Toxicology and Vitamin Deficiencies

• Effects of Toxic Doses
• Dilantin – atrophy of Purkinje and granular layers of cerebellum
• congenital fetal hydantoin syndrome (growth retardation, mental retardation, craniofacial abnormalities, limb abnormalities, microcephaly, hydrocephalus, neural tube defects)
• Level decreased by carbamazepine, pregnancy
• Level increased by almost everything else (coumadin, sulfa, INH, cimetidine, chloramphenicol, valproate, uremia)
• Depakote increases phenobarb and dilantin; Tegratol decreases them
• Opiates – hypothermia, decreased respiration, miosis, constipation, urinary retention, pruritis, sphincter of Oddi spasm (pancreatitis)
• withdrawal causes rhinorrhea, lacrimation, sweating, insomnia, mydriasis, cold/hot flashes
• Barbiturates – decreased mental status, respiratory/blood pressure/temperature changes
• intoxication causes poor respirations, coma, pulmonary edema; chronic use causes nystagmus
• Antipsychotics – phenothiazines can cause parkinsonism, dystonia, tardive dyskinesia, neuroleptic malignant syndrome (hyperthermia with increased CK and autonomic instability), ridigity, stupor, catatonia, cholestatic jaundice
• Vincristine – axonal degeneration, peripheral neuropathy
• causes respiratory failure if injected intrathecally
• Nitrosuria – necrotizing encephalomyelitis, arterial obliteration, axonal swelling
• Methotrexate – meningoencephalitis, transverse myelitis, stroke, subacute necrotizing leukoencephalitis
• Marchiafava-Bignami – cheap red wine
• demyelination and necrosis of genu and body of corpus callosum
• Central Pontine Myelinolysis – osmotic injury to vascular endothelium
• From increasing serum sodium level too fast (often in an attempt to correct hyponatremia)
• involves gray and white matter
• demyelination and necrosis without inflammation
• Chemotherapeutic Agent Toxicities

• Vincristine – microtubules
• Causes Peripheral neuropathy
• Vinblastine – microtubules
• Causes peripheral neuropathy
• Procarbazine
• Causes diffuse aching, reversible ataxia and polyneuropathy
• 5-FU and Ara-C
• Cerebellar ataxia
• Methotrexate
• Aseptic meningitis and necrotizing leukoencephalopathy
• Cisplatin
• Periheral polyneuropathy
• Paclitaxel – inhibits tubulin depolymerization
• Sensory neuropathy
• Actinomycin D – inhibits transcription
• Dinitrophenol – inhibits oxidative phosphorylation
• Heavy Metal Toxicities
• Arsenic

• Reacts with enzyme sulfhydryl radicals
• Fowler’s solution used to treat syphilis
• Causes seizures, encephalopathy, peripheral neuropathy, punctate white matter hemorrhages, nausea/vomiting/abdominal pain

• chronic exposure causes increased pigments in palms and soles

• MEE’s lines – transverse white lines on fingernails
• Test hair and urine for arsenic levels
• Treat with BAL (dimercaprol), gastric lavage, and exchange transfusion
• Lead
• Toxicity also called plumbism
• Causes emesis, ataxic, lethargy, seizures, encephalopathy, abdominal pain
• May increase ICP over time causing papilledema
• in children causes irritability/seizures then ataxia and coma
• in adults causes peripheral neuropathy (often radial causing wrist drop), anemia with RBC stippling, metaphyseal lines, gingival lines; increased urinary copoprophyrin and delta ALA
• Lead lines at metaphyses of long bones
• Basophilic stippling of RBCs and bone marrow normoblasts
• In adults, see black line along gingival margins and bilateral wrist drop
• Increased urine excretion of coproprophyrin and d-aminolovulic acid
• Historic diagnosis – add acetic acid to urine – turns red under Woods lamp
• Treat with BAL, EDTA, oral penicillamine
• Manganese
• Seen in manganese ore workers and minors
• Neuronal loss in the pallidium and striatum
• parkinsonism, psychiatric changes, headache
• Causes hallucinations and either dystonic or Parkinsonian syndrome
• No good treatment
• Mercury
• Causes confusion, pregressive cerebellar syndrome (ataxia, dysarthria), choreoathetosis, concentric constriction of the vsual fields, tremor, hearing loss, psychiatric dysfunction, tremor, peripheral neuropathy, cerebellar changes, GI upset and acute tubular necrosis in the kidney
• treat with penicillamine (not BAL which increases mercury levels in brain)
• Behavioral changes – Mad Hatter
• Children have painful neuropathy – acrodynia
• Neuronal loss in the calcarine cortex and cerebellar granular layer
• Inhibits RNA translation
• Treatment with penicillamine and dimercaptosuccinic acid
• DO NOT treat with BAL (increases mercury in the brain)
• Thallium
• Causes painful sensory polyneuropathy, optic atrophy, opthalmoplegia, alopecia
• Detectable in urine
• Oral potassium may help with excretion
• Iron
• Treat with defroxamine
• Gold
• Causes polyneuropathy
• Treat with BAL, penicillamine
• Organophosphates (such as malthion or parathion)
• Long-lasting acetylcholinesterare inhibitors – indirect cholinergic agonists
• Acute – causes sweating, salivation, lacrimation, cramping, emesis, diarrhea, miosis, bradycardia, confusion
• Chronic
• Distal symmetric sensorimotor neuropathy
• Weakness of proximal muscles and motor cranial nerves
• Treat with atropine, Pralidoxime (2-PAM)
• Pland and Animal Toxins
• Jamison weed (atropine)

