Nutritional, Alcohol-Related & Toxic Neurologic Disorders

Thiamine Deficiency: Wernicke and Korsakoff

Who is at risk. Thiamine (vitamin B1) stores last only a few weeks. Deficiency follows alcohol use disorder, hyperemesis gravidarum, bariatric surgery, anorexia nervosa, prolonged vomiting, malabsorption, dialysis and refeeding after starvation.

Mechanism. Thiamine pyrophosphate is the cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and transketolase. Without it, highly metabolic periventricular neurons fail, producing symmetric lesions of the mammillary bodies, medial (dorsomedial) thalami and periaqueductal gray. MRI shows T2/FLAIR hyperintensity in these regions acutely and mammillary body atrophy later, and red cell transketolase activity is low — but neither test should delay treatment.

Wernicke encephalopathy. The classic triad is acute confusion, eye signs (nystagmus, lateral rectus palsy, conjugate gaze palsy) and gait ataxia, yet only a minority of patients show all three. The diagnosis is clinical: any at-risk patient with one or more features should be treated.

Korsakoff syndrome. Untreated or late-treated Wernicke leaves a chronic amnestic state: severe anterograde amnesia with some retrograde loss, confabulation (sincere invention of details to fill memory gaps), apathy and poor insight, while attention, language and alertness are relatively preserved. Because it reflects structural thalamic and mammillary damage, it is largely irreversible. The best treatment is prevention — prophylactic thiamine for every at-risk patient and prompt treatment of Wernicke.

An alert patient with isolated amnesia and confabulation has Korsakoff syndrome; a fluctuating, inattentive patient has delirium.

Osmotic Demyelination Syndrome

Mechanism. When hyponatremia has lasted more than 48 hours, brain cells adapt by exporting organic osmolytes. A rapid rise in serum sodium then dehydrates oligodendrocytes faster than they can recover osmolytes, producing demyelination that is most prominent in the central pons (central pontine myelinolysis) but can involve the basal ganglia and thalami.

Presentation. Characteristically biphasic: the encephalopathy improves as sodium rises, then days later dysarthria, dysphagia, spastic quadriparesis, pseudobulbar affect, behavioral change, seizures or coma develop. The worst outcome is a locked-in state with only vertical eye movements and blinking preserved. Extrapontine lesions cause parkinsonism or other movement disorders. MRI may not show the pontine "trident" lesion until 1–2 weeks after onset.

Prevention and rescue. Monitor sodium frequently during correction and anticipate brisk water diuresis once the cause (for example, volume depletion or thiazides) is removed. If the limit is exceeded, re-lower sodium with D5W, with or without desmopressin to stop free-water losses.

Alcohol-Related Neurologic Disease

Cerebellar degeneration. Chronic heavy drinking degenerates the anterior superior vermis, producing a broad-based gait with leg ataxia while arm coordination, speech and eye movements are largely spared. It stabilizes or partly improves with abstinence, thiamine and nutrition.

Alcoholic neuropathy. A painful, length-dependent axonal sensorimotor polyneuropathy with burning feet and small-fiber sensory loss, caused by direct alcohol toxicity plus thiamine and other nutritional deficiencies; it slowly improves with abstinence and nutrition.

Marchiafava-Bignami disease. A rare demyelination and necrosis of the corpus callosum in chronic, malnourished drinkers, first described in Italian red-wine drinkers. It presents acutely with confusion, seizures, dysarthria or coma, or subacutely with dementia and interhemispheric disconnection signs such as apraxia and alien hand. MRI shows T2/FLAIR hyperintensity and swelling of the corpus callosum; treatment is high-dose thiamine and other B vitamins.

Vitamin and Mineral Syndromes

Copper deficiency. Excess zinc (supplements, zinc-containing denture cream) induces intestinal metallothionein, which binds copper and blocks its absorption; bariatric surgery and malabsorption also deplete copper. The result is a myeloneuropathy indistinguishable from B12-related subacute combined degeneration plus anemia and neutropenia. B12 and methylmalonic acid are normal, while serum copper and ceruloplasmin are low. Stopping zinc and replacing copper corrects the cytopenias, but neurologic deficits often persist.

Vitamin B6. Deficiency from isoniazid, hydralazine, penicillamine, alcohol or malnutrition causes painful distal sensory neuropathy, seizures (pyridoxal phosphate is the cofactor for GABA synthesis), sideroblastic anemia, cheilosis and glossitis; at-risk patients starting isoniazid receive prophylactic pyridoxine. Paradoxically, chronic megadoses above the 100 mg/day upper limit are toxic to dorsal root ganglia and cause a sensory neuronopathy with ataxia that improves after the supplement is stopped.

Vitamin E and niacin. Vitamin E deficiency from fat malabsorption produces a Friedreich-like spinocerebellar syndrome with ataxia, areflexia, proprioceptive loss, ophthalmoplegia and retinopathy. Niacin deficiency causes pellagra, whose "4 Ds" are photosensitive dermatitis (Casal necklace), diarrhea, dementia and death; carcinoid syndrome diverts tryptophan, niacin's precursor, into serotonin, and Hartnup disease impairs tryptophan absorption.

Heavy Metals

Lead. Lead inhibits ALA dehydratase and ferrochelatase, producing a microcytic anemia with basophilic stippling and elevated zinc protoporphyrin. Adults exposed through battery recycling, smelting, removing old paint, retained bullets or folk remedies develop a motor neuropathy with wrist or foot drop, colic, hypertension, gout and nephropathy. Children absorb more lead and develop learning and behavioral deficits and, at high levels, encephalopathy with cerebral edema and seizures; radiographs may show metaphyseal lead lines. Diagnosis is a venous blood lead level. After removing the source, children with levels of 45 μg/dL or more receive oral succimer, and those with encephalopathy or levels of 70 μg/dL or more receive dimercaprol followed by CaNa2EDTA.

Arsenic, mercury and thallium. Acute arsenic poisoning causes vomiting, rice-water diarrhea, QT prolongation and a garlic odor, then within 1–3 weeks a painful ascending axonal neuropathy that can mimic Guillain-Barré; chronic exposure (contaminated well water) adds Mees lines, hyperpigmentation and palmar keratoses. Mercury vapor (broken thermometers, gold mining) causes erethism — the shyness, irritability and tremor of the "mad hatter" — plus gingivitis, while methylmercury from contaminated fish causes ataxia and constricted visual fields. Thallium, found in rodenticides and used in poisonings, causes an excruciating painful neuropathy followed by alopecia 2–3 weeks later; oral Prussian blue binds it in the gut and interrupts its recirculation.

In lead encephalopathy, dimercaprol is started before CaNa2EDTA because EDTA given alone can mobilize lead into the brain.