Acute toxic-metabolic encephalopathy in children

INTRODUCTION — Acute toxic-metabolic encephalopathy (TME) is a condition of acute global cerebral dysfunction manifested by altered consciousness, behavior changes, and/or seizures in the absence of primary structural brain disease or direct central nervous system (CNS) infection. The causes of TME are diverse (table 1). The presentation of this condition in the infant or child may be subtle and not easily recognized. Because TME often is reversible and interruption of neuronal activity in the developing brain can have a long-lasting effect, prompt recognition and treatment are important.

An overview of the causes, clinical features, and an approach to the diagnostic evaluation and management of TME in children will be reviewed here. Neonatal encephalopathy is discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy" and "Etiology and pathogenesis of neonatal encephalopathy".)

DEFINITION — Acute TME is a broad term used to describe a condition of acute global cerebral dysfunction manifested by altered consciousness, behavior changes, and/or seizures occurring as a consequence of systemic disorders or exposures. The term is not used to describe cerebral dysfunction due to primary brain disease, including structural pathology (eg, tumor, hemorrhage, hydrocephalus), central nervous system (CNS) infection (eg, meningitis, encephalitis), or immune-mediated inflammation (eg, autoimmune encephalitis, acute disseminated encephalomyelitis) [1]. All forms of TME interfere with the function of the ascending reticular activating system and/or its projections to the cerebral cortex, thus leading to impairment of arousal and/or awareness, and/or seizures [2].

PATHOPHYSIOLOGY — Normal neuronal activity requires a balanced environment of electrolytes, water, amino acids, excitatory and inhibitory neurotransmitters, and metabolic substrates [3]. In addition, normal blood flow, normal temperature, normal osmolality, and physiologic pH are required for optimal brain function [2]. Complex systems, such as those mediating arousal and awareness and those involved in higher cognitive functions, are more likely to malfunction when the local milieu is deranged [2-4].

Despite a wide array of pathophysiologic mechanisms (table 1), the clinical manifestations of acute TME tend to be very similar because of a common final mechanism: interruption of polysynaptic pathways and altered excitatory-inhibitory amino acid balance and cerebral edema [5-8]. (See 'Specific etiologies of encephalopathy' below.)

The pathophysiology of acute TME usually is multifactorial and varies according to etiology. TME generally results from neuroinflammation, cytotoxic injury, or disruption of neurotransmission [1].

Neuroinflammation in TME results from alterations in central nervous system (CNS) homeostasis that activate microglial cells and infiltrating myeloid cells, astrocytes, and oligodendrocytes [9]. This process releases cytokines that have independent neurotoxic effects and also disrupt the blood-brain barrier (BBB). Loss of the tight junction of the BBB results in extravasation of protein in cerebrospinal fluid (CSF) and facilitates vasogenic edema [10].

Causes of cytotoxic injury include:

●Disruption of energy production by inadequate cerebral blood flow or lack of oxygen or glucose.

●Neuronal injury caused by exogenous drugs or toxins, or endogenous toxins that result from systemic infections (eg, lipopolysaccharide), neurotoxic cascade (eg, glutamate release, calcium homeostasis), inadequate removal of wastes by the liver or kidney, or an inborn error of metabolism.

●Cerebral edema or elevated intracranial pressure (ICP), which may further compromise cerebral blood flow [4].

Causes of disrupted neurotransmission may include:

●Electrolyte disturbances that affect the electrical properties of cellular membranes [2,8].

●Endogenous or exogenous toxins or drugs that disrupt membrane polarization or interfere with neuronal activity by affecting neurotransmitters.

●Disturbed BBB leading to the accumulation of systemic toxins as well as normal plasma constituents in the brain or CSF that interfere with neuronal function. Increased permeability of the BBB is evidenced by elevated protein in the CSF, a frequent finding in TME [11].

SPECIFIC ETIOLOGIES OF ENCEPHALOPATHY — Acute TME can be caused by a variety of clinical disorders (table 1). Some syndromes of TME are relatively restricted to certain age ranges. For example, severe metabolic encephalopathies are more often seen in infants and young children, whereas alcohol intoxication is more often seen in adolescents.

Hypoxic-ischemic encephalopathy — Hypoxic-ischemic encephalopathy (HIE) often is a straightforward diagnosis after an obvious precipitating event such as drowning, airway obstruction, or cardiopulmonary arrest. Hypoxic-ischemic events that occur antenatally, perinatally, or postnatally are a common cause of encephalopathy in newborns. (See "Etiology and pathogenesis of neonatal encephalopathy".)

Other causes of HIE include severe hypotension caused by massive hemorrhage or cardiac arrhythmias or hypoxemia caused by carbon monoxide poisoning. The duration and severity of hypoxia or hypotension and the patient's preexisting neurologic status strongly influence the degree of neurologic insult [12,13]. (See "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis".)

Sepsis — The term "sepsis-associated encephalopathy" (SAE) refers to diffuse brain dysfunction resulting from a systemic infection and not referable to a direct central nervous system (CNS) infection or other organ dysfunction (eg, liver or renal failure). Although potentially reversible, the syndrome can exert long-term cognitive impairments [14]. In patients with systemic infection or sepsis, encephalopathy may result from hypotension and cerebral hypoperfusion (ie, septic shock) and/or from the effects of host's immune response and alterations of the blood-brain barrier (BBB). Encephalopathy can occur in patients who are hypotensive and in those who are normotensive. Clinical manifestations of SAE are typically nonfocal; mental status derangements range from mild (eg, attentional impairments or disorientation) to severe (eg, coma). Less well studied in children, SAE in adults may present as an excitable state (agitation, irritability, confusion, delirium) or a depressed state (lethargy, obtundation, or coma) [15]. Electroencephalogram (EEG) findings, although nonspecific, tend to reflect increasing severity of SAE in the following order: normal, theta, delta, and triphasic waves and burst suppression [16]. Burst suppression associated with SAE is often reversible and generally portends less severe outcomes than that seen in other settings (eg, HIE). Abnormal brain magnetic resonance imaging (MRI) findings are common among children with sepsis. In one study of 389 children with sepsis, 63 percent had abnormal findings on MRI performed either during the initial hospitalization or in subsequent follow-up [17]. (See "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)

Metabolic disorders — The most common metabolic disorders that can result in encephalopathy are hypoglycemia and diabetic ketoacidosis (DKA), but there are many other metabolic causes of encephalopathy.

