recommended first-line treatment includes high-dose methotrexate, which may be combined with rituximab or autologous stem-cell transplantation, reserving whole-brain radiotherapy for relapses.
In a small fraction of patients with systemic fungal infections (mycoses), fungi invade the CNS to produce meningitis or focal intraparenchymal lesions (Table 4-14). Several fungi are opportunistic organisms that cause infection in patients with cancer or HIV infection, those receiving immunosuppressive drugs, and other debilitated hosts. Intravenous drug abuse is a potential route for infection with Candida and Aspergillus. Diabetic acidosis is strongly correlated with rhinocerebral mucormycosis. In contrast, meningeal infections with Coccidioides, Blastomyces, and Actinomyces usually occur in previously healthy individuals. Cryptococcus (the most common cause of fungal meningitis in the United States) and Histoplasma infection can occur in either healthy or immunosuppressed patients. Cryptococcal meningitis is the most common fungal infection of the nervous system in patients with HIV infection. Geographic factors are also important in the epidemiology of certain mycoses: Blastomyces is seen especially in the Mississippi River Valley, Coccidioides in the southwestern United States, and Histoplasma in the eastern and midwestern United States.
Table 4-14.Causes of Fungal Meningitis. ||Download (.pdf) Table 4-14. Causes of Fungal Meningitis.
|Name ||Opportunistic ||Systemic Involvement ||Distinctive CSF Findings ||Treatment |
|Aspergillus species ||+ ||Lungs, nasal sinuses ||Polymorphonuclear pleocytosis ||Voriconazole 6 mg/kg intravenously every 12 hours for 2 doses, then 4 mg/kg intravenously or 200 mg orally twice daily |
|Blastomyces dermatitidis ||– ||Lungs, skin, bones, joints, viscera ||Polymorphonuclear pleocytosis || |
Amphotericin B (liposomal) 5 mg/kg intravenously daily for 4-6 weeks, then
Itraconazole 200 mg orally 2-3 times daily for 3 days, then 200 mg orally twice daily for 12 months
|Candida species ||+ ||Mucous membranes, skin, esophagus, genitourinary tract, heart ||Polymorphonuclear or mononuclear pleocytosis; may be Gram-positive || |
Amphotericin B (liposomal) 3-5 mg/kg intravenously daily
Flucytosine 25 mg/kg orally four times daily, then 400 mg orally daily for 8 weeks, then maintenance with
Fluconazole 400-800 mg orally daily
|Coccidioides immitis ||– ||Lungs, skin, bones ||Eosinophilic pleocytosis; positive complement fixation ||Fluconazole 400-800 mg intravenously or orally daily for 1 year |
|Cryptococcus neoformans ||± (HIV) ||Lungs, skin, bones, joints ||Lymphocytic pleocytosis, viscous fluid, positive India ink prep and cryptococcal antigen || |
Amphotericin B (liposomal) 3-5 mg/kg intravenously daily
Flucytosine 25 mg/kg orally four times daily, then 400 mg orally daily for 8 weeks, then maintenance with
Fluconazole 200 mg orally daily
|Histoplasma capsulatum ||± ||Lungs, skin, mucous membranes, heart, viscera ||Lymphocytic pleocytosis || |
Amphotericin B (liposomal) 5 mg/kg/d intravenously for 4-6 weeks, then
Itraconazole 200 mg orally 2-3 times daily for 12 months
|Mucor species ||+ (diabetes) ||Orbits, paranasal sinuses ||– ||Amphotericin B (liposomal) 3-10 mg/kg intravenously daily for 10-12 weeks, correction of hyperglycemia and acidosis, and wound debridement |
Fungi reach the CNS by hematogenous spread from the lungs, heart, gastrointestinal or genitourinary tract, or skin, or by direct extension from parameningeal sites such as the orbits or paranasal sinuses. Invasion of the meninges from a contiguous focus of infection is particularly common in mucormycosis but may also occur in aspergillosis and actinomycosis.
Pathologic findings in fungal infections of the nervous system include a primarily mononuclear basal meningeal exudative reaction (see Figure 4-13), focal abscesses or granulomas in the brain or spinal epidural space, cerebral infarction related to vasculitis, and ventricular enlargement caused by communicating hydrocephalus.
Fungal meningitis is usually a subacute illness resembling tuberculous meningitis. Common symptoms include headache and lethargy or confusion. Nausea and vomiting, visual loss, seizures, or focal weakness may also occur, and fever may be absent. Facial or eye pain, nasal discharge, proptosis, or visual loss should prompt urgent consideration of Mucor infection in diabetic patients with acidosis.
Careful examination of the skin, orbits, sinuses, and chest may reveal evidence of systemic fungal infection. Neurologic examination may show signs of meningeal irritation, a confusional state, papilledema, visual loss, ptosis, exophthalmos, ocular or other cranial nerve palsies, and focal neurologic abnormalities such as hemiparesis. Because some fungi (eg, Cryptococcus) can cause spinal cord compression, there may be evidence of spine tenderness, paraparesis, pyramidal signs in the legs, or loss of sensation over the legs and trunk.
