Acute Encephalopathies

Julie Thorne Parke

The term encephalopathy refers to a diffuse disturbance of brain function resulting in behavioral changes, altered consciousness, or seizures. The term usually is reserved for noninfective causes of brain dysfunction. The term encephalitis refers to brain dysfunction resulting from an infectious process. Clinically, it may be difficult to differentiate the two, and an infectious process must always be considered in a patient with evidence of an acute disturbance of brain function.

BOX 397.1 Causes of Acute Encephalopathy in Childhood

Oxygen or Substrate Deprivation

Hypoxia-Ischemia

Cardiorespiratory arrest
Cardiac dysrhythmia
Congestive heart failure
Hypotension
Diffuse intravascular coagulation
Near drowning
Suffocation
Pulmonary disease
Carbon monoxide poisoning

Hypoglycemia

Ketotic hypoglycemia
Defects in gluconeogenesis
Insulin-secreting pancreatic tumors
Hepatitis
Reye syndrome
Alcohol intoxication

Metabolic and Endocrinologic Disturbance

Fluid and electrolyte imbalance

Water intoxication
Hyponatremia or hypernatremia
Hypomagnesemia or hypermagnesemia
Hypocalcemia or hypercalcemia
Hypophosphatemia or hyperphosphatemia
Acidosis or alkalosis
Burn encephalopathy

Endocrinologic disturbance

Diabetes mellitus
Hypothyroidism or hyperthyroidism
Hypoparathyroidism or hyperparathyroidism
Hypopituitarism

Organ failure

Hepatic
Renal
Pancreatic
Intussusception or volvulus
Hypertensive encephalopathy

Inborn errors of metabolism

Aminoacidurias (branched-chain ketoacidosis)
Organic acidurias (propionic, methylmalonic, isovaleric acidemias, beta-ketothiolase deficiency)
Urea cycle defects
Disorders of fatty acid oxidation
Disorders of pyruvate metabolism
Mitochondrial respiratory chain disorders
Carnitine deficiency syndromes

Postinfectious Disorders

Acute disseminated encephalomyelitis
Reye syndrome

Exogenous Toxins

Drugs (sedatives, anticholinergics, psychotropics, salicylates)
Insecticides/pesticides
Heavy metals, lead

Footnote

Modified from

Plum F, Posner JB, eds. The diagnosis of stupor and coma, 3rd ed. Philadelphia: FA Davis, 1982.

Many conditions can cause acute brain dysfunction in children that results in progressive alterations of consciousness (Box 397.1). Many of these conditions are treatable and may have a favorable outcome if an accurate diagnosis is made and appropriate therapy is instituted.

PATHOPHYSIOLOGY

To function normally, the brain must be supplied adequately with substrates and cofactors for production of energy and for synthesis of structural components. Adequate blood flow to deliver the substrates and to remove waste products must be present. Many encephalopathies are caused by cytotoxic injury, which occurs if production of energy is disrupted by a lack of oxygen or glucose or by inadequate cerebral blood flow. Cytotoxic injury also may occur with direct poisoning of the neuron by exogenous toxins or drugs or by endogenous toxins arising from an error of metabolism or from inadequate removal of toxic wastes by the kidneys or liver. Cytotoxic injury frequently is accompanied by cerebral edema and increased intracranial pressure (ICP), which amplifies cerebral ischemia.

Other encephalopathies may be caused by interference with neurotransmission rather than actual cytotoxic injury. Severe electrolyte disturbances may alter the electrical properties of cellular membranes. Various toxins and drugs may produce similar interference with polarization of membranes or may alter neurotransmitters, thus interfering with neuronal activity.

CLINICAL PRESENTATION

The earliest signs of acute encephalopathy may be subtle and may include personality disturbances, a shortened attention span, and changes in mentation. Cognitive deficits, such as difficulty in processing new information and perceptual and memory deficits, occur commonly in the initial stages. Abnormal movements, particularly fine tremors, asterixis, or myoclonus, may be present. Primitive reflexes, such as the grasp, snout, sucking, and rooting responses, may be elicited on examination. With increasing severity of brain dysfunction, alteration in the level of consciousness occurs, progressing from lethargy and obtundation to stupor and coma. Some patients retain an alert appearance but become increasingly disoriented and agitated. Other patients have alternating periods of hyperalertness and drowsiness, gradually progressing to longer periods of unresponsiveness. Seizures occur frequently and may be generalized or focal.

Diffuse symmetric abnormalities in motor tone and strength are common findings. Focal motor abnormalities are seen uncommonly and, if present, tend to fluctuate in severity or change in location. The pupillary examination may be helpful in determining the cause of the encephalopathy. Preservation of the pupillary light reflexes in the presence of respiratory depression and deep coma suggests a metabolic coma. The absence of pupillary light reflexes suggests asphyxia, ingestion of an anticholinergic drug or glutethimide, or structural disease as the cause of coma.

ETIOLOGY

Hypoxic-Ischemic Encephalopathy

Oxygen and glucose are the two major substrates needed for production of energy in the brain. The supply of these two substrates and the cofactors necessary to allow their usage depend on an adequate cerebral blood flow. The brain is particularly vulnerable to even brief interruptions of blood flow or oxygen supply because it possesses almost no reserves of nutrients and metabolizes at one of the highest rates of any organ in the body. If the brain’s oxygen supply is insufficient, whether because of decreased availability or decreased delivery, consciousness is lost rapidly. If oxygenation is restored immediately, consciousness returns without sequelae. However, if oxygen deprivation lasts longer than 1 or 2 minutes, signs of encephalopathy may persist for hours or permanently. Total ischemic anoxia lasting longer than approximately 4 minutes usually results in severe, irreversible brain damage. In rare instances, especially near-drowning events, recovery of brain function occurs despite more prolonged periods of anoxia.

