Neurotoxins are compounds that are toxic, or potentially toxic, to the central and/or peripheral nervous system. Capable of mimicking neurologic disorders, neurotoxins can be classified into one of three categories: (1) drugs(prescription and illicit), (2) chemicals (industrial, household, and abused agents), and (3) environmental (biologic agents and naturally occurring chemicals).
Establishing causation is paramount to the correct diagnosis and the treatment for any patient with a suspected neurotoxic syndrome. The steps involved in determining if a neurotoxin is the causative agent are those established by Sir Austin Bradford Hill in differentiating association from causation in epidemiologic studies.
1. Exposure. Did an exposure occur? Requires quantifying the level of a toxin in biologic specimens (blood, urine, and hair) or in the environment (air and water). In some cases, historical features alone may be adequate.
2. Temporality. Did symptoms begin concurrent with or after the exposure? A few toxins have long latent periods before symptoms develop but most cause symptoms that begin shortly after exposure.
3. Dose–response. Do persons with higher doses and longer exposures have more severe symptoms?
4. Similarity to reported cases. Are the symptoms similar to those previously reported?
5. Improvement as exposure is eliminated. Do symptoms improve when the toxin exposure is eliminated or reduced? Most toxin-induced symptoms improve after cessation of exposure; although a period of worsening symptoms, or even chronic symptoms, can occur after exposure to a few toxins.
6. Existence of animal model. Do animal studies establish biologic feasibility? Animal studies can be helpful to predict toxicity in the absence of human studies; although some toxins do not have animal models and some toxins affect animals differently than humans.
7. Other causes eliminated. Are nontoxicologic causes excluded?
This overview is intended as a quick reference of those toxins clinicians are most likely to encounter. For more detailed work on the topic, see the recommended readings.
I. PERIPHERAL NERVOUS SYSTEM
A. Peripheral neuropathy. Toxic peripheral neuropathies typically present as acute or subacute, symmetric axonopathies, affecting the distal axons of the lower extremities.
1. Heavy metals.
a. Arsenic.
(1) Sources. Ground and well water, seafood (organic arsenic, nontoxic), paints, fungicides, insecticides, pesticides, herbicides, wood preservatives, cotton desiccants, and homicidal agents.
(2) Route of exposure. Ingestion is the most common, but absorption through skin and inhalation can occur.
(3) Acute toxicity.
(a) Systemic signs. Gastrointestinal (GI; nausea, vomiting, abdominal pain, and bloody diarrhea) symptoms occur within 24 hours of exposure; if severe, can be followed by hypovolemic shock, pancytopenia, and ventricular arrhythmias.
(b) Neurologic manifestations. Within 2 weeks, patients may develop a distal symmetric peripheral neuropathy presenting with burning and numbness in the feet. May present as ascending weakness similar to Guillain–Barré’s syndrome. Encephalopathy can develop in severe poisoning.
(4) Chronic toxicity.
(a) Systemic signs. Hypertension, peripheral vascular disease, renal failure, hepatitis, and keratoses of the palms and soles; associated with cancers of the skin, lung, liver, bladder, kidney, and colon.
(b) Neurologic manifestations. Peripheral neuropathy, stocking-glove distribution, and sensory > motor.
(5) Physical examination findings. Hyperpigmentation and keratosis develop on the palms and soles. Mees lines (transverse semilunar white bands across the nails) may be present in a minority of cases and may take as long as 40 days to develop.
(6) Mechanism of toxicity. Trivalent arsenite binds sulfhydryl groups on critical enzymes inhibiting the Krebs cycle and oxidative phosphorylation. Pentavalent arsenate uncouples oxidative phosphorylation.
(7) Diagnosis.
(a) Laboratory. The 24-hour urine arsenic concentration is the gold reference standard for confirming recent exposures (<30 days): normal results <50 μg per L or <100 μg per 24 hours. False-positive results are common after seafood ingestion (from nontoxic organic arsenic) and necessitate repeating after abstaining from seafood. Blood testing (normal result <7 μg per dl) is less reliable owing to short half-life of arsenic. Hair testing (normal <1 mg per kg) may be useful for chronic or remote exposures.
(b) Radiographs. May show radiopacities in the GI tract.
(c) Nerve conduction studies (NCS). Severe acute exposure may cause conduction slowing characteristic of proximal demyelination (similar to acute inflammatory demyelinating polyradiculopathy), and distal, motor, and sensory axonopathy. In less severe, or chronic, exposures patients develop a distal, sensory greater than motor axonopathy.
(d) ECG can show a prolonged QT interval with risk for torsades de pointes.
(8) Treatment.
(a) Removal of exposure.
(b) If material is retained in the GI tract, consider either whole-bowel irrigation or use of cathartics.
(c) If clinical presentation is highly suggestive, then begin chelation therapy before laboratory confirmation.
i. Dimercaptosuccinic acid (DMSA) is useful in the treatment of subacutely or chronically poisoned patients (10 mg per kg by mouth three times a day for 5 days then twice a day until the urinary arsenic level is <50 μg per L per 24 hours). Complications include transient increases in liver function tests.
ii. British anti-Lewisite (BAL) is useful in severe exposures when oral therapy cannot be given or the patient has an ileus (3 to 5 mg per kg intramuscularly [IM] every 4 to 6 hours until urinary arsenic level is <50 μg per kg per 24 hours). Complications include pain over the injection site, hypertension, febrile reactions, and agitation.
iii. Dimercaptoproprane-1-sulfonate is not approved in the United States but used in other countries (loading dose of 1,200 to 2,400 mg per day in equal divided doses [100 to 200 mg 12 times daily] followed by maintenance of 100 mg orally two to four times a day).
(d) RBC and plasma exchange may be useful to remove components of RBC lysis and to further reduce arsenic levels in cases of intravascular hemolysis from arsine gas poisoning.
b. Lead.
(1) Sources. Lead-based paint (houses painted before 1978), soil, ceramic glaze, gun ranges, battery manufacturing, retained foreign bodies, and ethnic folk remedies.
(2) Route of exposure. Ingestion or inhalation.
(3) Systemic signs. Abdominal pain, anorexia, constipation, anemia, nephropathy (Fanconi’s syndrome), hypertension, and rarely gout.
(4) Neurologic manifestations.
(a) CNS signs are more common in children: encephalopathy, coma, visual perceptual defects, seizures, and signs of increased intracranial pressure (bulging fontanel or papilledema).
(b) PNS signs are more common in adults: peripheral neuropathy manifesting as a motor axonopathy (arms > legs and extensors > flexors [causes foot or wrist drop]). It can be symmetric or asymmetric.
(5) Physical examination findings. Bluish black lines around gums (Burton’s lines) are rarely noted.