Hypoglycemia — Hypoglycemia is a serious cause of encephalopathy that is generally treatable. The most common cause is ketotic hypoglycemia, which typically occurs after a mild infectious illness in thin, undernourished young children, and leads to vomiting, encephalopathy, and seizures [1]. Other causes of hypoglycemia include excessive insulin administration [18,19], hepatitis, ethanol ingestion, and inborn errors of metabolism (eg, glycogen storage disorders, defects in gluconeogenesis, and fatty acid oxidation defects). Other relatively uncommon but important etiologies are endocrinopathies (eg, growth hormone or cortisol deficiency), Reye and Reye-like syndromes [20], and insulin-secreting pancreatic tumors. (See "Causes of hypoglycemia in infants and children" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

The clinical manifestations of hypoglycemia are varied. Neurologic signs can range from confusion or delirium to coma [1]. Focal or generalized seizures can occur, and focal deficits may suggest a stroke. Signs of increased epinephrine release (eg, tremor, diaphoresis) may occur but are not universal. Because hypoglycemia has such a wide range of manifestations, blood glucose concentrations should be measured in any patient with acute neurologic dysfunction. Prompt treatment of low glucose levels with intravenous glucose generally will reverse the neurologic signs, although prolonged or recurrent episodes may result in persistent deficits. (See "Approach to hypoglycemia in infants and children".)

Diabetic ketoacidosis — DKA may occur as a complication in a child with known diabetes mellitus (DM) or it may be the presenting manifestation of new-onset DM [21]. Affected children typically have nausea, vomiting, abdominal pain, deep and labored hyperventilation (Kussmaul breathing), and altered levels of consciousness ranging from lethargy to coma. Treatment includes volume repletion and insulin administration. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis" and "Diabetic ketoacidosis in children: Treatment and complications".)

DKA is most common in children with type 1 DM but occasionally occurs in association with type 2 DM. Children and adolescents with type 2 DM may also present with a hyperosmolar hyperglycemic state (HHS). HHS differs from DKA in that ketoacidosis is absent or mild and the degree of dehydration is usually more profound. Mental obtundation and coma are more frequent in HHS than DKA because of the usually greater degree of hyperosmolality in HHS [22]. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents", section on 'Hyperosmolar hyperglycemic state'.)

Cerebral edema is an uncommon but potentially devastating consequence of DKA. Children and those with newly diagnosed diabetes are at highest risk. Symptoms typically emerge during treatment for DKA but may be present prior to initiation of therapy. Cerebral edema in DKA is discussed in greater detail separately. (See "Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)

Inborn errors of metabolism — Encephalopathy can be a prominent feature of many inborn errors of metabolism that present in the newborn period. In addition, some disorders result in recurrent episodes of encephalopathy, often associated with vomiting and hypotonia, and which may be associated with an intercurrent illness, poor feeding, or prolonged fasting. Laboratory abnormalities at presentation may include hypoglycemia, hyperammonemia, lactic acidosis, or ketoacidosis, depending on the type of inborn error of metabolism (table 2). (See "Inborn errors of metabolism: Classification" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features".)

Electrolyte derangements — Fluid and electrolyte disturbances are common causes of acute encephalopathy. The severity of encephalopathy often correlates with the degree of electrolyte disturbance and the speed at which it has evolved.

●Hyper- or hypo-osmolality – Serum osmolality >330 mOsmol/kg or <260 mOsmol/kg may result in alterations in the level of consciousness, primarily if they occur acutely [1].

●Hypernatremia – Hypernatremia is defined as a serum sodium concentration >145 mEq/L [23]. Causes include severe diarrhea, diabetes insipidus, and excessive sodium administration. Nonspecific initial manifestations of symptomatic hypernatremia include irritability, restlessness, weakness, vomiting, muscular twitching, fever, and, in infants, high-pitched cry and tachypnea. Encephalopathy is not typically seen until serum sodium level exceeds 160 mEq/L. Because the most common cause of pediatric hypernatremia is excessive fluid losses, patients may also have manifestations of hypovolemia, including tachycardia, dry mucous membranes, and poor peripheral perfusion. (See "Hypernatremia in children".)

Encephalopathy associated with hypernatremia can result from the electrolyte disturbance itself or as a complication of its treatment [23]. Acutely, osmotic water loss from brain cells causes brain shrinkage that predisposes to focal bleeding, thrombosis, and infarction. In response to initial shrinkage, the brain adapts by taking up and producing organic osmolytes that promote water movement back into the brain [24]. Because of this adaptation, and particularly where the evolution of the electrolyte imbalance has been relatively slow, neurologic symptoms are less likely to occur once the hypernatremia has been present for more than a few days. In patients with hypernatremia, rehydration should be performed cautiously. Rapid rehydration with hypotonic fluids may result in cerebral edema or pontine or extrapontine myelinolysis, leading to seizures, coma, or permanent neurologic deficit [25,26]. Management of hypernatremia in children is discussed in detail separately. (See "Hypernatremia in children", section on 'Treatment'.)

●Hyponatremia – Hyponatremia generally is defined as a serum sodium concentration <137 mEq/L. Common causes include gastrointestinal losses, syndrome of inappropriate antidiuretic hormone secretion (SIADH), cerebral salt wasting (CSW) [27], and water intoxication. CNS trauma, hemorrhage, or surgery (especially for sellar and suprasellar tumors) are often precipitants for SIADH or CSW resulting in hyponatremia [27,28]. Symptomatic hyponatremia manifests most commonly with neurologic dysfunction and is impacted more by the rate of change in sodium concentration than the absolute degree of hyponatremia. Neurologic symptoms are typically observed with plasma sodium levels <125 mEq/L, and severe symptoms (lethargy, obtundation, and seizures) may occur as the level falls below 120 mEq/L [29]. (See "Hyponatremia in children: Etiology and clinical manifestations", section on 'Clinical manifestations'.)