Major causes leading to hypoxic-ischemic encephalopathy include obstruction of the airway, as in drowning, choking, or suffocation, and sudden decrease in cardiac output, as in cardiorespiratory arrest, severe dysrhythmias, severe hypotension, or massive systemic hemorrhage. Carbon monoxide poisoning may produce hypoxic encephalopathy because carbon monoxide binds tightly to hemoglobin and diminishes its oxygen-carrying capacity. Subacute chronic hypoxia, such as occurs in congestive heart failure, severe anemia, or pulmonary disease, also may cause encephalopathy. However, severe neurologic changes usually occur only after a prolonged period of chronic hypoxia, and the cause of hypoxia generally is evident. Cerebral edema is a consistent feature in patients who have had an acute anoxic-ischemic event and may be quite severe. Some patients may show a “lucent” interval of 12 to 24 hours before lapsing into coma with signs of cerebral edema. Occasionally, patients who have had oxygen deprivation or carbon monoxide intoxication develop delayed postanoxic encephalopathy characterized by rapid neurologic deterioration several weeks after the initial insult.

The treatment of hypoxic-ischemic encephalopathy includes adequate oxygenation, rapid restoration of perfusion, management of cerebral edema, and maintenance of good fluid and electrolyte balance. Anticonvulsant therapy also may be necessary. The prognosis is difficult to determine early in the course because patients may remain comatose for days and may eventually recover with few sequelae. Early evidence of brainstem dysfunction is a poor prognostic sign.

Metabolic and Endocrinologic Disturbances

Hypoglycemia

Hypoglycemia is a serious, correctable cause of metabolic encephalopathy. The tolerance to hypoglycemia varies, but symptoms usually occur when blood glucose levels fall to less than 40 mg/dL. The severity of symptoms is determined by the availability of alternative substrates for cerebral metabolism. Patients with hypoglycemic encephalopathy may present with a variety of neurologic symptoms, including simple confusion, delirium, abrupt focal neurologic signs resembling a stroke, focal or generalized seizures, or coma. Because the spectrum of clinical presentations is so wide, hypoglycemia should be suspected in every patient with acute neurologic dysfunction. Blood should be drawn immediately for a glucose determination, and glucose should be administered. If treated promptly, neurologic symptoms are reversible. Persistent deficits may occur with prolonged or recurrent hypoglycemic attacks. The most common symptomatic form of hypoglycemia in children is ketotic hypoglycemia (Box 397.2).

Diabetic Ketoacidosis

Diabetes mellitus is the most common endocrine disease presenting as acute encephalopathy, although pituitary, adrenal, parathyroid, and thyroid disorders occasionally present with similar symptoms. Diabetic ketoacidosis typically occurs in patients with relatively severe diabetes who neglect to take their insulin or who have an associated acute infection. Polyuria, polydipsia, and fatigue lead to a dehydrated state with metabolic acidosis. Nausea, vomiting, and acute abdominal pain
may be prominent early in the course. Hyperventilation occurs commonly and reflects the body’s attempt to compensate for the metabolic acidosis. The neurologic examination is nonfocal, and brainstem function usually is intact.

BOX 397.2 Ketotic Hypoglycemia

Ketotic hypoglycemia is seen most frequently in thin, young children who have a mild infectious illness that precipitates vomiting, altered mental status, and seizures, accompanied by hypoglycemia and ketosis. The cause of this disorder is not clear, but it may be the result of limited liver glycogen stores and an inability to mobilize gluconeogenic precursors. Patients with this disorder should be treated immediately with glucose and then should be maintained on dietary therapy consisting of frequent feedings during the day and bedtime snacks. Another common cause of hypoglycemia is insulin overdose. Less common causes of hypoglycemia include hereditary defects in gluconeogenesis, insulin-secreting pancreatic tumors, deficiency of growth hormone or cortisol, hepatitis, and Reye syndrome. Excessive ingestion of alcohol also may produce hypoglycemia.

The treatment of diabetic ketoacidosis may have serious neurologic consequences. Sudden lowering of serum osmolality may produce a shift of water into the brain, thus causing marked cerebral edema. This condition should be suspected when patients recovering from diabetic ketoacidosis complain of headache or become increasingly lethargic. Profound hypophosphatemia may occur as dehydration is corrected and the serum glucose level is lowered, causing further neurologic dysfunction. In addition to ketoacidosis, hypoglycemia, uremia, hypertension, and cerebral infarction should be considered in the diabetic patient presenting with acute encephalopathy.

Disorders of Fluid and Electrolyte Balance

Disturbances in water and sodium metabolism can cause a spectrum of neurologic signs and symptoms, ranging from confusion and seizures to deep coma with increased ICP. Neuronal function depends on a correct ionic environment and can be altered by any changes in composition or volume of body fluids. Electrolyte disturbances occur fairly frequently in young children because their cutaneous water losses are relatively higher than those of adults and renal conservation of water is less efficient than that in adults. Young children have a reduced tolerance for water deprivation or abnormal water loss. Disorders of electrolytes and serum osmolality are common causes of acute encephalopathy in children. Consciousness is altered if serum osmolality is less than 260 mOsm/kg or greater than 330 mOsm/kg. The total concentration of osmotically active materials in the interstitial and intracellular fluids is equal because water diffuses freely across the cell membranes. A decrease in extracellular osmolality leads to cellular overhydration, whereas an increase in extracellular osmolality leads to cellular dehydration.

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