(6) Mechanism of toxicity. In children, lead affects many neurotransmitters by increasing the release of dopamine, acetylcholine, and γ-amino butyric acid, and by blocking N-methyl-D-aspartate glutamate receptors. Disruption of intercellular junctions interferes with the blood–brain barrier causing capillary leakage and increasing pressure. In adults, lead causes Schwann cell destruction followed by demyelination and axonal destruction.
(7) Diagnosis.
(a) Laboratory. The gold standard for testing is blood lead levels. Normal result is <10 μg per dl. In children levels >10 μg per dl necessitate investigation and environmental lead reduction. Levels >45 μg per dl necessitate chelation. In adults, levels >40 μg per dl necessitate removal from work site. Levels >70 μg per dl necessitate chelation. CBC may show microcytic anemia with basophilic stippling.
(b) Radiographs may show lead lines (increased metaphyseal densities) in growth plates and retained radiopaque material in GI tract.
(c) NCS may show normal or decreased conduction velocity.
(8) Treatment.
(a) Remove from exposure.
(b) If material is retained in GI tract, consider either whole bowel irrigation or cathartics.
(c) Chelation therapy.
i. DMSA may be used as the sole agent if patients are able to take oral medications (10 mg per kg by mouth three times a day for 5 days and then three times a day for 14 days, after 1-week remeasure the lead level). Start for levels >45 μg per dl in children, or for symptomatic adults with levels >70 μg per dl. Continue until levels are <25 μg per dl in children or <30 μg per dl in adults.
ii. BAL (3 to 5 mg per kg IM four times a day if unable to take orals).
iii. Ethylenediaminetetraacetic acid (35 to 50 mg per kg every day by continuous intravenous [IV] infusion in combination with BAL). Start 4 hours after initiation of BAL.
c. Thallium.
(1) Sources. Homicidal agent, rodenticides (no longer in United States), and manufacturing of optic lenses and semiconductors.
(2) Route of exposure. Ingestion and dermal.
(3) Systemic signs. Constipation, myalgias and arthralgias, alopecia beginning approximately within 2 weeks of exposure.
(4) Neurologic manifestations. Within 1 week of exposure, patients develop a rapidly progressive ascending, predominantly sensory, peripheral neuropathy (symptoms are dysesthesias and paresthesias of the feet, and less commonly the hands). Can see encephalopathy, insomnia, and cranial neuropathies.
(5) Physical examination findings. Blackened hair roots (under low-power light microscopic) and Mees’ lines on fingernails (rarely).
(6) Mechanism of toxicity. Interferes with K+-dependent processes resulting in a decrease in catabolism of carbohydrates and impaired ATP generation through oxidative phosphorylation, inhibits sulfhydryl-containing enzymes.
(7) Diagnosis. Twenty-four hour urine thallium concentration (normal <10 μg per specimen), hair thallium concentration (normal <20 ng per g), examination of darkened hair roots under light microscopy, and NCS show sensorimotor axonopathies with severity of abnormalities correlating with the severity of symptoms.
(8) Treatment. Prussian blue (3 g orally three times a day). If Prussian blue cannot be obtained, multidose activated charcoal should be given until available.
d. Mercury.
(1) Sources. There are three forms that differ in characteristic and toxicity.
(a) Elemental mercury. Used in thermometers, barometers, thermostats, electronics, batteries, and dental amalgams.
(b) Inorganic mercury salts. Found naturally as mercury (II) sulfide, mercuric chloride, mercuric oxide, mercuric sulfide, mercurous chloride, mercuric iodide, ammoniated mercury, and phenylmercuric salts. These compounds have been used in cosmetics and skin treatments. Most exposures come from old skin products and exposure to germicides, pesticides, and antiseptics.
(c) Organic mercury. Used as preservatives and antiseptics, and previously common for industrial and medicinal purposes in the early 20th century. Ethyl mercury (thimerosal) was used in multidose vaccine vials, although it has been recently removed. Methyl mercury exposure occurs through the consumption of predatory fish.
(2) Route of exposure. Elemental mercury exposure occurs by inhalation of the vapor, ingestion of the liquid, or cutaneous exposure. Ingestion and cutaneous exposure are of little clinical consequence as mercury is poorly absorbed via these routes. Ingestion of inorganic mercury salts results in the greatest absorption, but it may also be inhaled and dermally absorbed. Organic mercury exposure occurs primarily by ingestion and dermal absorption.
(3) Systemic signs.
(a) Elemental mercury. Acute toxicity presents within hours of a large inhalational exposure with GI upset, chills, weakness, cough, and dyspnea. Patients may progress to adult respiratory distress syndrome and renal failure. Chronic toxicity develops over weeks to months, depending on the level of exposure and presents with constipation, abdominal pain, poor appetite, dry mouth, headache, and muscle pains.
(b) Inorganic mercury salts are corrosive to the GI mucosa causing oral pain, burning, nausea, vomiting, diarrhea, hematemesis, bloody stools, or abdominal discomfort with ingestions. Patients may develop acute tubular necrosis within 2 weeks exposure and membranous glomerulonephritis and nephrotic syndrome with chronic exposures.
(c) Organic mercury. Patients may develop renal failure.
(4) Neurologic manifestations.
(a) Elemental mercury. Chronic exposure can produce proximal weakness involving the pelvic and pectoral girdle. Patients can develop erethism (memory loss, drowsiness, lethargy, depression, and irritability). Patients can also suffer from incoordination, fine motor tremor of the hands, and a sensorimotor neuropathy without conduction slowing.
(b) Inorganic mercury salts. Patients can develop erethism as above.
(c) Organic mercury.
i. PNS. Paresthesias of mouth and extremities occur as result of a predominantly sensory neuropathy.
ii. CNS. Damage occurs to gray matter of cerebral and cerebellar cortex, mainly affecting the temporal and occipital lobes. Patients present with concentric constriction of bilateral visual fields, ataxia, incoordination, tremor, dysarthria, and auditory impairment. In utero exposure may cause a cerebral palsy-like condition known as Minamata disease.
(5) Physical examination findings.
(a) Elemental mercury. Oral findings include reddened, swollen gums, mucosal ulcerations, and tooth loss. Patients may display characteristics of acrodynia (sweating, hypertension, tachycardia, weakness, poor muscle tone, and an erythematous desquamating rash to the palms and soles). Symptoms associated with acrodynia may mimic the presentation of pheochromocytoma (mercury also may elevate catecholamine levels).
(b) Inorganic mercury salts. Prolonged use can cause skin changes including hyperpigmentation most pronounced in skin folds of face and neck, swelling, and a vesicular or scaling rash. Patients can develop symptoms associated with acrodynia as described above.
(c) Organic mercury. Mainly display abnormal neurologic exams as described above in I.A.1.d.(4).(c).