• Indirect cholinergic agonist
• Causes tachycardia, flushed skin, mydriasis, confusion
• Treat with physostigmine
• Ergot
• From the rye fungus Claviceps purpurea
• Used as a vasoconstrictor for migraine or uterine atony
• Overdose causes degeneration of posterior columns and peripheral neuropathy
• Loss of sensation and reflexes (similar to tabes dorsalis)
• Can result in seizures and myoclonus
• Lathyrism
• Toxin in chickling cetch
• Seen in India and North Africa
• Causes pain, parasthesias, and LE weakness
• Dagnosed by beta-N-oxalylaminoalanine (BOAA, an excitatory amino acide) in urine
• Mushrooms
• Amantia phalloides and muscaria
• Cyclopeptides disrupt RNA metabolism
• Cause nausea, emesis, diarrhea, ataxia, seizures, hallucinations, coma
• No effective antidote
• Buckthorn toxin
• Causes rapidly-progressively motor polyneuropathy
• Resembles Guillian-Barre clinically but has normal CSF findings
• From a shrub in Mexico
• Fish neurotoxins
• Tetrodotoxin, cinguatoxin, saxitoxin, brevitoxin
• Block sodium channels
• Cause nausea, emesis, diarrhea, perioral and distal parasthesias, coma
• Supportive treatment only
• a-bungarotoxin
• Anticholinergic
• Black widow spider venom – depletion of acetylcholine stores in neuromuscular junction
• causes cramp, spasm, weakness
• treat with calcium and magnesium
• Tetraethylammonium (TEA) – blocks potassium channels
• Vitamin Deficiencies
• Thiamine – used for transketolase
• mostly in mamillary bodies, also periventricular thalamus, periaqueductal gray, dorsal motor nucleus of vagus, vestibular nuclei, superior cerebellar vermis, cranial nerves III-IV
• Wernicke’s encephalopathy – release of excitatory neurotransmitters
• causes conjugate gaze abnormalities with lateral rectus palsy, nystagmus, ataxia, confusion
• brown-gray discoloration with edema and hemorrhage in gray matter and white matter from demyelination, necrosis, loss of Purkinje cells and dentate astrocytes
• Korsakoff psychosis – loss of short-term memory
• affects mediodorsal thalamus (similar to HSV)
• Thiamine (B1) – beri-beri, in rice eaters
• peripheral neuropathy with axonal degeneration, demyelination, orthostasis, heart disease
• Niacin – tryotophan deficiency in corn eaters
• pellagra (skin rash, decreased posterior column function, spastic lower extremities, weakness, confusion)
• B12 – subacute combined deficiency
• spongiform demyelination of posterior column of lower cervical/upper thoracic spinal cord
• decreased vision, decreased mental status, peripheral neuropathy
• low intracellular levels of B12 confirmed by high levels of serum methylmalonic acid and homocysteine
• Pyridoxine – causes lower extremity pain/weakness
• Vitamin A – decreased vision, pseudotumor
• Vitamin D – rickets
• Vitamin C – biliary atresia, thick dystrophic axons in posterior column, polyneuropathy