# Neurotoxicology and Metabolic Encephalopathies

## Introduction

Metabolic encephalopathies and neurotoxic exposures are among the most common causes of altered mental status encountered by neurologists. These conditions are important because they are frequently reversible when identified early. A systematic approach to diagnosis, guided by clinical context and targeted laboratory evaluation, is essential for optimal patient outcomes.

## General Principles

Encephalopathy refers to a diffuse disturbance of brain function manifesting as altered attention, cognition, and level of consciousness. Metabolic and toxic encephalopathies typically produce symmetric, non-focal neurological findings. The presence of focal signs should raise suspicion for a structural lesion, though certain metabolic conditions (hypoglycemia, hepatic encephalopathy, hyponatremia) can produce focal deficits. EEG characteristically shows diffuse slowing in the theta to delta range with triphasic waves in specific conditions.

## Hepatic Encephalopathy

Hepatic encephalopathy is caused by accumulation of ammonia and other neurotoxins due to hepatic dysfunction or portosystemic shunting. The West Haven classification ranges from grade I (subtle cognitive changes) through grade IV (coma). Clinical features include asterixis (negative myoclonus), constructional apraxia, personality changes, and hyperammonemia. EEG may show characteristic triphasic waves, though these are not specific to hepatic encephalopathy. Treatment consists of lactulose (titrated to 2-3 bowel movements daily) and rifaximin, along with identification and treatment of precipitants (infection, GI bleeding, constipation, electrolyte imbalance).

## Uremic Encephalopathy

Uremic encephalopathy develops in advanced kidney failure, typically with GFR less than 15 mL/min. Clinical features include cognitive decline, asterixis, myoclonus, seizures, and peripheral neuropathy. Dialysis disequilibrium syndrome is a paradoxical neurological worsening during or after rapid dialysis due to osmotic fluid shifts, presenting with headache, nausea, seizures, and cerebral edema. Treatment is initiation or optimization of renal replacement therapy.

## Electrolyte Disturbances

### Hyponatremia

Hyponatremia is the most common electrolyte disorder causing encephalopathy. Symptoms correlate with the rate of decline more than the absolute level and include headache, nausea, confusion, seizures, and coma. Osmotic demyelination syndrome (ODS) occurs with overly rapid correction of chronic hyponatremia (greater than 8-10 mEq/L in 24 hours) and classically affects the central pons but can be extrapontine. Treatment involves restricting the correction rate and using hypertonic saline (3%) for severe symptomatic hyponatremia.

### Hypercalcemia

Hypercalcemia causes lethargy, confusion, psychosis, and coma. It is associated with a shortened QT interval on ECG. Common causes include primary hyperparathyroidism and malignancy.

### Hypo- and Hypermagnesemia

Hypomagnesemia causes seizures, tremor, tetany, and cardiac arrhythmias. Hypermagnesemia causes depressed reflexes, respiratory depression, and cardiac arrest.

## Hypoglycemic Encephalopathy

The brain is critically dependent on glucose as its primary energy substrate. Symptoms develop when blood glucose falls below approximately 50-60 mg/dL and include tremor, diaphoresis, confusion, seizures, focal deficits (hemiplegia), and coma. Prolonged severe hypoglycemia causes selective neuronal death in the cortex, hippocampus, and basal ganglia. Treatment is immediate IV dextrose (D50) or intramuscular glucagon, with identification and treatment of the underlying cause.

## Wernicke Encephalopathy

Wernicke encephalopathy is caused by thiamine (vitamin B1) deficiency. The classic triad consists of encephalopathy, oculomotor dysfunction (nystagmus, ophthalmoplegia), and gait ataxia, though the complete triad is present in only one-third of cases. Risk factors include alcohol use disorder, malnutrition, bariatric surgery, hyperemesis gravidarum, and prolonged TPN without supplementation. MRI shows T2/FLAIR hyperintensity in the mammillary bodies, medial thalami, periaqueductal gray, and tectal plate. Treatment is emergent IV thiamine (500 mg IV three times daily for 3 days, then 250 mg daily) administered before glucose.

## Toxic Encephalopathies

### Opioid Toxicity

Opioid toxicity presents with miosis (pinpoint pupils), respiratory depression, and depressed consciousness. Treatment is naloxone 0.4-2 mg IV, which may require repeat dosing or continuous infusion.