Water movement into and out of the brain in hyponatremia occurs in the opposite direction from those in hypernatremia. Acutely, osmotic water entry from brain cells causes cerebral edema that is largely responsible for the associated neurologic symptoms [24]. In response to initial brain swelling, the brain adapts by losing solutes, thereby leading to osmotic water movement out of the brain [24]. Thus, neurologic symptoms are less likely to occur once the hyponatremia has been present for more than a few days. Overly rapid correction of severe hyponatremia can lead to a severe and sometimes irreversible osmotic demyelination syndrome [24,26]. Symptomatic hyponatremia and complications of its treatment carry greater risk of death or permanent disability than hypernatremia [26,29]. Evaluation and management of hyponatremia in children are discussed in greater detail separately. (See "Hyponatremia in children: Evaluation and management".)

●Calcium and magnesium abnormalities – Encephalopathy also can result from abnormalities in the serum levels of calcium or magnesium.

•Hypocalcemia is defined as a serum calcium concentration <9 mg/dL (2.25 mmol/L) after the newborn period. Definitions of hypocalcemia in neonates are presented separately (see "Neonatal hypocalcemia", section on 'Definition of hypocalcemia'). Hypocalcemia usually results from decreased secretion of parathyroid hormone (PTH) or, less often, resistance to either PTH or calcitriol [30] (see "Etiology of hypocalcemia in infants and children"). Clinical signs of hypocalcemia result from increased neuromuscular irritability. They include nonspecific features, such as vomiting, irritability, and muscle weakness, and more characteristic features, such as tetany and positive Trousseau and Chvostek signs [31]. Laryngospasm and seizures can develop.

•Hypercalcemia is defined as a serum calcium concentration >11 mg/dL (2.75 mmol/L). Serum calcium concentrations >15 mg/dL (3.75 mmol/L) are life threatening [30,32]. Causes vary according to age. In infants, causes include congenital hyperparathyroidism, subcutaneous fat necrosis, enriched formula feeds with excess calcium, and rare metabolic disorders (eg, hypophosphatasia, congenital lactase deficiency). In older children, causes include vitamin D intoxication, immobilization, parathyroid adenoma, and malignancy [32]. Clinical features of hypercalcemia include signs and symptoms related to the gastrointestinal tract (eg, anorexia, nausea, vomiting, and constipation), cardiovascular system (eg, hypertension, bradycardia), kidneys (eg, polydipsia, polyuria, nephrocalcinosis), and skin (eg, pruritus). Neurologic manifestations include headache, irritability, weakness, and lethargy that may progress to behavioral changes, seizures, delirium, and coma. (See "Etiology of hypercalcemia".)

•Hypomagnesemia is defined as a serum magnesium level <1.5 mEq/L (0.75 mmol/L). Hypomagnesemia in children most commonly results from excessive gastrointestinal or renal losses [30]. Rarely, hypomagnesemia is congenital and caused by a mutation in one of several genes (see "Etiology of hypocalcemia in infants and children", section on 'Hypomagnesemia'). The signs and symptoms of this disorder are similar to those of hypocalcemia and result from increased neuromuscular irritability. Patients may present with confusion, irritability, or hallucinations [1]. Choreiform movements, myoclonus, nystagmus, coma, and generalized seizures may occur in severe cases [30]. Tremors, muscle twitching, and myoclonic jerks often are seen on examination. As with hypocalcemia, carpopedal spasm and positive Trousseau and Chvostek signs may be present.

•Hypermagnesemia is defined as a serum magnesium level >2.2 mEq/L (1.1 mmol/L). Hypermagnesemia can occur due to accidental or iatrogenic overdose of magnesium-containing medications, especially in patients with renal failure [30]. Additional causes are reviewed separately (see "Hypermagnesemia: Causes, symptoms, and treatment"). Magnesium displaces calcium at the neuromuscular junction, resulting in decreased neuromuscular excitability. Weakness and hyporeflexia are usually seen at levels between 7 to 9 mmol/L; complete paralyses and fixed dilated pupils are seen at levels >9 mmol/L, resulting in a possible pseudocoma [30]. Cardiovascular effects include hypotension and electrocardiographic changes.

Endocrine disorders

●Hypothyroidism (myxedema coma) – Hypothyroidism can lead to a decline in mental status ranging from apathy, neglect, and decreased cognition to confusion, psychosis, or coma. Myxedema coma is rare in children [33]. Precipitating factors include stressors such as infections (urosepsis or pneumonia), burns, hypothermia, or medications. Notable signs include extreme hypothermia, bradycardia, central hypoventilation, and hypoxia. Hyponatremia is often observed, and patients usually have a history of fatigue, weight gain, constipation, and cold intolerance. Hypothyroidism is more frequent among children with other autoimmune disorders. (See "Myxedema coma" and "Acquired hypothyroidism in childhood and adolescence".)

●Hyperthyroidism (thyroid storm) – Hyperthyroidism can lead to alterations in mentation including agitation, irritability, apathy, psychosis, and, rarely, coma. Seizures, either generalized or localization-related, and chorea can also occur. Triphasic delta waves may be seen on interictal EEG. Patients manifesting psychosis tend to have higher mortality rates than those with milder neurologic and psychiatric symptoms [34]. Tremor, tachycardia, cardiac dysrhythmias, and hypertension are often clues to thyroid dysfunction. Thyroid storm is a medical emergency that if unchecked can result in death. (See "Thyroid storm".)