(6) Mechanism of toxicity. All three forms combine with sulfhydryl groups on cell membranes and interfere with cellular processes.
(7) Diagnosis.
(a) Elemental mercury. Clinical presentation, history of exposure, and elevated body burden of mercury. Because of a short half-life, blood levels have limited usefulness (concentrations are typically <10 μg per L). Twenty-four-hour urine levels are normally <50 μg of mercury.
(b) Inorganic mercury salts. Twenty-four-hour urine levels are the gold standard.
(c) Organic mercury. Best identified in blood or hair as 90% of methylmercury is bound to hemoglobin within the RBCs. Urinary mercury levels are unreliable because methylmercury is eliminated in bile. Normal whole blood values are <0.006 mg per L. Diets rich in fish can increase levels to 0.200 mg per L or higher.
(8) Treatment.
(a) Elemental mercury. Remove the patient from the source. As there is minimal toxicity from ingestion, there is no role for GI decontamination. The usefulness of chelation therapy remains unclear. Suggested agents include DMSA, dimercaprol, and D-penicillamine (doses I.A.1.a.(8).(c).).
(b) Inorganic mercury salts. Volume resuscitation and prompt chelation are critical to prevent renal injury. BAL is effective within 4 hours of ingestion, but DMSA may be substituted if oral intake is tolerated. Hemodialysis is indicated in renal failure for the elimination of dimercaprol–Hg complexes. See I.A.1.a.(8).(c). for doses.
(c) Organic mercury. Remove from the source. Chelation may be attempted although studies have not demonstrated appreciable improvement. BAL is not recommended because of increased CNS concentrations of mercury post treatment.
e. Other metals.
(1) Cisplatin. Used in chemotherapy, toxicity manifests as distal symmetric paresthesia that may not occur for months after treatment. NCS show sensory neuronopathy.
(2) Gold salts. Used in rheumatoid arthritis, rarely associated with seizures and encephalopathy. Toxicity manifests as distal symmetric sensorimotor polyneuropathy.
(3) Zinc. Sources include denture creams and vitamin supplements. Zinc toxicity results in copper deficiency by inhibiting dietary copper absorption. Copper deficiency is associated with anemia, neutropenia, and myeloneuropathy. Diagnosis is made by history and a CBC combined with serum and 24-hour urine copper and zinc levels. Treatment is removal of the zinc-containing product and copper supplementation.
2. Solvents.
a. N-hexane, methyl-n-butyl ketone, 2,5-hexandione.
(1) Sources. Exist in industrial and household glues, varnish, cement, and ink.
(2) Route of exposure. Inhalational and abused (huffing or bagging).
(3) Systemic signs. Anorexia, weight loss, and renal tubular acidosis (mixtures containing toluene).
(4) Neurologic manifestations. Distal weakness, paresthesias, sensory loss, and areflexia. Progression of neuropathy may occur for weeks after exposure ends (coasting). NCS show motor > sensory polyneuropathy with reduced sensory and motor amplitudes and prolonged motor conduction velocity.
(5) Physical examination findings. Solvent odor on breath and absent Achilles’ reflexes.
(6) Mechanism of toxicity. Impairs neurofilamentous transport.
(7) Diagnosis.
(a) Clinical history and physical examination findings.
(b) Sural nerve biopsy (axonal degeneration, demyelination, and paranodal axonal swelling with neurofilament accumulation).
(c) Electromyography (denervation and decreased recruitment).
(8) Treatment. Removal from the source results in improvement, although symptoms may progress for a time after exposure (coasting).
b. Other solvents.
(1) Acrylamide. Sensorimotor neuropathy.
(2) Carbon disulfide. Distal axonal neuropathy with axonal swellings, extrapyramidal signs, and psychosis.
(3) Ethyl alcohol (chronic). Sensorimotor neuropathy effecting distal lower extremities first.
(4) Ethylene oxide. Distal axonopathy.
(5) Methyl-ethyl-ketone. Nontoxic alone, but synergistically promotes peripheral neuropathy from other solvents.
(6) Methyl bromide. Both peripheral and pyramidal effects.
(7) Styrene. Sensorimotor, demyelinating neuropathy.
(8) Trichloroethylene. Cranial mononeuropathies.
3. Organophosphates or carbamates.
a. Sources. Chemical warfare agents and pesticides.
b. Route of exposure. Ingestion, inhalation, and absorption through skin.
c. Systemic signs. Cholinergic excess secondary to stimulation of muscarinic receptors resulting in vomiting, diarrhea, lacrimation, salivation, diaphoresis, bronchospasm, bronchorrhea, miosis, bradycardia, or tachycardia (SLUDGE syndrome).
d. Neurologic manifestations.
(1) CNS. Decreased mental status and seizures.
(2) PNS.
(a) Acute. Excess acetylcholine causes depolarizing paralysis: fasciculations and cramping followed by flaccid paralysis.
(b) Intermediate syndrome. Proximal muscle weakness, including respiratory symptoms, beginning 1 to 4 days after cholinergic phase.
(c) Organophosphate-induced delayed neurotoxicity. Occurs 1 to 4 weeks after organophosphate poisoning and manifests as symmetric, distal, predominantly motor polyneuropathy. NCV studies reveal denervation of affected muscles along with reduced amplitude and prolonged conduction velocity.
e. Physical examination findings: Miosis, weakness, and signs of cholinergic excess (acute exposure).
f. Mechanism of toxicity: Acetylcholine excess.
g. Diagnosis.
(1) History and physical examination findings.
(2) Plasma cholinesterase is less specific but has a rapid turnaround time (decrease in level by 50% of baseline or serial increasing levels after poisoning indicates exposure).
(3) RBC cholinesterase is more specific but has a long turnaround time (decrease of 25% of baseline level indicates exposure).
h. Treatment.
(1) Remove from exposure and decontaminate the skin with soap and water.
(2) Respiratory and cardiovascular support.
(3) Atropine initial dose of 2 mg IV and then double dose every 5 to 10 minutes until drying of respiratory secretions.
(4) Pralidoxime initial dose of 1.5 g IV over 30 minutes and then infusion of 500 mg per hour until resolution of muscle weakness.
(5) Diazepam 10 mg or lorazepam 2 mg IV for seizures with repetition of dosage as needed.
4. Gases.
a. Nitrous oxide.
(1) Sources. Anesthesic agent.
(2) Route of exposure. Inhalation.
(3) Systemic signs. Signs similar to vitamin B12 (cobalamin) deficiency including fatigue, depression, psychosis, and glossitis.
(4) Neurologic manifestations include sensorimotor peripheral polyneuropathy may result, in addition to myelopathy affecting the posterior and anterolateral columns of the cervicothoracic spinal cord. Optic neuropathyand cognitive impairment may also occur.