### Serotonin Syndrome

| Feature | Serotonin Syndrome | Neuroleptic Malignant Syndrome |
|---|---|---|
| Onset | Rapid (hours) | Gradual (days) |
| Causative agent | Serotonergic drugs (SSRIs + MAOIs, tramadol, linezolid) | Dopamine antagonists (antipsychotics) |
| Reflexes | Hyperreflexia, clonus | Bradyreflexia |
| Muscle tone | Myoclonus, clonus (lower extremity) | Lead-pipe rigidity |
| Pupils | Mydriasis | Normal |
| Diaphoresis | Present | Present |
| Treatment | Cyproheptadine, BZDs, cooling | Dantrolene, bromocriptine, cooling |

Serotonin syndrome is caused by serotonergic drug interactions (SSRIs plus MAOIs, tramadol, linezolid). Clinical features include altered mental status, hyperthermia, clonus (especially lower extremity), hyperreflexia, diaphoresis, and diarrhea. It is distinguished from neuroleptic malignant syndrome by the presence of clonus and hyperreflexia (NMS has rigidity and bradyreflexia). Treatment involves discontinuing offending agents, cyproheptadine, benzodiazepines, and cooling measures.

### Neuroleptic Malignant Syndrome

NMS is caused by dopamine receptor blockade (antipsychotics, antiemetics, withdrawal of dopaminergic medications). Clinical features include hyperthermia, severe rigidity ("lead pipe"), altered consciousness, autonomic instability, and elevated CK. Treatment involves discontinuing the offending agent, dantrolene, bromocriptine, and supportive care.

### Heavy Metal Toxicity

Lead causes encephalopathy, peripheral neuropathy (wrist drop), abdominal pain, and basophilic stippling on blood smear. Mercury causes tremor, personality changes (erethism), visual field constriction, and peripheral neuropathy. Arsenic causes encephalopathy, painful sensorimotor neuropathy, Mees lines on nails, and GI symptoms. Manganese causes parkinsonism (manganism) with predominant dystonia, psychiatric symptoms, and MRI T1 hyperintensity in the globus pallidus.

### Carbon Monoxide Poisoning

Carbon monoxide poisoning presents with headache, confusion, cherry-red skin color (unreliable), and loss of consciousness. A delayed neuropsychiatric syndrome with cognitive and personality changes may develop days to weeks after exposure. MRI shows bilateral globus pallidus lesions and white matter demyelination. Treatment is 100% oxygen, with hyperbaric oxygen therapy in severe cases.

## Diagnostic Approach

The workup includes a comprehensive metabolic panel, hepatic function tests, ammonia level, thyroid function tests, and serum and urine toxicology screens. Arterial blood gas assesses acid-base status. Serum osmolality and osmolar gap (elevated in methanol and ethylene glycol poisoning) should be obtained. Heavy metal levels are checked when exposure is suspected. EEG evaluates for subclinical seizures and grades encephalopathy severity. MRI brain with DWI provides structural evaluation and pattern recognition.

## Clinical Pearls

Thiamine must always be administered before glucose in malnourished or alcoholic patients to prevent precipitation of acute Wernicke encephalopathy. Triphasic waves on EEG are suggestive of but not specific to hepatic encephalopathy; they can be seen in uremia, sepsis, and medication toxicity. The rate of sodium correction is more important than the absolute level; overly rapid correction risks osmotic demyelination syndrome. Serotonin syndrome and NMS can appear similar; the presence of clonus and hyperreflexia favors serotonin syndrome, while lead-pipe rigidity and bradyreflexia favor NMS. Focal neurological deficits can occur in metabolic encephalopathies (especially hypoglycemia and hepatic encephalopathy) and should not automatically exclude a metabolic cause.

## References
- Weiss N, Regard L, Bhatt M, et al. Metabolic encephalopathies. Presse Med. 2023;52(1):104157.
- Wijdicks EFM. Hepatic encephalopathy. N Engl J Med. 2016;375(17):1660-1670.
- Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
- Galvin R, Brathen G, Ivashynka A, et al. EFNS guidelines for diagnosis, therapy, and prevention of Wernicke encephalopathy. Eur J Neurol. 2010;17(12):1408-1418.