Blood cultures should be obtained. Serum glucose and arterial blood gas levels should be determined in diabetic patients. The urine should be examined for Candida. Chest X-ray may show hilar lymphadenopathy, patchy or miliary infiltrates, cavitation, or pleural effusion in several fungal infections. The CT scan or MRI may demonstrate intracerebral mass lesions associated with Cryptococcus (Figure 4-17) or other organisms, a contiguous infectious source in the orbit or paranasal sinuses, or hydrocephalus.
T2-weighted MRI in cryptococcal meningitis. Note the bilateral increase in signal in the basal ganglia (arrows) with relative sparing of the thalami (T). This is caused by gelatinous fungal pseudocysts in the territory of the lenticulostriate arteries. (Used with permission from A. Gean.)
CSF pressure may be normal or elevated. The fluid is usually clear, but may be viscous in cryptococcal infection. Lymphocytic pleocytosis of up to 1,000 cells/mL is common, but a normal cell count or polymorphonuclear pleocytosis can be seen in early fungal meningitis, immunosuppressed patients, or Aspergillus infection. CSF protein may be normal initially, but subsequently rises, usually not exceeding 200 mg/dL; higher levels (up to 1 g/dL) suggest subarachnoid block. Glucose is normal or decreased, but rarely below 10 mg/dL. Microscopic examination of Gram-stained and acid-fast smears and India ink preparations may reveal the infecting organism. Fungal cultures of CSF and other body fluids and tissues should be obtained, but are often negative. In suspected mucormycosis, biopsy of the affected tissue (usually nasal mucosa) is essential. Useful CSF serologic studies include cryptococcal antigen and Coccidioides complement-fixing antibody. Cryptococcal antigen is more sensitive than India ink for detecting Cryptococcus and should always be looked for in both CSF and serum when that organism is suspected, as in patients with HIV infection.
Fungal meningitis may mimic brain abscess and other subacute or chronic meningitides, such as those caused by tuberculosis or syphilis. CSF findings and CT or MRI scans are useful in differential diagnosis.
Treatment of fungal meningitis is summarized in Table 4-14. In addition to antibiotics, CSF drainage is used to control intracranial pressure in cryptococcal meningitis. Mortality is high, complications of treatment are common, and neurologic sequelae are frequent.
Protozoal, helminthic, and rickettsial infections may cause CNS disease, particularly in immunosuppressed patients (including those with HIV infection), and in certain regions of the world. The relationship of these infections to host immunity and recommended treatments are summarized in Table 4-15.
Table 4-15.Parasitic Infections of the Central Nervous System. ||Download (.pdf) Table 4-15. Parasitic Infections of the Central Nervous System.
|Parasite ||Opportunistic ||Treatment |
|Plasmodium falciparum (malaria) ||– || |
|Toxoplasma gondii ||± || |
|Naegleria fowleri (primary amebic meningoencephalitis) ||– || |
Amphotericin B7 +
|Acanthamoeba or Hartmannella species (granulomatous amebic encephalitis) ||+ || |
|Taenia solium (cysticercosis) ||– || |
|Angiostrongylus cantonensis (eosinophilic meningitis) ||– || |
|Rickettsia rickettsii (Rocky Mountain spotted fever) ||– || |
Malaria, the most common human parasitic infection, is caused by the protozoan Plasmodium falciparum or other Plasmodium species and is transferred to humans by the female Anopheles mosquito. Clinical features include fever, chills, myalgia, nausea and vomiting, anemia, renal failure, hypoglycemia, and pulmonary edema. Cerebral involvement occurs when plasmodia reach the CNS in infected red blood cells and occlude cerebral capillaries. Neurologic involvement becomes apparent weeks after infection. In addition to acute confusional states, cerebral malaria can produce coma, focal neurologic abnormalities, and seizures. The most common findings on neurologic examination of affected adults are bilateral pyramidal signs (especially extensor plantar responses), sustained upgaze, signs of meningeal irritation, and decorticate or decerebrate posturing. The diagnosis is made by finding plasmodia in red blood cells on thick and thin peripheral blood smears (Figure 4-18). The CSF may show increased pressure, xanthochromia, mononuclear pleocytosis, or mildly elevated protein. Antibiotic treatment is given in Table 4-15. In addition, the ECG should be monitored for QTc segment prolongation during intravenous quinidine administration, and hypoglycemia may require IV administration of dextrose. Mannitol and corticosteroids are not helpful and may be deleterious. The mortality rate in cerebral malaria is about 20%.
Peripheral blood smear from a patient with Plasmodium falciparum malaria, showing parasites (dark spots) within red blood cells. (Used with permission from Kaushansky K, Lichtman M, Beutler E, Kipps T. Williams Hematology. 8th ed. New York, NY: McGraw-Hill, 2010.)
Toxoplasmosis results from ingestion of Toxoplasma gondii cysts in raw meat or cat excrement and is usually asymptomatic. Symptomatic disease is associated with reactivation of latent infection in the setting of HIV infection, underlying malignancy, or immunosuppressive therapy. Systemic manifestations include skin rash, lymphadenopathy, myalgias, arthralgias, carditis, pneumonitis, and splenomegaly. CNS involvement can cause abscesses or encephalitis, and symptoms and signs include headache, altered mental status, seizures, and focal deficits. The CSF may show mild mononuclear cell pleocytosis or slight protein elevation, and the organism may be seen on wet mounts of centrifuged CSF. MRI is superior to CT scanning for demonstrating the characteristic ring-enhancing lesions (Figure 4-19). Diagnosis can be made by detection of anti-Toxoplasma IgG antibodies. Folinic acid 10 mg orally daily should accompany antibiotic treatment (Table 4-15) to prevent pyrimethamine-induced leukopenia and thrombocytopenia.