(5) Physical examination findings. Megaloblastic anemia, ataxia, sensory loss, weakness, and Lhermitte’s sign.
(6) Mechanism of toxicity. Nitrous oxide disrupts methionine synthetase by oxidizing cobalamin (I) to cobalamin(II).
(7) Diagnosis. Patients may have a normal cobalamin level. Elevated serum homocysteine and methylmalonic acid are useful for confirming the diagnosis (cobalamin is involved in their metabolism). MRI of spinal cord may show increased signal intensity in the posterior and lateral columns on T2-weighted images. NCS show mainly sensorimotor axonopathy.
(8) Treatment. Replace vitamin B12: cyanocobalamin 1,000 to 2,000 mcg by mouth (P.O.) daily for 1 to 2 weeks followed by 100 mcg P.O. daily, or 1,000 mcg IM daily for 5 days, then 1,000 mcg IM weekly for 4 weeks then, 1,000 mcg IM every 1 to 3 months, or 1,500 mcg intranasally weekly for 3 to 4 weeks, and then 500 mcg intranasally weekly. Patients should slowly improve.
b. Ethylene oxide. Chronic workplace exposure in industry or through the sterilization of hospital supplies can result in symmetric distal sensorimotor polyneuropathy.
5. Pharmaceuticals.
a. Dapsone. Chronic use in dermatologic and rheumatologic disorders may result in a motor neuropathy characterized by weakness and atrophy affecting the upper extremities more than the lower. NCS show motor axonopathy. It may also cause anterior ischemic optic neuropathy or optic atrophy.
b. Pyridoxine. Sensory neuropathy can occur from either large acute doses or excessive long-term use. Permanent sensory neuropathy has been reported after massive doses (>50 g) over a short time. Recovery may occur after removal of the drug.
c. Other pharmaceuticals associated with peripheral neuropathy include amiodarone, colchicine, dideoxycytidine, hydralazine, isoniazid, metronidazole, nitrofurantoin, and thalidomide.
B. Toxins affecting ion channels.
1. Ciguatera poisoning.
a. Sources. Ingestion of reef fish (barracuda, sea bass, parrot fish, red snapper, grouper, amber jack, king fish, and sturgeon).
b. Systemic signs. Symptoms usually begin within 2 to 6 hours of ingestion and may include abdominal pain, vomiting and diarrhea, dysuria, and pruritus. Cardiovascular symptoms include hypotension, bradycardia, or arrhythmia.
c. Neurologic manifestations. Headache, perioral paresthesias spreading centrifugally to hands and feet, hot–cold dysesthesia, and insomnia.
d. Mechanism of toxicity is from prolonged opening of sodium channels.
e. Diagnosis is based on the clinical symptoms and history. Samples of fish can be sent out for high-performance liquid chromatography and mass spectrometry to detect ciguatoxin.
f. Treatment. Supportive care, mannitol 1 g per kg IV over 30 minutes has been suggested as an effective treatment if given early; however, supporting studies are lacking. Complete recovery usually occurs within a few weeks, but fatigue and weakness may persist.
2. Tetrodotoxin poisoning.
a. Sources. Ingestion of puffer or globefish. Although processing of fugu (puffer fish fillets) is licensed, puffer-fish poisoning accounts for more deaths than any other type of food poisoning in Japan.
b. Systemic signs. Vomiting, hypotension, and respiratory arrest.
c. Neurologic manifestations. Paresthesia of the perioral region and extremities followed by paralysis of voluntary and respiratory muscles.
d. Mechanism of toxicity. Blockade of sodium channels.
e. Diagnosis. History of puffer fish ingestion and clinical features. NCS show complete conduction block effect on myelinated nerve fibers and sparing of axons.
f. Treatment. Supportive care.
3. Other toxins affecting ion channels. Grayanotoxin (rhododendron and sodium channel opener), scorpion toxin (sodium channel opener), and saxitoxin (shellfish and sodium channel blocker).
C. Toxins affecting neuromuscular junction.
1. Black widow spider venom.
a. Sources. Black widow spider (Latrodectus mactans).
b. Systemic signs. Hypertension, nausea, diaphoresis, and restlessness.
c. Neurologic manifestations. Diffuse muscle spasms and rigidity.
d. Mechanism of toxicity. Increased release of neurotransmitters (e.g., acetylcholine and norepinephrine) followed by the depletion of transmitter stores.
e. Diagnosis. History and clinical examination. Bite location may show a “target lesion” with a pale center surrounded by erythema.
f. Treatment. IV opioids for pain control and benzodiazepines for muscle relaxation. In severe cases, antivenom (equine-based antiserum) can be given, but carries the risk of anaphylaxis: Pretreatment with diphenhydramine and having epinephrine at the bedside is recommended.
2. Botulism.
a. Sources. Replicating Clostridium botulinum, and occasionally Clostridium baratii and Clostridium butyricum, produce distinctive botulinal neurotoxins (types A to G).
(1) Food. Ingestion of food contaminated with preformed toxin.
(2) Infant. Ingestion of foods (honey) contaminated with C. botulinum spores.
(3) Wounds. Commonly in IV drug users, infected with C. botulinum.
b. Systemic signs. Sore throat, dry mouth, vomiting, and diarrhea followed by abdominal distention and constipation.
c. Neurologic manifestations. Descending motor paralysis including ophthalmoplegia, dysphagia, mydriasis (in 50%), skeletal, and respiratory muscles. In infant botulism, babies have constipation followed by a subacute progression of bulbar and extremity weakness (within 4 to 5 days) manifested by inability to suck and swallow, weakened cry, ptosis, and hypotonia, which may progress to generalized flaccidity and respiratory compromise.
d. Mechanism of toxicity involves inhibition of presynaptic vesicles preventing the release of acetylcholine.
e. Diagnosis.
(1) History and examination. Difficult to differentiate from Miller Fisher syndrome, although ataxia, paresthesia, areflexia, and elevated CSF protein are more common in Miller Fisher syndrome. In infants, the differential diagnosis includes sepsis, viral syndrome, dehydration, diphtheria, cerebrovascular accident, hypothyroidism, hypermagnesemia, Lambert–Eaton’s myasthenic syndrome, myasthenia gravis, poliomyelitis, Guillain–Barré’s syndrome, encephalitis, and meningitis.
(2) Laboratory. Confirmation of C. botulinum in serum, stool, gastric contents, wound culture, food specimens, or positive mouse bioassay.
(3) NCS. Facilitation on repetitive nerve stimulation (in 60% of cases).
f. Treatment.
(1) Supportive care and antibiotics for wound botulism. In infant botulism, respiratory decompensation is associated with administration of aminoglycoside antibiotics and neck flexion during positioning for lumbar puncture or imaging. Antibiotics are not indicated for infant botulism.