●Adrenal insufficiency/adrenal crisis – Addison disease is a potentially life-threatening illness that results from destruction of the adrenal cortex and consequent decreased production of glucocorticoids and mineralocorticoids (see "Clinical manifestations and diagnosis of adrenal insufficiency in children"). Adrenal crisis occurs in settings of Addison disease during episodes of stress and is a medical emergency. Potential triggers include dehydration, trauma, surgery, infection, or other physical stress, or stopping glucocorticoid treatment. Clinical presentation may begin with confusion and mild psychiatric symptoms, including mood and behavioral changes [35]. In severe instances, cognitive impairments, psychosis (visual and auditory hallucinations), loss of consciousness, or coma can occur. EEG may show background slowing. Systemic signs include hypotension, nausea and vomiting, abdominal pain, and fever. Hyponatremia and hyperkalemia are often associated with the adrenal dysfunction. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)

Hypertensive encephalopathy and reversible posterior leukoencephalopathy — The clinical features of hypertensive encephalopathy (HTE) and reversible posterior leukoencephalopathy syndrome (RPLS) overlap. Symptoms of HTE/RPLS include headache, nausea/vomiting, altered mental status, seizures, and visual disturbances; symptoms are generally transient and resolve when hypertension is treated effectively. RPLS is an acute encephalopathy characterized radiographically by cortical and white matter signal changes on T2 and fluid-attenuated inversion recovery (FLAIR) MRI (image 1). Lesions are hypo- or isointense on diffusion-weighted imaging (DWI), suggesting increased water diffusion due to vasogenic edema. MRI signal changes in HTE tend to be somewhat more occipital in location and more often associated with visual loss than RPLS. RPLS is correlated with level of hypertension and often occurs in patients with renal disease, uremia, preeclampsia, or eclampsia. RPLS has also been described in patients without hypertension as a neurotoxic manifestation of immunosuppressive therapy, autoimmune disorders, cancer chemotherapy, and infection [36]. MRI signal changes are noted in order of decreasing frequency in the following regions: parietal, occipital, frontal, temporal, cerebellum, brainstem, and deep gray and corpus callosum [36]. (See "Reversible posterior leukoencephalopathy syndrome".)

Organ failure

Hepatic encephalopathy — Hepatic failure may be acute or chronic, and etiology varies with the age of the child [37]. Causes of acute liver failure (ALF) include viral hepatitis, ingestion of hepatotoxic substances, inborn errors of metabolism, autoimmune hepatitis, and Reye syndrome [1]. Drugs that can result in liver failure include acetaminophen, isoniazid, erythromycin, tetracycline, sodium valproate, and pimozide [38]. Causes of chronic hepatic failure include Wilson disease, biliary atresia, and chronic heart failure. In these conditions, excessive protein intake, gastrointestinal bleeding, or intercurrent infection can precipitate hepatic encephalopathy (HE). (See "Acute liver failure in children: Etiology and evaluation".)

Assessing pediatric HE is challenging because children, especially infants, do not exhibit a clear gradation in severity as do adults. Because of these limitations, risk prediction in ALF relies more heavily on laboratory measures (eg, coagulation or ammonia level). HE, when present in ALF, confers a survival rate of only approximately 20 percent without transplantation. Seizures occur in approximately 20 percent of children with ALF. EEG abnormalities, including slowing, interictal spikes, and seizures, are associated with a poorer outcome [39]. Increased intracranial pressure (ICP) may be present in ALF without MRI correlate of edema. ICP monitoring may be helpful in some cases [40]. The pathogenesis of HE is uncertain. It may reflect a reversible metabolic encephalopathy, brain atrophy, brain edema, or any combination of these conditions. Cerebral edema has been ascribed both to cytotoxic edema from solute neurotoxicity (eg, ammonia, glutamine) and to breakdown of the BBB due to neuroinflammation [41]. In advanced coma, the effects of brain swelling, impaired cerebral perfusion, and reversible impairment of neurotransmitter systems cannot be distinguished. (See "Hepatic encephalopathy: Pathogenesis".)

Clinical features with HE range from confusion, apathy, or lethargy to decerebrate or decorticate posturing [1]. Hallucinations and agitation may occur. A relatively characteristic feature is asterixis, a flapping tremor of the hands that is evident when the wrist is extended. Other motor disturbances include grimacing and jerking and seizure activity.

Uremic encephalopathy — Uremic encephalopathy can occur as a complication of advanced acute or chronic renal failure. The specific cause of this disorder is uncertain. The severity of neurologic abnormalities may not correlate with the level of azotemia, suggesting that the encephalopathy does not depend exclusively upon the serum concentration of urea. Creatinine, guanidines, parathormone, and impaired oxygen utilization are thought to be responsible for some of the neurologic symptoms, including peripheral neuropathies.

Early clinical features of uremic encephalopathy include lethargy, irritability, disorientation, hallucinations, and rambling speech [6]. Coma occasionally occurs in acute renal failure. Most patients with uremia have mild diffuse weakness or peripheral neuropathy and show unsteadiness in their movements. Tremor, myoclonus, and asterixis ("uremic flap") are common occurrences and tend to vary in parallel with mental status. Tetany may be present, and focal or generalized seizures may occur. Clinical signs typically are reversed by hemodialysis. (See "Chronic kidney disease in children: Complications", section on 'Uremia'.)

Encephalopathy also can occur during or immediately after dialysis as a component of dialysis disequilibrium syndrome. This disorder is thought to be caused primarily by cerebral edema resulting from overly rapid removal of urea during hemodialysis. Early findings of this disorder include headache, nausea, disorientation, restlessness, blurred vision, and asterixis. More severely affected patients progress to confusion, seizures, coma, and even death. (See "Dialysis disequilibrium syndrome".)

Drugs and toxins — Encephalopathy resulting from toxic drug effect is an important diagnostic consideration in a patient with altered mental status or seizures.

Drug-induced encephalopathy can result from accidental ingestion, intentional overdose, recreational abuse, iatrogenic overdose, or idiosyncratic drug effect [1]. Drugs that result in altered levels of consciousness when present in high concentration include sedatives (alcohol, opiates, barbiturates, and benzodiazepines), anticonvulsants (eg, phenytoin, carbamazepine, valproate), anticholinergic agents, and salicylates (table 3).

The type of intoxicant tends to vary by age: The most common intoxicants in toddlers and young children are household products or prescribed medications, while in adolescents the most common intoxicants are alcohol and drugs of abuse. However, with its legalization, marijuana intoxication occurring primarily by ingestion is increasingly reported among young children (<6 years old). (See "Cannabis (marijuana): Acute intoxication", section on 'Children'.)