T1-weighted, gadolinium-enhanced MRI in cerebral toxoplasmosis complicating HIV infection. Note the multiple calcifications (arrow, right) and ring-enhanced lesions (arrow, left) in the basal ganglia and cerebral cortex.
C. Primary Amebic Meningoencephalitis
The free-living ameba Naegleria fowleri causes primary amebic meningoencephalitis in previously healthy young persons exposed to warm, polluted fresh water. Amebas gain entry to the CNS through the cribriform plate, producing a diffuse meningoencephalitis that affects the base of the frontal lobes and posterior fossa. It is characterized by headache, fever, nausea and vomiting, signs of meningeal irritation, and disordered mental status. The CSF shows a polymorphonuclear pleocytosis with elevated protein and low glucose; highly motile, refractile trophozoites can sometimes be seen on CSF wet mounts. The disease is usually fatal but occasional recovery has been reported with antibiotic treatment (Table 4-15).
D. Granulomatous Amebic Encephalitis
Granulomatous amebic encephalitis results from infection with Acanthamoeba/Hartmanella species and commonly occurs with chronic illness or immunosuppression. The disorder typically lasts 1 week to 3 months and is characterized by subacute or chronic meningitis and granulomatous encephalitis. The cerebellum, brainstem, basal ganglia, and cerebral hemispheres are affected. An acute confusional state is the most common clinical finding. Fever, headache, meningeal signs, seizures, hemiparesis cranial nerve palsies, cerebellar ataxia, and aphasia may be seen. CSF pleocytosis is lymphocytic or polymorphonuclear, protein is elevated, and glucose is low or normal. Sluggishly motile trophozoites may be seen on CSF wet mounts. Despite treatment (Table 4-15), the disease is usually fatal.
Cysticercosis is the most common helminthic infection of the CNS and is observed most often in Mexico, Central and South America, Africa, and Asia. Infection follows ingestion of larvae of the pork tapeworm Taenia solium. Larvae form single or multiple cysts in the brain, ventricles, and subarachnoid space, and neurologic manifestations result from mass effect, obstruction of CSF flow, or inflammation. Seizures are the most common manifestation of parenchymal brain disease; obstructive hydrocephalus is associated with intraventricular lesions; communicating hydrocephalus, meningitis, and stroke result from subarachnoid involvement; myelopathy or radiculopathy may complicate spinal cysticercosis; and visual impairment is observed with ocular infection. Ophthalmoscopic examination may show ocular cysts, and there may be peripheral blood eosinophilia, soft tissue calcifications, or parasites in the stool. The CSF shows a lymphocytic pleocytosis with eosinophils sometimes present (Table 4-16). Opening pressure is often increased, but if it is decreased, imaging studies should be performed to detect possible spinal subarachnoid block. CSF protein is 50 to 100 mg/dL and glucose is 20 to 50 mg/dL in most cases. CT scan or MRI is the most useful diagnostic test and may show contrast-enhanced mass lesions (sometimes containing live parasites) with surrounding edema, intracerebral calcifications, or ventricular enlargement (Figure 4-20).
Table 4-16.Causes of CSF Eosinophilia. ||Download (.pdf) Table 4-16. Causes of CSF Eosinophilia.
|Parasitic CNS infections |
|Angiostrongylus cantonensis (eosinophilic meningitis) |
|Gnathostoma spinigerum (gnathostomiasis) |
|Baylisascaris procyonis |
|Taenia solium (cysticercosis) |
|Other helminthic infections |
|Other CNS infections |
|Coccidioides immitis meningitis |
|Tuberculous meningitis |
|Noninfectious causes |
|Hematologic malignancies (Hodgkin disease, non-Hodgkin lymphoma, eosinophilic leukemia) |
|Medications (ciprofloxacin, ibuprofen) |
|Foreign matter in subarachnoid space (antibiotics, myelography dye, ventriculoperitoneal shunts) |
|Idiopathic hypereosinophilic syndrome |
Neurocysticercosis. Noncontrast head CT showing new (cystic, black) and old (calcified, white) lesions. (Used with permission from Seth W. Wright, MD, and Universidad Peruana Cayetano Heredia, Lima, Peru.)
Treatment depends on symptoms and the site of involvement. Patients with seizures and calcified cysts should be treated with anticonvulsants. Cysts containing viable parasites or persistent or multiple enhancing lesions are usually treated with anticonvulsants, antihelminthic drugs (Table 4-15), and corticosteroids. Intraventricular, ocular, and spinal cysts may be amenable to surgical removal, and hydrocephalus is treated by ventriculoperitoneal shunting. Patients with ocular cysts should not be given antihelminthics.