(2) Botulinum antiserum for food and wound botulism. Obtained from the Centers for Disease Control and Prevention by the state health departments.
(3) For infant botulism, human-derived IV botulinum immune globulin (BIG) trials demonstrated safety and efficacy. BIG is now Food and Drug Administration approved and is available only from the California Department of Health Services (24-hour telephone: 510-231-7600 or Webpage http://www.infantbotulism.org/).
3. Other toxins affecting the neuromuscular junction include the venom of the funnel web spider (increases acetylcholine release), saliva from the Ixodid family of ticks (prevents acetylcholine release), hypermagnesemia (prevents acetylcholine release), venom from cobra, coral snake, mamba, and Mojave rattlesnakes (decreases nicotinic neurotransmission by various mechanisms).
D. Myopathy.
1. Immobility. Toxins that depress mental status or produce coma can result in extended periods of immobility compressing muscular compartments causing subsequent muscle breakdown and rhabdomyolysis. Examples include alcohol, barbiturates, benzodiazepines, and narcotics.
2. Excess activity. Toxins, or activities, that result in skeletal energy consumption exceeding energy supply can cause rhabdomyolysis. This can be the direct effect of the drug or secondary to agitation. Examples include amphetamines, cocaine, phencyclidine (PCP), and anticholinergic drugs.
3. Myotoxins.
a. Hypokalemia. Drugs depleting total body potassium stores can cause muscle breakdown and rhabdomyolysis. Examples include toluene and amphotericin B (renal tubular acidosis), glycyrrhizinic acid in licorice (increases mineralocorticoid activity), and long-term use of diuretics.
b. Metabolic poisons. Compounds that interfere with the production of adenosine triphosphate can result in muscle breakdown and rhabdomyolysis. Examples include cyanide, hydrogen sulfide, salicylates, dinitrophenol, chlorophenoxy herbicides (2,4-D), and carbon monoxide (CO).
c. Direct-acting myotoxins. Numerous agents exist that have direct toxic effects on muscles resulting in myopathy and rhabdomyolysis. Examples include ethanol, heroin, corticosteroids, antimalarials, HMG-CoA reductase inhibitors, and snake bites.
II. CENTRAL NERVOUS SYSTEM
A. Acute delirium.
1. Anticholinergic syndrome occurs from blockade of central and peripheral muscarinic receptors.
a. Sources. Pharmaceuticals: tricyclic antidepressants, antihistamines, antipsychotics, class-1a antiarrhythmics, cyclobenzaprine, promethazine, benztropine, carbamazepine, amantadine, and scopolamine. Plants: jimson weed, nightshades, and mandrake.
b. Systemic signs. Dry mouth, mydriasis, dry axilla, hypoactive bowel sounds, urinary retention, tachycardia, and low-grade fever.
c. Neurologic manifestations. Acute delirium with visual hallucinations, increased motor activity (picking at bed sheets), and mumbling speech pattern.
d. Treatment.
(1) Activated charcoal. 1 g per kg by mouth if the patient is awake and is not at risk for aspiration and if ingestion is within 1 to 2 hours.
(2) Benzodiazepines. Repeated IV doses for agitation and tachycardia.
(3) Butyrophenones (haloperidol or droperidol) in addition to benzodiazepines for patients with severe agitation and acute psychosis (avoid in patients with a prolonged QT interval).
(4) Physostigmine. May be useful as a diagnostic tool in differentiating anticholinergic syndrome from other neurologic causes (e.g., encephalitis). Because of its short half-life and potential complications, physostigmine is generally not recommended for treatment. The dosage is 1 to 2 mg slow IV push over 10 minutes. Complications are seizures, cardiac dysrhythmia, and cholinergic crisis. Contraindicated in the care of patients with unknown ingestions, bradycardia, or ingestions increasing risk of seizures (tricyclic antidepressants).
(5) IV hydration and serial measurement of creatine kinase for rhabdomyolysis.
2. Sympathomimetic syndrome. Occurs from an increase in central and peripheral monoamines.
a. Sources. Pharmaceuticals (pseudoephedrine, phenylpropanolamine, methylphenidate, and phentermine), illicit drugs (cocaine, amphetamines, methamphetamine, methylenedioxymethamphetamine), and plants (ma huang).
b. Systemic signs. Tachycardia, hypertension, diaphoresis, mydriasis, fever, chest pain, myocardial infarction, and ventricular dysrhythmia.
c. Neurologic manifestations. Psychomotor agitation, seizures, mania, tactile hallucinations (formication), increased muscle tone, increased reflexes with clonus, impaired cognition and chronic psychiatric symptoms, hyponatremia-induced cerebral edema, and ischemic or hemorrhagic stroke.
d. Treatment.
(1) Activated charcoal. 1 g per kg by mouth if the patient is awake and is not at risk for aspiration and if ingestion is within 1 to 2 hours.
(2) Benzodiazepines. Repeat IV doses for seizures, agitation, tachycardia, hypertension, and chest pain. Avoid use of ß-blockers secondary to unopposed α-stimulation and corresponding vasospasm.
(3) Butyrophenones (haloperidol or droperidol) or atypical antipsychotics in addition to benzodiazepines for patients with severe agitation and acute psychosis.
(4) IV hydration and serial measurement of creatine kinase for rhabdomyolysis.
(5) Active cooling of hyperthermic patients.
3. Serotonin syndrome. Occurs from increase in extracellular concentrations of serotonin in the CNS. Typically occurs in patients taking more than one serotonergic agent.
a. Sources. Pharmaceuticals (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, meperidine, fentanyl, dextromethorphan, tramadol, venlafaxine, amphetamines, L-tryptophan, methylene blue, and lithium) and plants (St. John’s wort).
b. Systemic signs. Tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia.
c. Neurologic manifestations. Agitation, confusion, hallucinations, increased motor tone and activity (lower more than upper extremity), and hyperreflexia with lower extremity clonus.
d. Treatment.
(1) Activated charcoal. 1 g per kg by mouth if the patient is awake and is not at risk for aspiration and if ingestion is within 1 to 2 hours.
(2) Benzodiazepines. Repeat IV doses for agitation, tachycardia, and hypertension.
(3) Cyproheptadine, a 5-HT2a antagonist, can be given orally, 12 mg as first dose, then 8 mg every 6 hours. Some atypical antipsychotics (olanzapine) may also be beneficial secondary to 5-HT2a antagonism and parenteral administration. Avoid when possibility of neuroleptic malignant syndrome exists.
(4) IV hydration and serial measurement of creatine kinase for rhabdomyolysis.