Idiosyncratic drug-related encephalopathy, regardless of drug level, can be seen with valproate (usually with hyperammonemia), vigabatrin [42], levetiracetam (psychosis) [43], and chemotherapeutic agents [42,44]. The neurotoxicity linked to chemotherapy may be either dose related or idiosyncratic, and it is often associated with signs of acute toxic leukoencephalopathy on brain MRI (high signal on T2 and FLAIR) and even changes in DWI due to cytotoxic edema, especially with methotrexate use [42]. (See "Approach to the child with occult toxic exposure".)

Sedatives — Overdose of benzodiazepines, barbiturates, and alcohol can cause ataxia, nystagmus, and dysarthria; opiate overdose typically begins with somnolence. Excessive serum concentrations of these substances may result in hypotension, respiratory depression, flaccid paralysis with areflexia, and coma. Alcohol exposure in young children may also be associated with hypoglycemia. Ethanol withdrawal can result in tremors, agitation, hallucinations, and seizures, while opiate withdrawal symptoms include anxiety, insomnia, and dysautonomia. These syndromes are discussed separately:

●(See "Opioid intoxication in children and adolescents".)

●(See "Ethanol intoxication in children: Clinical features, evaluation, and management".)

●(See "Benzodiazepine poisoning".)

●(See "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis".)

●(See "Opioid withdrawal: Clinical features, assessment, and diagnosis".)

Anticholinergic agents — Toxic levels of anticholinergic agents (eg, tricyclic antidepressants, antipsychotic medication, antihistamines (table 4)) can result in CNS excitation, which may lead to confusion, delirium, hallucinations, and seizures. Some patients develop hyperpyrexia, cardiac arrhythmias, coma, and neuroleptic malignant syndrome [45]. (See "Anticholinergic poisoning" and "Tricyclic antidepressant poisoning" and "Over-the-counter cough and cold preparations: Approach to pediatric poisoning", section on 'Antihistamines'.)

Salicylates — Salicylate intoxication can produce encephalopathy manifested as lethargy, seizures, and coma, accompanied by respiratory depression and cardiovascular collapse [46]. These signs typically are preceded by hyperpnea, vomiting, restlessness, and delirium. Reye syndrome also is associated with salicylate ingestion [47]. (See 'Reye syndrome' below and "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Clinical manifestations'.)

Immunosuppressive and immune modulating agents — Several types of immunosuppressive agents occasionally cause encephalopathy. Glucocorticoids may cause insomnia, irritability, impaired concentration, and mood changes, including a florid steroid psychosis. Cyclosporine can cause somnolence, headache, dysarthria, depression, visual hallucinations, and seizures [48]. Tacrolimus also may cause an encephalopathy characterized by anxiety, tremor, vivid nightmares, and restlessness. As with chemotherapeutic agents, neuroimaging features of an acute toxic leukoencephalopathy can be transiently observed on MRI [42]. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Neurotoxicity' and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'CNS management'.)

Chimeric antigen receptor T (CAR-T) cell therapies can result in neurotoxicity producing an encephalopathy termed "immune effector cell-associated neurotoxicity syndrome" (ICANS). Within three to six days of treatment, patients can develop headache and tremor followed by confusion and delirium. ICANS is described separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

Antibiotic-associated encephalopathy — Antibiotic treatment is a rare cause of encephalopathy in children. Three antibiotic-associated encephalopathy (AAE) phenotypes have been proposed: type 1, delirium and seizures more often linked to cephalosporins and penicillin; type 2, psychosis, typically without seizures, linked to quinolones and macrolides; and type 3, encephalopathy and cerebellar signs linked to metronidazole. AAE is evident within five days of onset of treatment, except for isoniazid and metronidazole, in which the effect can be delayed for up to three weeks. MRI abnormalities are typically not seen in AAE except for metronidazole, which has been reported to show increased signal changes on MRI T2 in the dentate nucleus, brainstem, and corpus callosum [49].

Environmental toxins — A variety of environmental toxins can result in encephalopathy. Common agents include organophosphates, lead or other heavy metals, and hydrocarbons. Acute symptoms of organophosphate toxicity include headache, irritability, sweating, and twitching resulting in muscle weakness [50]. (See "Organophosphate and carbamate poisoning".)

Lead ingestion may result in irritability, lethargy, and delayed cognitive and motor development [51]. Severely affected patients may present with seizures or coma, resulting from cerebral edema. (See "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Encephalopathy'.)

Reye syndrome — Reye syndrome is a rapidly progressive encephalopathy with hepatic dysfunction, which often begins several days after apparent recovery from a viral illness, especially varicella or influenza A or B [20,52,53]. Most cases occur in spring or winter. It is characterized by vomiting and confusion, rapidly evolving to seizures and coma. Hepatomegaly is common, but icterus is usually mild or absent. Laboratory testing reveals markedly elevated aminotransferase activity, increased prothrombin time, hyperammonemia, hypoglycemia, and metabolic acidosis [20]. The liver and other visceral organs have marked steatosis, which may be evident on ultrasound or computed tomography (CT). Renal and cardiac failure may ensue. Increased ICP is an important contributor to the morbidity and mortality of Reye syndrome and should be managed accordingly. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis" and "Evaluation and management of elevated intracranial pressure in adults".)

From a peak incidence in 1980 of 1 case per 100,000 children, rates of Reye syndrome fell dramatically following the identification of salicylate use as a risk factor [52] and advisories against use of aspirin in febrile children, especially in cases with varicella or influenza (see "Clinical features of varicella-zoster virus infection: Chickenpox", section on 'Neurologic complications') [52]. Reye syndrome is a rare occurrence, with rates of one case per million children in the United States (1991 to 1994) [54].

A number of inborn errors of metabolism either predispose to Reye syndrome or are responsible for some cases of Reye-like syndrome. These include medium-chain acyl-coenzyme A dehydrogenase deficiency and other fatty acid oxidation disorders, and urea cycle disorders [20]. It is possible that some of the apparent decline in Reye syndrome is due to improved diagnosis of these inborn errors of metabolism. (See "Inborn errors of metabolism: Classification".)