F. Angiostrongylus cantonensis Meningitis
Angiostrongylus cantonensis (rat lungworm) is endemic to Southeast Asia, Hawaii, and other Pacific islands. Infection is transmitted by ingestion of raw or undercooked snails, shellfish, or frogs and produces meningitis with peripheral blood and CSF eosinophilia (Table 4-16). Symptoms include headache, neck stiffness, paresthesia, vomiting, and nausea. Lymphocytic CSF pleocytosis, CSF eosinophilia, brain CT or MRI, and ELISA can aid in diagnosis. Rarely, worms can be found in the eye or CSF. The acute illness usually resolves spontaneously in 1 to 2 weeks, although corticosteroids, analgesics, and reduction of CSF pressure by repeated lumbar puncture may be helpful.
Rickettsiae are intracellular parasitic gram-negative bacteria transmitted to humans by tick, flea, or louse bites. They cause a variety of diseases that can affect the nervous system and produce meningitis or encephalitis, including Rocky Mountain spotted fever, typhus, tsutsugamushi fever, and Q fever. Neurologic manifestations include headache, encephalopathy, coma, and death. Most rickettsial infections respond to antibiotics (Table 4-15).
ACUTE DISSEMINATED ENCEPHALOMYELITIS
Acute disseminated encephalomyelitis is an immune-mediated monophasic demyelinating disorder that typically occurs within 1 month after a bacterial or viral (usually upper respiratory) infection. Children are affected most often. Deficits evolve over 2-5 days. Clinical features include fever, seizures, confusion or coma, and focal neurologic deficits (eg, optic or other cranial neuropathies, hemiparesis, ataxia). MRI shows multifocal demyelinating lesions affecting primarily the supratentorial white matter, although gray matter and spinal cord can also be involved. The CSF may show lymphocytic or, less commonly, polymorphonuclear pleocytosis, but oligoclonal bands are absent. In a more fulminant variant, acute hemorrhagic leukoencephalitis, MRI shows bihemispheric demyelinating lesions associated with hemorrhage and edema, and the CSF may contain red blood cells. Treatment of both acute disseminated encephalomyelitis and acute hemorrhagic leukoencephalitis is with methylprednisolone 30 mg/kg/d (up to 1 g/d) intravenously for 5 days, followed by prednisone 1-2 mg/kg/d orally tapered over 4 to 6 weeks. Outcome in acute disseminated encephalomyelitis is usually good, but acute hemorrhagic leukoencephalitis has a high mortality.
Sarcoidosis is an idiopathic inflammatory disorder that produces noncaseating granulomas and prominently affects the lungs. Neurologic involvement occurs in 5-15% of cases and causes basal meningitis or intraparenchymal mass lesions. Clinical findings include cranial (especially facial) neuropathy, confusion, seizures, hydrocephalus, myelopathy, stroke, and endocrine disorders from hypothalamic or pituitary involvement. Laboratory abnormalities include elevated serum levels of angiotensin-converting enzyme, increased CSF protein and mononuclear pleocytosis, and positive Kveim test. High-resolution chest CT is more sensitive than chest X-ray for detecting hilar adenopathy or interstitial lung disease. Brain MRI may show meningeal enhancement, intraparenchymal lesions, or hydrocephalus. Treatment is with prednisone 20 to 60 mg orally daily, tapered over 1 to 6 months. In severe cases, this may be preceded by methylprednisolone 1 g intravenously daily for 3 to 5 days. Addition of azathioprine, methotrexate, hydroxychloroquine, cyclosporine A, mycophenolate mofetil, infliximab, or adalimumab may improve the response to treatment and reduce the likelihood of relapse.
Diffuse metastatic seeding of the leptomeninges may complicate systemic cancer (especially carcinoma of the breast, carcinoma of the lung, lymphoma, leukemia, carcinoma of the gastrointestinal tract, and melanoma) or primary brain tumors (especially glioma, medulloblastomas, and pineal tumors), producing disorders of the brain or spinal cord, including cognitive dysfunction. Two varieties of leptomeningeal metastasis are observed and may coexist: diffuse or nonadherent metastasis, consisting of free-floating cells in the subarachnoid space, and nodular metastasis, characterized by contrast-enhancing adherent tumor nodules. Neoplastic meningitis usually occurs 3 months to 5 years after the diagnosis of cancer, but may precede it. Abnormal neurologic signs are often more striking than the symptoms and usually suggest involvement at multiple levels of the neuraxis. Diffuse or nonadherent metastasis is diagnosed by CSF cytology (Table 4-17), whereas diagnosis of nodular metastasis depends on cranial and spinal MRI with contrast (Figure 4-21). Treatment depends on the type of leptomeningeal metastasis and the presence or absence of parenchymal brain metastasis and systemic disease. Treatment options include intrathecal and systemic chemotherapy (eg, methotrexate, cytosine arabinoside) and local or whole-brain radiotherapy. In treated cases, the average duration of survival is 3-6 months, but this is influenced by tumor type. Prognosis in leptomeningeal metastasis is best for leukemia and lymphoma, intermediate for breast cancer, and worst for non-small cell lung cancer and melanoma.