4. Hallucinogens.
a. Sources. Anticholinergic agents: see II.A.1.a. Illicit drugs (lysergic acid diethylamide, mescaline, PCP, and ketamine), plants (morning glory and nutmeg), mushrooms (Amanita muscaria mushrooms and psilocybin mushrooms), and animals (bufotoxin from Bufo family of toads).
b. Systemic signs. Tachycardia, hypertension, diaphoresis, and mydriasis.
c. Neurologic manifestations. Visual hallucinations, increased motor activity, and hyperreflexia.
d. Treatment.
(1) Activated charcoal. 1 g per kg by mouth if the patient is awake and is not at risk for aspiration and if ingestion is within 1 to 2 hours.
(2) Benzodiazepines. Repeat IV doses as needed for agitation.
(3) Butyrophenones (haloperidol or droperidol) in addition to benzodiazepines for patients with severe agitation and acute psychosis.
(4) IV hydration and serial measurement of creatine kinase for rhabdomyolysis.
5. γ -Aminobutyric acid (GABA)-agonist withdrawal syndromes result in a hyperadrenergic state with symptoms similar to those of sympathomimetic syndrome.
a. Benzodiazepines, barbiturates, and ethanol can cause a life-threatening withdrawal syndrome characterized by a hyperadrenergic state (tachycardia, hypertension, diaphoresis, piloerection, and fever), nausea, vomiting, diarrhea, altered mental status, hallucinations, and seizures. Management of acute symptoms involves repeated IV doses of benzodiazepines (high doses at times) followed by scheduled oral benzodiazepines for prevention.
b. Baclofen can cause a life-threatening withdrawal syndrome characterized by disorientation, hallucinations, fever, rebound spasticity, seizures, and coma. Treatment involves oral or intrathecal baclofen and benzodiazepines.
c. γ-Hydroxybutyrate (GHB). Abrupt discontinuance of chronically abused GHB compounds results in a withdrawal syndrome similar to benzodiazepine and ethanol withdrawal. Treatment is with IV or oral benzodiazepines and supportive care.
6. Wernicke’s encephalopathy.
a. At risk populations are persons with chronic alcoholism or patients with other thiamine deficiency states (e.g., hyperemesis gravidarum, anorexia nervosa, malignant tumor of the GI tract, pyloric stenosis, inappropriate parenteral nutrition, and in patients with gastric bypass surgery as early as 4 to 12 weeks postoperatively).
b. Symptoms. Characterized by altered mental status (global confusional state), ataxia, and ophthalmoplegia (nystagmus, sixth-cranial nerve palsy, conjugate palsy, vestibular paresis, and pupillary abnormalities). Although classically diagnosed with the triad of mental confusion (66% of patients), staggering gait (51% of patients), and ocular abnormalities (40% of patients), Wernicke’s encephalopathy can occur in the absence of some or all of the symptoms.
c. Diagnosis. Clinical features and improvement with treatment. Laboratory assessments of thiamine deficiency include erythrocyte thiamine transketolase, the blood thiamine concentration, or urinary thiamine excretion (with or without a 5-mg thiamine load). Abnormal MRI findings are hyperintense signals in the dorsal medial thalamic nuclei, periaqueductal gray area, and the third and fourth ventricle, and mamillary body enhancement acutely and atrophy chronically. MRI has a sensitivity of 53% and a specificity of 93% for the diagnosis of Wernicke’s encephalopathy. Treatment should be primarily based on clinical suspicion.
d. Treatment. IV thiamine (100 mg) and magnesium (2 g) followed by daily thiamine and multivitamin supplementation. Daily thiamine doses should be 50 to 100 mg for 7 to 14 days, then 10 mg per day until full recovery is achieved, followed by at least 1.2 mg per day.
e. Prognosis is favorable for most patients, but residual neurologic effects, including Korsakoff’s psychosis, memory loss, ataxia, nystagmus, and neuropathy, may persist.
B. Subacute encephalopathy.
1. Bismuth. Long-term use of bismuth salts for ostomy odor or in the management of peptic ulcer disease can manifest as subacute progressive encephalopathy.
a. Symptoms. Patients have symptoms of progressive dementia and delirium, ataxia, severe myoclonus, and in rare instances, seizures. Symptoms may not occur until after weeks or years of continued use. Other symptoms include dark stools and dark staining of the gums. This syndrome can be mistaken for Creutzfeldt–Jakob’s disease, Alzheimer’s dementia, or other progressive forms of encephalopathy and can be fatal if not diagnosed.
b. Diagnosis. In acute encephalopathy, the bismuth blood level is 150 to 2,000 μg per 100 ml instead of the normal 10 to 30 μg per 100 ml. Head CT may show increased attenuation in the basal ganglia and cerebral cortex.
c. Treatment. Stop the drug and provide supportive care. The syndrome usually regresses in 3 to 12 weeks after cessation of bismuth.
2. Lithium. Chronic use or acute overdose of lithium salts can manifest as progressive encephalopathy. Impaired excretion or excessive intake of lithium are the usual causes of lithium intoxication.
a. Symptoms. Patients come to medical attention with tremor, altered mental status, ataxia, myoclonus, and in rare instances, seizures. Other symptoms include nausea, vomiting, diabetes insipidus, hypothyroidism, mutism, and renal failure.
b. Diagnosis. An elevated serum lithium level supports the diagnosis. Therapeutic levels of lithium range from 0.6 to 1.2 mEq per L. Toxic effects of lithium generally are related to serum levels, with mild to moderate severity seen with levels of 1.5 to 2.5 mEq per L, serious toxicity with levels of 2.5 to 3.0 mEq per L, and life-threatening toxicity with levels 3.0 to 4.0 mEq per L.
c. Treatment. Emesis or lavage and a cathartic are indicated in acute overdose. Patients with severe symptoms require urgent hemodialysis. Dialysis clears extracellular lithium but the intracellular lithium may cause a rebound in the serum lithium concentrations after dialysis. IV saline should be given to rehydrate and avoid hyponatremia (excretion of sodium and lithium are related).
3. Carbon monoxide. Patients with CO poisoning may have a syndrome known as delayed neurologic sequelae, occurring 2 to 40 days after exposure and recovery. The incidence of delayed neurologic sequelae increases with the duration of unconsciousness and age >30.
a. Symptoms. Manifested as altered mental status, personality changes, memory loss, and encephalopathy. Patients may also have ataxia, seizures, urinary and fecal incontinence, parkinsonism, mutism, cortical blindness, and gait and motor disturbances. Physical examination findings may include hyperreflexia, frontal release signs (glabellar and palmar grasp), masked facies, and parkinsonian features.
b. Diagnosis. Neuropsychometric testing displays cognitive dysfunction. MRI findings may include bilateral globus pallidus infarcts and diffuse demyelination of subcortical white matter.
c. Treatment. Supportive care. It is unclear whether treatment of acute CO poisoning influences the risk of delayed neurologic sequelae. The majority of patients will show some recovery.