Cases of Reye syndrome have been reported only rarely in association with salicylate treatment for Kawasaki disease [55,56]. Similarly, there are scattered reports of Reye syndrome occurring during treatment with nonsteroidal antiinflammatory drugs for juvenile idiopathic arthritis or other connective tissue diseases. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis", section on 'Other clinical findings' and "Kawasaki disease: Initial treatment and prognosis", section on 'Aspirin'.)

MIMICS OF TOXIC-METABOLIC ENCEPHALOPATHY — The first goal of the diagnostic evaluation described below is to exclude disorders that can mimic acute TME, including:

●Intracranial hemorrhage (ICH) – ICH can result from accidental or abusive head trauma or from rupture of a vascular malformation. ICH will usually be identified reliably on neuroimaging. (See "Child abuse: Evaluation and diagnosis of abusive head trauma in infants and children" and "Intracranial subdural hematoma in children: Clinical features, evaluation, and management" and "Intracranial epidural hematoma in children" and "Hemorrhagic stroke in children".)

●Cerebral venous thrombosis – Cerebral sinus vein and dural venous thrombosis (CSVT) in children is most commonly associated with procoagulant states and/or dehydration. CSVT results in increased intracranial pressure (ICP). Sagittal sinus thrombosis, when complete, leads to severe ICP elevation, venous infarction, and seizures. The diagnosis is made with appropriate neuroimaging. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

●Central nervous system (CNS) infection – Meningitis and encephalitis can present with altered consciousness and/or seizures. Lumbar puncture (LP) with appropriate microbiology studies distinguishes these infectious causes from TME. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis" and "Acute viral encephalitis in children: Clinical manifestations and diagnosis".)

●Mass effect – Brain tumor and brain abscess are important considerations that can be identified with appropriate neuroimaging. Clinical findings include headache, hemiparesis or other focality on neurologic examination, and papilledema. (See "Clinical manifestations and diagnosis of central nervous system tumors in children" and "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".)

●Hydrocephalus – Hydrocephalus of any cause, when progressive, will cause increased ICP. Clinical findings include headache, vomiting, impaired upgaze, and lethargy evolving to coma. Hydrocephalus is readily identified on brain imaging. (See "Hydrocephalus in children: Physiology, pathogenesis, and etiology" and "Hydrocephalus in children: Clinical features and diagnosis".)

●Seizure-related – Nonconvulsive seizures and absence status epilepticus may result in confusion, altered mentation, and even coma. Prompt recognition is crucial and the electroencephalogram (EEG) is usually diagnostic if performed during the ictus. Unwitnessed seizures can result in a postictal state that mimics TME, in which case the EEG findings are likely to be generalized slowing and will not so readily indicate an epileptic origin. Findings include lethargy, confusion, agitation, and, at times, delirium or psychosis [57]. Resolution is observed within a few hours, especially if seizures are partial complex [58]. A rare prolonged postictal encephalopathy lasting 4 to 10 days has been described following prolonged or clusters of generalized seizures among patients with cognitive or structural abnormalities [59]. (See "Clinical features and complications of status epilepticus in children".)

●Acute disseminated encephalomyelitis – Acute disseminated encephalomyelitis (also known as postinfectious encephalomyelitis) typically occurs following a viral infection. Magnetic resonance imaging (MRI) is often helpful in excluding this diagnosis, but radiologic evidence of demyelination may not be evident early in the course of the illness. When parainfectious encephalopathy develops in children younger than two years of age, the clinical and pathologic features are different from those in older patients [1]. Generalized seizures and increased ICP occur more commonly in the younger patients. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)

●Autoimmune and paraneoplastic encephalitis – These are a heterogeneous group of neurologic disorders mediated by autoantibodies (including anti-N-methyl-D-aspartate [NMDA] receptor antibodies, voltage-gated potassium channel antibodies [VGKC Ab], and numerous others). Autoimmune encephalopathy is characterized by acute or subacute neuropsychiatric symptoms, including refractory seizures and/or status epilepticus, delirium, movement disorder, cognitive dysfunction, behavioral changes, hallucinations, profound insomnia, catatonia, and dysautonomia [60]. The diagnosis is based on detection of specific antibodies in the cerebrospinal fluid (CSF) or serum. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

●Migraine-related – Confusional migraine is a migraine variant seen most often among children and adolescents. It presents with confusion that is often accompanied by agitation, dysarthria, and memory and visual disturbances. Recovery within 24 hours is usual [61]. Headache may not necessarily be present, but a family history of migraine usually is. Hemiplegic migraine is a rare mimic of TME. Individuals with hemiplegic migraine can develop a transient encephalopathy and/or coma following fever or minor trauma [62]. Migraine variants are diagnoses of exclusion; the diagnosis is made only after the encephalopathy recurs and other possible causes have been ruled out. (See "Hemiplegic migraine" and "Types of migraine and related syndromes in children", section on 'Confusional migraine'.)

CLINICAL FEATURES — Most clinical features of acute TME are nonspecific and do not reliably identify a particular etiology.

Mental status — Clinical findings in TME can range from subtle cognitive difficulties to florid delirium. Delirium is characterized by fluctuating levels of alertness and arousal, cognitive deficits, and disorganized behavior. The arousal state can alternate between hyperactive (ie, hypervigilance, agitation, hallucinations, and increased sympathetic outflow) and hypoactive (ie, depressed sensorium) states. Worsening brain dysfunction results in progressive disturbance of the level of consciousness from lethargy to obtundation, stupor, and coma. The initial presentation may be subtle and include shortened attention span, disorientation, disturbed cognitive function, and personality changes [1]. Cognitive dysfunction may include impaired memory, perceptual deficits, and difficulty processing new information.

Motor examination — A variety of motor abnormalities may be observed in patients with TME. Many of them have abnormal tone; persistent hypotonia or hypertonia can be seen. These abnormalities typically are diffuse and symmetric.

Generalized or focal seizure activity occurs commonly. Abnormal movements, including myoclonic jerks, fine tremors, and asterixis (difficulty with postural maintenance, often seen as a coarse, flapping tremor of the hands) may occur. Primitive reflexes, such as suck or grasp responses, may be elicited on examination. Other common features include brisk deep tendon reflexes and extensor plantar responses. In severely obtunded subjects, decorticate and decerebrate posturing may occur [63]. Subtle movements, some of which might be generated by brainstem activity, including features such as nystagmus, posturing, or sucking, chewing, dry retching, grimacing, and crying, may be seen in neonatal seizures [64,65].