Table 4-17.Presenting Features of Leptomeningeal Metastases. ||Download (.pdf) Table 4-17. Presenting Features of Leptomeningeal Metastases.
|Feature ||Percentage of Patients |
|Gait disturbance ||46 |
|Headache ||38 |
|Altered mentation ||25 |
|Weakness ||22 |
|Back pain ||18 |
|Nausea or vomiting ||12 |
|Radicular pain ||12 |
|Paresthesia ||10 |
|Lower motor neuron weakness ||78 |
|Absent tendon reflex ||60 |
|Cognitive disturbance ||50 |
|Extensor plantar response ||50 |
|Dermatomal sensory deficit ||50 |
|Ophthalmoplegia ||30 |
|Facial weakness ||25 |
|Hearing loss ||20 |
|Neck meningeal signs ||16 |
|Seizures ||14 |
|Papilledema ||12 |
|Facial sensory deficit ||12 |
|Leg meningeal signs ||12 |
|Laboratory findings |
|MRI positive ||77 |
|CSF pleocytosis ||64 |
|CSF protein >50 mg/dL ||59 |
|CSF opening pressure >160 mm CSF ||50 |
|CSF cytology positive ||47 |
|CSF glucose <40 mg/dL ||31 |
|Both MRI and CSF cytology positive ||24 |
|CSF normal ||3 |
Gadolinium-enhanced T1 coronal MRI showing meningeal spread of breast cancer. There are contrast-enhancing (white) focal lesions in the meninges on the left, diffuse meningeal enhancement, and mass effect from a hemispheric lesion on the left.
Systemic sepsis can produce an encephalopathy that may be related to impaired cerebral blood flow, disruption of the blood–brain barrier, or cerebral edema. Gram-negative infections are the most common cause. Bacteremia, liver failure, or kidney failure may be present. Neurologic manifestations include confusional states or coma, seizures, focal neurologic deficits, rigidity, myoclonus, and asterixis. CSF examination is essential to exclude meningitis. The EEG is often abnormal. Therapy involves supportive measures, such as assisted ventilation, and treatment of the underlying infection. Mortality is high, but can be reduced by prompt diagnosis and treatment.
Antibiotics can cause confusional states characterized by encephalopathy with seizures or myoclonus (cephalosporins, penicillin), psychosis (quinolones, macrolides, procaine penicillin), or vertigo and cerebellar ataxia (metronidazole). Renal failure may be a predisposing factor, especially with cephalosporins. Symptoms typically resolve within about 1 week after the drug is discontinued, or about 2 weeks with metronidazole.
Vascular causes of acute confusional states include disorders of the blood vessels, heart, or blood.
A sudden increase in blood pressure, with or without preexisting chronic hypertension, may result in encephalopathy and headache, which develop over a period of hours to days. Patients at risk include those with acute glomerulonephritis or eclampsia. Impaired autoregulation of cerebral blood flow (Figure 4-22), vasospasm, and intravascular coagulation have all been proposed as contributing factors. Vomiting, visual disturbances, focal neurologic deficits, and focal or generalized seizures can occur. Blood pressure in excess of 250/150 mm Hg is usually required to precipitate the syndrome in patients with chronic hypertension, but previously normotensive patients may be affected at lower pressures. Retinal arteriolar spasm is almost invariable, and papilledema, retinal hemorrhages, and exudates are usually present. Lumbar puncture may show normal or elevated CSF pressure and protein. Areas of edema, located especially in parieto-occipital white matter, are seen on CT scan and MRI (Figure 4-23) and are reversible with treatment.
Cerebrovascular autoregulation. (A) Cerebral blood flow is normally held constant over a wide range of blood pressures. At very low pressures, cerebral hypoperfusion occurs, producing syncope. Pressures above the autoregulatory range can cause hypertensive encephalopathy. (B) Chronic hypertension shifts the autoregulatory range to higher blood pressures. Hypoperfusion and syncope can occur at normal pressures, and pressures associated with hypertensive encephalopathy are higher.
Axial FLAIR MRI in hypertensive encephalopathy showing increased signal (white) in the subcortical occipital white matter and occipital cortex bilaterally. These findings may represent reversible vasogenic edema.
The diagnosis of hypertensive encephalopathy is established when lowering the blood pressure results in rapid resolution of symptoms. This is accomplished with sodium nitroprusside, given by continuous intravenous infusion at an initial rate of 0.25 μg/kg/min and increased to as much as 10 μg/kg/min as required. The patient must be carefully monitored and the infusion rate adjusted to maintain a therapeutic effect without producing hypotension. Mean arterial blood pressure should be reduced by no more than 25% in the first 2 hours of treatment, and a target of 160/100 mm Hg should be aimed for in the following 4 hours. Treatment should be terminated immediately if neurologic function worsens. Untreated hypertensive encephalopathy can result in renal failure, stroke, coma, or death, but prompt treatment usually produces full clinical recovery.
Stroke and subarachnoid hemorrhage can also produce encephalopathy with acutely elevated blood pressure; when focal neurologic abnormalities are also present, stroke is most likely.