4. Aluminum. Long-term use of aluminum phosphate binders, aluminum-contaminated dialysates or medications containing aluminum (e.g., sucralfate) in the care of patients with renal failure can result in progressive encephalopathy. Patients come to medical attention with agitation, speech disorder, confusion, myoclonus, coma, and/or seizures. Aluminum exposure is also associated with osteomalacia and microcytic hypochromic anemia. Diagnosis is made by elevated aluminum level but if within normal limits and diagnosis is still suspected, bone biopsy may confirm the diagnosis. Treatment involves removal of sources of aluminum and for some patients, chelation with deferoxamine.
5. Neuroleptic malignant syndrome. Subacute encephalopathy associated with hyperthermia, rigidity with elevated creatine kinase, and autonomic instability in the setting of neuroleptic administration. Treatment is supportive care with external cooling and benzodiazepines as necessary. Consideration can also be given to bromocriptine and/or dantrolene for antidotal therapy.
C. Coma and CNS depression. Many toxins causing CNS depression and coma can mimic brain death, including loss of brainstem reflexes. Many of these toxins have long half-lives, so clinical criteria of brain death do not apply.
1. Sedative hypnotics.
a. Sources. Ethanol, benzodiazepines, barbiturates, central-acting muscle relaxants, chloral hydrate, buspirone, zolpidem, baclofen, clonidine, antihistamines, and numerous antidepressants and antipsychotics.
b. Systemic signs. Pressure sores, hypotension, bradycardia, and hypothermia.
c. Neurologic manifestations. Somnolence, coma, areflexia, nystagmus, and amnesia.
d. Treatment. Supportive care, activated charcoal 1 g per kg by mouth if the patient is awake and is not at risk for aspiration and if ingestion is within 1 to 2 hours. The use of flumazenil, a benzodiazepine antagonist, is generally not recommended because of increased risk of seizures in habituated patients.
2. Opioids, opiates.
a. Sources. Pharmaceuticals (hydrocodone, oxycodone, morphine, hydromorphone, oxymorphone, propoxyphene, meperidine, fentanyl, and methadone) and illicit drugs (heroin and designer opioids).
b. Systemic signs. Hypotension, bradycardia, bradypnea, pulmonary edema, track marks on skin, skin abscesses, decreased bowel sounds, and cyanosis.
c. Neurologic manifestations. Coma, miosis, deafness, areflexia, and seizures (meperidine and propoxyphene). Seizures from meperidine are the result of elevated levels of normeperidine (a major metabolite of meperidine). Risk factors for normeperidine seizures are renal failure and chronic dosing. Naloxone (Narcan; Endo Pharmaceuticals, Chadds Ford, PA, USA) does not reverse meperidine- or propoxyphene-related seizures.
d. Treatment. Supportive care, Naloxone 0.1 to 1 mg IV push followed by 1 mg every minute until reversal of respiratory depression or to a maximum of 10 mg (complications include acute opioid withdrawal).
3. GHB.
a. Sources. GHB, γ -butyrolactone, butanediol (used for mood enhancement, sleep induction, and by body builders for purported increased growth hormone release).
b. Systemic signs. Bradycardia, hypotension, hypothermia, nystagmus, and vomiting.
c. Neurologic manifestations. Areflexic coma (typically short duration—less than 6 hours with rapid reversal), normal or miotic pupils, and seizures.
d. Treatment. Supportive care.
4. Carbon monoxide.
a. Sources. Automotive exhaust, smoke inhalation, faulty heaters, external heating sources, propane- and gas-powered tools and vehicles.
b. Systemic signs. Tachycardia, hypotension, chest pain, dyspnea, myocardial infarction, cardiac arrhythmia, flushed skin, pressure sores, nausea, and vomiting.
c. Neurologic manifestations. Headache, confusion, cognitive deficits, coma, seizures, stroke, parkinsonism, and delayed neurologic sequelae (see II.B.3.).
d. Diagnosis. CO levels are indicative of exposure but are not reliable predictors of toxicity or symptoms. The normal result is <5% for nonsmokers and <10% for smokers.
e. Treatment.
(1) Removal from source of CO.
(2) 100% oxygen (via non-rebreather) for 6 to 12 hours for mild or moderate symptoms.
(3) Indications for hyperbaric oxygen therapy.
(a) Loss of consciousness; or
(b) Coma or persistent neurologic deficit; or
(c) Myocardial ischemia or ventricular dysrhythmia; or
(d) Hypotension or cardiovascular compromise; or
(e) Pregnancy with any of the above, levels >20%, or signs of fetal distress.
5. Cocaine or stimulant washout syndrome occurs among abusers of cocaine or other stimulants, the increased use of which decreases the level of CNS catecholamines resulting in depressed mental status, confusion, or coma (unresponsive to stimuli, including intubation). Patients may have disconjugate gaze. Other physical examination findings, vital signs, and laboratory findings generally are normal. Symptoms may last for 8 to 24 hours, and treatment is supportive. This should always be a diagnosis of exclusion.
D. Cerebellar disorders.
1. Toluene-solvent abuse syndrome.
a. Sources. Toluene-containing paint thinner, paint stripper, and glue.
b. Route of exposure. Inhalational: huffing (inhaling soaked rags) or bagging (inhaling from bags containing solvent).
c. Systemic signs. Abdominal pain, anorexia, weight loss, gastritis, possible renal tubular acidosis (hypokalemia and acidosis), rhabdomyolysis, hepatitis, and solvent odor on breath.
d. Neurologic manifestations. Tremor of the head and extremities, ataxia, staggering gait, cognitive deficits, personality changes, optic nerve atrophy, hearing loss, loss of smell, extremity spasticity, and hyperreflexia.
e. Diagnosis.
(1) Laboratory. Elevated serum toluene levels and urine hippuric acid levels confirm exposure, but may are not always detected.
(2) Imaging. MRI of the brain often shows cerebellar and cerebral atrophy. Evidence of white-matter disease can be seen with increased signal intensity on T2-weighted images in the periventricular, internal capsular, and brainstem pyramidal regions.
(3) Electrophysiologic studies. Brainstem auditory evoked response testing may show sparing of early components and loss or decrement of the late components (waves III and IV). Abnormal pattern visual evoked cortical potentials and prolonged P-100 peak latency may occur in patients with toxic optic neuropathy caused by toluene abuse.
f. Treatment. Supportive care and addiction rehabilitation.
2. Mercury poisoning (see also section I.A.1.d.). Poisoning with elemental mercury vapor or organic mercury along with other symptoms described in the previous section (I.A.1.d.) can result in cerebellar symptoms including ataxia and tremor with pathologic neuronal damage seen in visual cortex, cerebellar vermis and hemispheres, and postcentral cortex.