Pupillary response — The pupillary response can be helpful in identifying the etiology of TME. In an obtunded patient, examination of the pupils may suggest a possible intoxication (eg, mydriasis with anticholinergic drugs, miosis with opiates) (table 3).

However, in the setting of coma and loss of other brainstem functions (eg, doll's eyes, corneal reflex), the finding of poor pupillary response to light suggests severe anoxic/ischemic damage from hypoxic-ischemic encephalopathy (HIE) or elevated intracranial pressure (ICP).

The pupillary response is typically, although not invariably, preserved in other metabolic etiologies (eg, diabetic ketoacidosis [DKA], hypoglycemia, electrolyte derangements, inborn error of metabolism, liver or renal failure). Unequal pupils may suggest a brainstem insult or an intracranial lesion or cerebral edema causing compression of the oculomotor nerve or nucleus within the brainstem.

Respiratory abnormalities — Respiratory abnormalities occur commonly in patients with TME. Hyperventilation caused by metabolic and/or respiratory acidosis, or hypoventilation causing respiratory acidosis or caused by metabolic alkalosis, can result from a variety of causes [2].

Autonomic dysfunction — Autonomic dysfunction may be evident in some cases as manifested by temperature instability, labile blood pressure, and/or gastrointestinal dysmotility.

DIAGNOSTIC APPROACH — The goals of the diagnostic evaluation are to identify the underlying cause of acute TME (table 1) and exclude important mimics that can have a similar presentation, including intracranial hemorrhage (ICH), abusive head trauma, cerebral venous thrombosis, meningitis, encephalitis, mass lesions, hydrocephalus, nonconvulsive seizures, immune-mediated encephalitis/encephalomyelitis, and confusional migraine. (See 'Mimics of toxic-metabolic encephalopathy' above.)

The history may help establish a possible etiology. Relevant information includes signs or symptoms of systemic illness, duration and progression of the encephalopathy, previous episodes of confusion or altered conscious state, and possible exposure to medications or toxins. The family history may also be helpful (eg, metabolic disorders in siblings or hemiplegic migraine).

Routine blood and urine tests — For patients with TME of uncertain etiology, the initial laboratory investigation includes the following:

●Complete blood count.

●Blood glucose, electrolyte panel, and serum concentrations of blood urea nitrogen, creatinine, calcium, magnesium, and phosphate.

●Liver enzymes (aspartate aminotransferase and alanine aminotransferase) and serum bilirubin.

●Coagulation studies (prothrombin time, activated partial thromboplastin time, and international normalized ratio).

●Lactate and ammonia levels.

●Arterial blood gas.

●Urine and serum toxicology screening, including blood lead level in children with potential lead exposure. A positive urine test for marijuana should be quantified, especially in young encephalopathic children. (See "Approach to the child with occult toxic exposure", section on 'Toxicology screens' and "Childhood lead poisoning: Clinical manifestations and diagnosis".)

●Thyroid function tests and serum cortisol concentrations if there are signs or symptoms suggesting an endocrinopathy. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents" and "Acquired hypothyroidism in childhood and adolescence".)

●Blood and urine tests for inborn errors of metabolism if indicated based on the clinical findings. (See "Inborn errors of metabolism: Identifying the specific disorder" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features".)

Cerebrospinal fluid studies — Lumbar puncture (LP) should be performed in all patients with unexplained encephalopathy unless there are contraindications (eg, coagulopathy, mass lesion). In many cases, neuroimaging is required before LP to exclude contraindications (mass lesion, midline shift). (See 'Neuroimaging' below.)

When performing an LP, it is important to measure the opening pressure to evaluate for elevated intracranial pressure (ICP), which can occur in many types of TME.

Samples of cerebrospinal fluid (CSF) should be sent for:

●Cell count and differential

●Glucose and protein

●Gram stain and bacterial culture

●Viral testing, including an encephalitis panel herpes simplex virus polymerase chain reaction, and other tests as clinically indicated (see "Acute viral encephalitis in children: Clinical manifestations and diagnosis", section on 'Identifying the viral pathogen' and "Viral meningitis in children: Clinical features and diagnosis", section on 'Detection of virus')

●Additional microbiologic tests as clinically warranted (eg, fungal cultures in patients who are immunocompromised) (see "Acute viral encephalitis in children: Clinical manifestations and diagnosis", section on 'Identifying the viral pathogen')

●Antibodies to N-methyl-D-aspartate (NMDA) receptors and voltage-gated potassium channel antibodies (VGKC Ab) (see "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Antibody testing')

●CSF lactate and pyruvate levels

Neuroimaging — Neuroimaging should be performed in most cases unless the etiology is readily apparent based on the initial evaluation (eg, if rapid blood tests reveal a severe electrolyte derangement, neuroimaging may not be necessary). Magnetic resonance imaging (MRI) is the preferred modality because it provides greater diagnostic detail and it doesn't expose the child to ionizing radiation [66,67]. For patients who are stable, MRI should be performed as the initial imaging study if it can be obtained in a timely fashion. However, MRI requires a long period of immobility for optimal imaging and often requires sedation/anesthesia. For unstable patients in the acute setting, computed tomography (CT) is often obtained as the initial study because it is often more readily available, is faster, and generally does not require sedation/anesthesia. CT is a useful tool to screen for gross abnormalities, including hemorrhage, advanced edema, herniation, skull fractures, hypoxic-ischemic injury, focal infarction, hydrocephalus, and large tumors or other mass lesions. MRI is more sensitive and specific to detect demyelination, early infarction and edema, anoxic changes, and cerebral sinus thrombosis. MRI should be performed if the diagnosis remains uncertain or if additional detail is needed for diagnostic or prognostic purposes.

Electroencephalography — The electroencephalogram (EEG) can both confirm global cerebral dysfunction and exclude subclinical seizures with greater sensitivity and reliability than can the clinical examination alone [4,15,37,47]. Patients with altered mental status such as confusion, obtundation, or coma should have an EEG to exclude nonconvulsive status epilepticus and subclinical seizures, and to assess severity of TME. In patients with overt seizures, the EEG will document epileptiform activity and characterize background activity. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis".)