The clinical syndrome of hypertensive encephalopathy overlaps with posterior reversible encephalopathy syndrome (PRES), which is defined by subcortical, most often parieto-occipital white matter changes, consistent with edema, seen on CT or MRI. Patients often have a history of immunosuppressive drug treatment; most but not all have increased blood pressure at presentation. Presenting features include headache, altered mental status, seizures, and visual deficits. Treatment includes discontinuing drugs that may have precipitated the disorder and treating elevated blood pressure if present.
PRES, in turn, overlaps with reversible cerebral vasoconstriction syndrome (RCVS), which is often associated with the use of vasoconstrictive, serotonergic antidepressant, or illicit recreational drugs. Blood pressure is sometimes elevated. The most distinctive clinical feature of RCVS is onset with thunderclap headache, but it may also produce seizures or focal neurologic deficits. CT or MRI may be normal, or may show border zone infarcts, intracerebral hemorrhage, or vasogenic edema. The characteristic imaging abnormality is multifocal vasoconstriction on angiography. Treatment is with nimodipine. The disorder is typically self-limited with resolution within ~1 month. RCVS is discussed in Chapter 13 in the differential diagnosis of stroke.
Subarachnoid hemorrhage, usually due to rupture of a cerebral aneurysm, must receive early consideration in the differential diagnosis of an acute confusional state. Subarachnoid hemorrhage may produce encephalopathy, coma, meningeal signs, and focal neurologic deficits, but the most prominent symptom is usually headache. For this reason, the disorder is discussed in Chapter 6, Headache & Facial Pain.
An embolus to the top of the basilar artery that subsequently breaks up and sends fragments distally can produce ischemia affecting the territory of both posterior cerebral arteries. This condition (top of the basilar syndrome) may cause an acute confusional state accompanied by pupillary (sluggish responses to light and accommodation), visual (homonymous hemianopia, cortical blindness), visuomotor (impaired convergence, paralysis of upward or downward gaze, diplopia), and behavioral (hypersomnolence, peduncular hallucinosis) abnormalities. Vertebrobasilar ischemia is discussed in more detail in Chapter 13, Stroke.
NONDOMINANT HEMISPHERIC INFARCTION
Agitated confusion of sudden onset can result from infarction (usually embolic) in the territory of the inferior division of the nondominant (usually right) middle cerebral artery. If the superior division is spared, there is no associated hemiparesis. Agitation may be so pronounced as to suggest drug intoxication or withdrawal, but autonomic hyperactivity is absent. The diagnosis is confirmed by brain CT scan or MRI. Rarely, isolated anterior cerebral artery infarcts or posterior cerebral artery infarcts cause acute confusion.
SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus (SLE) is an autoimmune disorder that causes skin rash, arthritis, serositis, nephritis, anemia, leukopenia, and thrombocytopenia. In addition, SLE produces neurologic involvement in about one-half of patients and is the most common autoimmune cause of encephalopathy. Clinically active systemic disease need not be present for neurologic symptoms to occur. The pathophysiology of nervous system involvement is unclear, but may involve vasculopathy resulting in blood-brain barrier defects and neurotoxic effects of autoantibodies and cytokines. Neuropathologic findings include fibrinoid degeneration of arterioles and capillaries, microinfarcts, and intracerebral hemorrhages, but true vasculitis of cerebral blood vessels is rare. Clinical features include headache, cognitive impairment, mood disorders, seizures, stroke, acute confusional states, chorea, transverse myelitis, and aseptic meningitis. Seizures are usually generalized but may be focal. Laboratory abnormalities include anti-phospholipid, anti-ribosomal P protein, anti-glutamate receptor, and anti-endothelial cell antibodies and a false-positive serologic test for syphilis. CSF shows mild elevation of protein or a modest, usually mononuclear, pleocytosis in some cases. MRI may show white or gray matter lesions, brain atrophy, and ischemic or hemorrhagic strokes.
In patients with SLE, encephalopathy can be caused by a variety of factors, including coagulopathy, infection, uremia, emboli from endocarditis, and corticosteroid therapy. Cerebral lupus is treated with corticosteroids, beginning at 60 mg/d of prednisone or the equivalent. In patients already receiving steroids, the dose should be increased by the equivalent of 5 to 10 mg/d of prednisone. After symptoms resolve, steroids should be tapered to a maintenance dose of 5 to 10 mg/d. Treatments used in refractory cases or to reduce exposure to steroids include cyclophosphamide, azathioprine, mycophenolate mofetil, rituximab, plasma exchange, and intravenous immunoglobulin. Seizures are treated with anticonvulsants. Neurologic symptoms of SLE improve in >80% of patients treated with corticosteroids, but may also resolve without treatment. Cerebral involvement in SLE has not been shown to adversely affect the overall prognosis.
Acute confusional states can occur in primary central nervous system vasculitis, primary systemic vasculitis, and vasculitis secondary to systemic infection or neoplasm.
