Causes of acute toxic-metabolic encephalopathy in children and their clinical features

Diagnosis	Mental status changes	Seizures	Focal neurologic signs	Elevated ICP	Characteristic neuroimaging findings	Other features
Hypoxic-ischemic encephalopathy
	Ranges from lethargy to coma*	++	++	+	Edema, infarction, restricted DWI signal changes	Typically a straightforward diagnosis after an obvious precipitating event, such as drowning, airway obstruction, or cardiopulmonary arrest
Sepsis
	Ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)	+/–	–	–	T2 FLAIR and restricted DWI signal changes	Signs of systemic infection (eg, fever, elevated WBC) Diagnosis is confirmed with appropriate microbiology studies
Metabolic disorders
Hypoglycemia	Ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	++	+	+/–	–	Signs of increased epinephrine release (eg, tremor, diaphoresis) may be present, but are not universal
Diabetic ketoacidosis	Ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	+/–	–	+	Cerebral edema	Nausea, vomiting, abdominal pain, hyperventilation (Kussmaul breathing) May occur in new-onset DM or as a complication of known DM
Inborn errors of metabolism	Ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	Depends on specific disorder^¶				Patients may have recurrent episodes of encephalopathic changes associated with vomiting and hypotonia that may be associated with an intercurrent illness or prolonged fasting Laboratory abnormalities may include hypoglycemia, hyperammonemia, or lactic acidosis, depending on the type of inborn error of metabolism^¶
Electrolyte derangements
Hypernatremia	Ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	+	–	–	Pontine or extrapontine myelinolyses	Nonspecific initial manifestations 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 Most common cause of hypernatremia in children is excessive fluid losses; patients may have manifestations of hypovolemia, including tachycardia, dry mucous membranes, and poor peripheral perfusion
Hyponatremia	Ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	++	–	+	Edema; pontine or extrapontine myelinolyses	Neurologic symptoms are typically observed with plasma sodium levels <125 mEq/L Severe symptoms (lethargy, obtundation, and seizures) may occur as the level falls below 120 mEq/L
Hypercalcemia	Irritability, behavioral changes; ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	+/–	–	–	–	Anorexia, nausea, vomiting, hypertension, bradycardia, nephrocalcinosis, pruritus, headache, weakness Life-threatening symptoms may occur with serum concentrations >15 mg/dL (3.75 mmol/L)
Hypocalcemia	Ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	++	–	–	–	Tetany, positive Trousseau and Chvostek signs, laryngospasm
Hypermagnesemia	Ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	–	Fixed dilated pupils	–	–	Weakness, respiratory depression, hypotension, ECG changes
Hypomagnesemia	Delirium, irritability, hallucinations; ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	+	–	–	–	Tremors, muscle twitching, myoclonic jerks, choreiform movements, and nystagmus; coma and generalized seizures may occur in severe cases
Endocrine disorders
Hypothyroidism	Apathy, slow cognition, psychosis; ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)	–	–	–	–	Hyponatremia, hypothermia, bradycardia, central hypoventilation History of fatigue, weight gain, constipation, and cold intolerance A precipitating trigger (eg, infection, burn) may be present
Hyperthyroidism	Agitation, irritability, psychosis, and, rarely, coma	+/–	–	–	–	Tremor, tachycardia, cardiac dysrhythmias, hypertension fever, fatigue, weight loss
Adrenal crisis	Delirium; mood and behavioral changes; cognitive impairments; psychosis; hallucinations; ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)	–	–	–	–	Hypotension, nausea and vomiting, abdominal pain, fever, hyponatremia, hyperkalemia Potential triggers include dehydration, trauma, surgery, infection, or other physical stress or stopping glucocorticoid treatment
Hypertension
	Irritability, anxiety, agitation	PRES: ++ HTE: +	–	–	Cortical and white matter signal changes in parieto-occipital region T2 and FLAIR	Severe hypertension
Organ failure
Hepatic failure	Delirium, apathy; ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	+	Decerebrate/decorticate posture	+	Edema	Jaundice, ascites, and other clinically evident signs of liver failure are usually present Asterixis, grimacing, jerking movements
Renal failure/uremia	Disorientation, hallucinations, rambling speech; ranges from mild (eg, confusion, disorientation, lethargy) to severe (eg, coma)*	+	–	–	–	Laboratory evidence of severe renal impairment Anorexia, tremor, weakness, peripheral neuropathy, myoclonus, and asterixis ("uremic flap")
Reye syndrome
	Confusion, rapidly evolves to coma	++	+/–	++	Edema, restricted DWI signal changes	Hepatomegaly, markedly elevated transaminases, hyperammonemia, hypoglycemia, metabolic acidosis Typically begins several days after apparent recovery from a viral illness, especially varicella or influenza A or B
Drugs and toxins
	Depends on specific agent^Δ

ICP: intracranial pressure; DWI: diffusion-weighted imaging; FLAIR: fluid attenuation inversion recovery; WBC: white blood cell; DM: diabetes mellitus; ECG: electrocardiogram; PRES: posterior reversible encephalopathy syndrome; HTE: hypertensive encephalopathy.

* The severity of encephalopathy generally reflects the degree of metabolic derangement or hypoxic insult, with the exception of uremic encephalopathy, in which the severity of encephalopathy does not always correlate with the degree of azotemia.

¶ Refer to separate UpToDate content on inborn errors of metabolism for additional details.

Δ Numerous drugs and toxins can cause encephalopathy in children. Broad categories include sedatives (eg, benzodiazepines, barbiturates, alcohol, opiates), anticholinergic agents (eg, tricyclic antidepressants, antipsychotic medication, antihistamines), antiseizure medications (eg, phenytoin, carbamazepine, valproate), salicylates, immunosuppressive agents, antibiotics, and environmental toxins (eg, lead, organophosphates). Refer to separate UpToDate content on these agents for further details.

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Causes of acute toxic-metabolic encephalopathy in children and their clinical features