MANAGEMENT APPROACH — Management of acute TME depends upon the nature and extent of encephalopathy. Patients with severe encephalopathy (ie, those with seizures, cardiorespiratory compromise, coma, or severe neurologic compromise) should be admitted to the intensive care unit. General measures should be instituted immediately, regardless of the cause. Once an etiology is identified, specific treatment should be applied.

General measures include:

●Cardiopulmonary support – Patients who are unable to adequately protect their airway should be intubated and given appropriate ventilatory support. In patients with cardiovascular compromise, vasopressor therapy may be necessary. Maintenance of an appropriate systemic blood pressure is important to achieve adequate cerebral perfusion pressure. (See "Technique of emergency endotracheal intubation in children" and "Shock in children in resource-abundant settings: Initial management".)

●Monitoring and supportive care – In the acute stage, vital signs, including heart rate and blood pressure, are monitored continuously. The head of the bed should be maintained at 30°. Measurements of blood gas should be obtained to monitor ventilatory status and metabolic status. Blood glucose and electrolyte concentrations should be assessed serially. Fluid input and output should be measured. (See "Treatment and prognosis of coma in children", section on 'Treatment'.)

●Review medications – The patient's medication list should be reviewed and all drugs with potential toxicity to the central nervous system (CNS) should be discontinued, if possible.

●Fever control – Fever should be lowered with antipyretics and/or cooling blankets. (See "Treatment and prognosis of coma in children", section on 'Temperature control'.)

●Fluid management – It is important to monitor fluid balance (eg, input, urine output, daily weight) and electrolyte status in patients with severe encephalopathy, as is the case with all critically ill children. Hypovolemia (if present) should be addressed with appropriate volume expansion (eg, 20 mL/kg normal saline bolus). Subsequent fluid management generally consists of isotonic maintenance intravenous fluids to maintain euvolemia. Fluid restriction is not typically necessary unless there is an underlying condition that places the child at risk for hypervolemia (eg, syndrome of inappropriate antidiuretic hormone secretion [SIADH], oliguric renal failure). Patients who have depressed mental status and those in whom airway reflexes are not intact are kept nil per os. Enteral feeding tubes are used to provide adequate nutrition in patients who are not able to feed by mouth. Parenteral nutrition is generally reserved for patients who are unable to resume enteral feeding after one week. (See "Maintenance intravenous fluid therapy in children" and "Overview of enteral nutrition in infants and children" and "Parenteral nutrition in infants and children".)

●Management of seizures – Seizures that are diagnosed clinically or by electroencephalogram (EEG) should be controlled. (See "Management of convulsive status epilepticus in children".)

●Management of elevated intracranial pressure (ICP) – Invasive ICP monitors, which are commonly used in the management of traumatic brain injury, are rarely indicated for management of TME, though there are some exceptions (eg, hepatic encephalopathy [HE], Reye syndrome, certain severe inborn errors of metabolism) and practice varies considerably [68]. For children with clinically suspected or known intracranial hypertension, management should include cerebroprotective measures to lower ICP and promote adequate cerebral perfusion. (See "Elevated intracranial pressure (ICP) in children: Management".)

SUMMARY AND RECOMMENDATIONS

●Acute toxic-metabolic encephalopathy (TME) is a condition of acute global cerebral dysfunction manifested by altered consciousness, behavior changes, and/or seizures in the absence of primary structural brain disease or direct central nervous system (CNS) infection. The causes of TME are diverse (table 1). The presentation of this condition in the infant or child may be subtle and not easily recognized. Because TME often is reversible and interruption of neuronal activity in the developing brain can have a long-lasting effect, prompt recognition and treatment are important. (See 'Introduction' above.)

●Despite a wide array of pathophysiologic mechanisms, the clinical manifestations of TME tend to be very similar. Most clinical features of acute TME are nonspecific and do not reliably identify a particular etiology. Changes in mental status range from subtle cognitive difficulties to florid delirium. Motor abnormalities may include hypotonia or hypertonia, abnormal movements (myoclonic jerks, fine tremors, and asterixis), and generalized or focal seizures. Pupillary response and respiratory abnormalities depend on the underlying cause of the TME. (See 'Clinical features' above.)

●The first goal of the diagnostic evaluation is to exclude conditions that can mimic TME, including intracranial hemorrhage (ICH), abusive head trauma, cerebral venous thrombosis, CNS infection (meningitis, encephalitis), mass lesions, hydrocephalus, nonconvulsive seizures, immune-mediated encephalitis/encephalomyelitis, and confusional migraine. (See 'Mimics of toxic-metabolic encephalopathy' above.)

●For patients with TME of uncertain etiology, the initial diagnostic evaluation includes routine blood and urine tests; lumbar puncture (LP) with measurement of opening pressure and appropriate cerebrospinal fluid (CSF) studies; neuroimaging; and electroencephalography (EEG). (See 'Diagnostic approach' above.)

●Management of acute TME depends upon the nature and extent of encephalopathy. Patients with severe encephalopathy (ie, those with seizures, cardiorespiratory compromise, coma, or severe neurologic compromise) should be admitted to the intensive care unit. General measures should be instituted immediately, regardless of the cause. Once an etiology is identified, specific treatment should be applied. General supportive care is largely aimed at preventing secondary brain injury and includes (see 'Management approach' above):

•Respiratory support (eg, intubation and mechanical ventilation if warranted, avoiding hypoxia, avoiding hyper- or hypocarbia) (see "Technique of emergency endotracheal intubation in children")

•Cardiovascular support (addressing hypovolemia if present, maintaining age-appropriate systolic blood pressure) (see "Shock in children in resource-abundant settings: Initial management")

•Maintaining the head of the bed at 30°

•Control of fevers (see "Treatment and prognosis of coma in children", section on 'Temperature control')

•Avoidance hypo- or hyperglycemia

•Control of seizures (see "Management of convulsive status epilepticus in children")

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Edwin Myer, MD, who contributed to an earlier version of this topic review.