Primary central nervous system vasculitis, sometimes referred to as granulomatous angiitis, is usually manifested by headache and encephalopathy; it may also cause seizures or stroke (discussed in Chapter 13, Stroke). There is no involvement of other organs, and laboratory studies reveal no evidence of systemic vasculitis. The CSF usually shows mild lymphocytic pleocytosis and elevated protein. MRI may demonstrate bilateral, multifocal infarcts or diffuse changes consistent with ischemic demyelination. Angiography shows beading of small to medium-sized arteries due to multifocal narrowing. This finding also occurs in reversible cerebral vasoconstriction syndrome (see Hypertensive Encephalopathy earlier in this chapter). Definitive diagnosis of primary central nervous system vasculitis is by angiography or brain biopsy. Treatment is with methylprednisolone, 1 g/d intravenously for 3-5 days, followed by prednisone, 1/mg/kg/d orally for 1 month and then tapered over 1 year. Addition of cyclophosphamide, 2 mg/kg/d orally for 3 to 6 months, followed by azathioprine, 2 mg/kg/d orally for 2 to 3 years, may be associated with a lower relapse rate.
Large vessel systemic vasculitis (eg, giant cell or Takayasu arteritis) produces ischemic optic neuropathy and stroke, rather than confusional states. Medium-size vessel systemic vasculitis due to polyarteritis nodosa can cause encephalopathy, focal neurologic deficits, and seizures, but these occur late in the course, when the diagnosis is likely already known. Small vessel systemic vasculitis due to cryoglobulinemia, Henoch-Schönlein purpura, or granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) can also produce encephalopathy. These diseases are diagnosed based on the pattern of systemic involvement and by laboratory tests. Treatment of systemic vasculitis affecting the central nervous system is similar to that described above for primary central nervous system vasculitis.
COMPLICATIONS OF CARDIAC SURGERY
Cardiac surgery, including coronary artery bypass grafting and valve repair or replacement, is associated with neurologic complications, especially stroke and encephalopathy. Several factors—embolization, hypoperfusion, arrhythmia, metabolic disturbances, and pharmacologic agents—may contribute. Evaluation should include a review of medications, search for metabolic derangements, and CT scan or MRI to detect perioperative stroke. Sedatives and other psychoactive medications should be avoided. Postoperative encephalopathy is typically transient, but some patients show more persistent cognitive dysfunction, which affects memory disproportionately and lasts for weeks to months. Cognitive decline that continues for years after cardiac surgery is likely due to another cause.
DISSEMINATED INTRAVASCULAR COAGULATION
Disseminated intravascular coagulation (DIC) results from pathologic activation of the coagulation and fibrinolytic systems in the setting of an underlying disorder such as sepsis, malignancy, or trauma. The principal manifestation is hemorrhage. Common findings in the brain include small multifocal infarctions and petechial hemorrhages involving gray and white matter. Subdural hematoma, subarachnoid hemorrhage, and hemorrhagic infarction in the distribution of large vessels may also occur.
Neurologic manifestations are common and include confusional states, coma, focal signs, and seizures. They may precede hematologic abnormalities, which include hypofibrinogenemia, thrombocytopenia, fibrin degradation products, and prolonged prothrombin time. Microangiopathic hemolytic anemia may also occur. The differential diagnosis includes thrombotic thrombocytopenic purpura (see later), which is distinguished by its tendency to occur in previously healthy individuals and its association with normal plasma fibrinogen and normal or only slightly elevated fibrin degradation products. Treatment is directed at the underlying disease and correction of anemia, thrombocytopenia, and coagulopathy. Prognosis is related to the severity of the underlying disease.
THROMBOTIC THROMBOCYTOPENIC PURPURA
TTP (Moschcowitz disease) is a rare multisystem disorder defined by the pentad of thrombocytopenic purpura, microangiopathic hemolytic anemia, neurologic dysfunction, fever, and renal disease. It is caused by autoantibodies against or mutations in the gene for the metalloprotease ADAMTS13. This allows multimers of von Willebrand factor to accumulate in the plasma, where they stimulate platelet aggregation. The result is platelet-fibrin thrombus formation with occlusion of small blood vessels, especially at arteriolar-capillary junctions. Pathologic findings in the brain include disseminated microinfarcts and, less frequently, petechial hemorrhages that are present mainly in gray matter.
Patients usually present with altered consciousness, headache, focal neurologic signs, or seizures, or with cutaneous purpura, ecchymoses, or petechiae. Neurologic symptoms may be fleeting and recurrent. Hematologic studies show Coombs-negative hemolytic anemia, thrombocytopenia, and normal or only slightly abnormal PT, PTT, fibrinogen, and fibrin degradation products. Compared with DIC (see preceding section), TTP is suggested by a platelet count of <20,000/μL and PT within 5 seconds of the upper limit of the normal range. There may be hematuria, proteinuria, or azotemia. CSF is usually normal. The diagnosis can be made by gingival biopsy or splenectomy.
Treatment includes daily plasma exchange to provide ADAMTS13 and remove autoantibodies, rituximab (375 mg/m2 intravenously weekly for 4 weeks), or both. With treatment, mortality is 10% to 20%.
Blunt head trauma can produce a confusional state or coma. Acceleration or deceleration forces and physical deformation of the skull can cause shearing of white matter with axonal injury, contusion from contact between the inner surface of the skull and the polar regions of the cerebral hemispheres, torn blood vessels, vasomotor changes, brain edema, and increased intracranial pressure.
Concussion is a syndrome that follows head trauma and is characterized by transient confusion, memory impairment, or incoordination. Other symptoms, which include headache, fatigue, irritability, dizziness, nausea, vomiting, blurred vision, and imbalance, tend to resolve after 1 to 2 days but persist for weeks to months (postconcussion syndrome) in ~15% of patients. Because a concussion may increase the risk of subsequent concussion, athletes who sustain a concussion while playing sports should delay their return to play until postconcussive symptoms have resolved and they have gradually resumed normal activity over about 1 week.
Traumatic intracranial hemorrhage can be epidural, subdural, or intracerebral. Epidural hematoma (Figure 4-24) most often results from a lateral skull fracture that lacerates the middle meningeal artery or vein. Patients may or may not lose consciousness initially, but in either event a lucid interval lasting several hours to 1 to 2 days is followed by the rapid evolution, over hours, of headache, progressive obtundation, hemiparesis, and finally ipsilateral pupillary dilatation from uncal herniation. Death may follow if treatment is delayed.
Epidural (left) and subdural (right) hematomas. (Used with permission from Waxman SG. Clinical Neuroanatomy. 26th ed. New York, NY: McGraw-Hill, 2009.)
Subdural hematoma after head injury can be acute, subacute, or chronic. In each case, headache and altered consciousness are the principal manifestations. Delay in diagnosis and treatment may lead to a fatal outcome. In contrast to epidural hematoma, the time between trauma and the onset of symptoms is typically longer, the hemorrhage tends to be located over the cerebral convexities, and associated skull fractures are uncommon.
Intracerebral contusion (bruising) or intracerebral hemorrhage related to head injury is usually located at the frontal or temporal poles. Blood typically enters the CSF, resulting in signs of meningeal irritation and sometimes hydrocephalus. Focal neurologic signs are usually absent or subtle.
The diagnosis of posttraumatic intracranial hemorrhage is made by CT scan or MRI. Epidural hematoma tends to appear as a biconvex, lens-shaped, extra-axial mass that may cross the midline or the tentorium but not the cranial sutures. Subdural hematoma is typically crescent-shaped and may cross the cranial sutures but not the midline or tentorium. Midline structures may be displaced contralaterally.
Epidural and subdural hematomas are treated by surgical evacuation. The decision to operate for intracerebral hematoma depends on the clinical course and location. Evacuation, decompression, or shunting for hydrocephalus may be indicated.
Generalized tonic-clonic (grand mal) seizures are typically followed by a transient confusional state (postictal state) that resolves within 1 to 2 hours. Sleepiness and confusion are usually prominent, but coma, agitation, amnesia, aphasia, or psychosis may occur. When postictal confusion does not clear rapidly, an explanation for the prolonged postictal state must be sought. This occurs in three settings: status epilepticus, an underlying structural brain abnormality (eg, stroke, intracranial hemorrhage), or an underlying diffuse cerebral disorder (eg, dementia, meningitis or encephalitis, metabolic encephalopathy). Patients with an unexplained prolonged postictal state should be evaluated with blood chemistry studies, lumbar puncture, EEG, and CT scan or MRI.
Complex partial seizures—also termed temporal lobe seizures, psychomotor seizures, or focal seizures with impairment of consciousness or awareness—produce alterations in consciousness characterized by confusion or other cognitive, affective, psychomotor, or psychosensory symptoms. Such symptoms include withdrawal, agitation, and automatisms such as staring, repetitive chewing, swallowing, lip-smacking, or picking at clothing. Spells are typically brief and stereotypical, and psychomotor manifestations may be obvious to the observer (see Chapter 12, Seizures & Syncope). The diagnosis is made or confirmed by EEG.
NONCONVULSIVE STATUS EPILEPTICUS
Nonconvulsive (focal or absence) status epilepticus can produce confusion or coma, personality change, aphasia, subtle motor activity, or nystagmus. The diagnosis is established by a favorable clinical or EEG response to the administration of anticonvulsants (eg, lorazepam 4 mg or diazepam 10 mg given intravenously).
Symptoms similar to those associated with acute confusional states—including incoherence, agitation, distractibility, hypervigilance, delusions, and hallucinations—can also be seen in a variety of psychiatric disorders. These include psychotic disorders, bipolar disorders, depressive disorders, anxiety disorders, and somatic disorders. Such diagnoses may be mistakenly assigned to patients with acute confusional states; conversely, patients with psychiatric disturbances may be thought, incorrectly, to have neurologic disease.
Unlike acute confusional states, psychiatric disorders are rarely acute in onset but typically develop over a period of at least several weeks. The history may reveal previous psychiatric disease or hospitalization or a precipitating psychologic stress. Physical examination may show abnormalities related to autonomic overactivity, including tachycardia, tachypnea, and hyperreflexia, but no definitive signs of neurologic dysfunction. Routine laboratory studies are normal in the psychiatric disorders listed previously, but are useful for excluding organic disorders.
Although the mental status examination in acute confusional states is often characterized by disorientation and fluctuating consciousness, patients with psychiatric disorders tend to maintain a consistent degree of cognitive impairment, appear awake and alert, have intact memory, and are oriented to person, place, and time. Disturbances in the content and form of thought (eg, delusions), perceptual abnormalities (eg, hallucinations), and flat or inappropriate affect are common, however. Psychiatric consultation should be sought regarding diagnosis and management.