3. Anticonvulsants including phenobarbital, phenytoin, and carbamazepine, in elevated concentration or acute overdose, manifest with predominantly ataxia, nystagmus, and CNS depression. Chronic use of phenytoin may also result in cerebellar atrophy.
4. Ethanol. Both acute intoxication and chronic abuse of ethanol can result in ataxia, tremor, and altered mental status. Wernicke’s encephalopathy should be considered when any patient with chronic alcoholism has changed mental status and ataxia not related to acute intoxication.
E. Parkinsonism.
1. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a byproduct in the production of a synthetic analog of meperidine, can cause acute parkinsonism in drug users, scientists, and pharmaceutical workers. Although not neurotoxic, MPTP is metabolized by monoamine oxidase to a compound that inhibits electron transport in dopaminergic neurons. This syndrome was characterized by the rapid (24 to 72 hours) development of end-stage parkinsonism with tremor, rigidity, bradykinesia, postural instability, masked facies, and decreased blink rate. Investigation of the mechanism of toxicity has led to the development of an animal model for Parkinson’s disease.
2. Manganese. A parkinsonian-like illness has been described among miners or workers exposed to manganese oxide and among those who have ingested potassium permanganate, associated with methcathinone abuse. This syndrome is the result of degradation of the globus pallidus and striatum rather than the substantia nigra. It begins with a prodrome of nonspecific symptoms (insomnia, irritability, and muscle weakness) and progresses to psychiatric manifestations (hallucinations, emotional lability, and delusions) and finally to classic parkinsonian features of gait disturbance, masked facies, bradykinesia, rigidity, and less commonly tremor, which tends to be more postural or kinetic rather than resting. Patients with manganese-induced parkinsonism also experience dystonia consisting of facial grimacing and/or plantar flexion of the foot. These patients have little or no response to levodopa.
3. Neuroleptic drugs. The use of neuroleptic agents, both typical and atypical, has been associated with the acute development of extrapyramidal side effects, most commonly parkinsonism. Patient’s age and duration and potency of neuroleptic treatment are risk factors for neuroleptic-induced parkinsonism. The presentation of neuroleptic-induced parkinsonism includes bradykinesia or akinesia, which may be associated with decreased arm swing, masked facies, drooling, decreased eye blinking, and soft, monotonous speech; tremor, which is most commonly a rhythmic, resting tremor; and rigidity of the extremities, neck, or trunk. Cessation of the neuroleptic typically results in resolution of symptoms within a few weeks. Patients can be treated with anticholinergics or dopaminergic agents although levodopa is not recommended because of insufficient efficacy and risk of exacerbating psychosis. Prolonged use of neuroleptics can result in tardive dyskinesia with choreiform movements of the face, tongue, and limbs. If recognized early, most symptoms of tardive dyskinesia resolve within 5 years.
4. Mitochondrial toxins (CO, cyanide, and hydrogen sulfide). Agents that inhibit the mitochondrial respiratory chain can cause development of bilateral globus pallidus infarction and subsequently a parkinsonian syndrome. This typically results from a combination of hypotension and hypoxia in severe poisoning and can have neuropsychiatric manifestations or more classic parkinsonism.
F. Seizures. Toxins cause seizures by one of four mechanisms: (1) decrease in the seizure threshold of a patient with an underlying seizure disorder, (2) direct effects on the CNS, (3) withdrawal seizures, or (4) metabolic derangements. Most toxin-related seizures are generalized tonic–clonic. Most patients with toxin-induced seizures can be treated with standard seizure algorithms, except that treatment is more often successful with benzodiazepines and barbiturates then with phenytoin.
1. Stimulants (see also II.A.2.).
a. Sources. Cocaine, amphetamines, methamphetamine, and PCP.
b. Mechanism of toxicity. Secondary to increased levels of CNS catecholamines with subsequent excitation of the sympathetic nervous system. Can cause vasculitis, vasospasm, accelerated atherosclerosis and increase risk of both ischemic and hemorrhagic stroke.
c. Treatment.
(1) Diazepam 10 mg or lorazepam 2 mg IV, repeat doses as needed, or
(2) Phenobarbital 20 mg per kg IV at rate of 25 to 50 mg per minute.
2. Cholinergics (see also I.A.3.)
a. Sources. Organophosphate and carbamate insecticides and chemical warfare agents.
b. Mechanism of toxicity. Increased CNS concentration of acetylcholine with secondary release of glutamate.
c. Treatment.
(1) Diazepam 10 mg, lorazepam 2 mg IV, repeat doses as needed, or phenobarbital 20 mg per kg IV at rate of 25 to 50 mg per minute for seizures.
(2) Atropine 2 to 4 mg IV for signs of cholinergic excess.
(3) Pralidoxime 1.5 g IV over 30 minutes for nicotinic symptoms.
3. GABA antagonists.
a. Sources. Tricyclic antidepressants, phenothiazines, flumazenil, chlorinated hydrocarbons, hydrazines, cephalosporins, ciprofloxacin, imipenem, penicillins, isoniazid, steroids, clozapine, olanzapine, cicutoxin (water hemlock), picrotoxin (fish berries), and wormwood (absinthe).
b. Mechanism of action. Direct or indirect inhibition of GABAA receptors or decreased synthesis of GABA through inhibition of either glutamic acid decarboxylase or pyridoxal kinase (e.g., isoniazid and hydrazines).
c. Treatment.
(1) Diazepam 10 mg, lorazepam 2 mg IV, repeat doses as needed, or phenobarbital 20 mg per kg IV at rate of 25 to 50 mg per minute for seizures.
(2) Pyridoxine. For isoniazid or hydrazine overdose. The amount of pyridoxine administered should be equivalent (gram for gram) to the estimated amount of isoniazid ingested. It can be given IV push to patients with severe symptoms or as an IV infusion. If an unknown amount of isoniazid has been ingested, 5 grams IV can be given empirically.
4. Glutamate agonists.
a. Sources. Domoic acid (shellfish), ibotenic acid (A. muscaria mushrooms), and ß-N-oxalylamino-L-alanine (BOAA found in legumes of the genus Lathyrus).
b. Mechanism of action. Direct agonists at glutamate receptors (N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid).
c. Other clinical features. Patients with lathyrism from BOAA have spastic paraplegia.
d. Treatment.
(1) Diazepam 10 mg or lorazepam 2 mg IV for seizures, repeat doses as needed or phenobarbital 20 mg per kg IV at rate of 25 to 50 mg per minute.
5. Antihistamines.
a. Sources. First-generation (sedating) antihistamines (diphenhydramine, chlorpheniramine, and brompheniramine).
b. Mechanism of action. Central histamine-1 receptor antagonism.
c. Other clinical features. See anticholinergic syndrome (II.A.1.).
d. Treatment.
(1) Diazepam 10 mg or lorazepam 2 mg IV for seizures, repeat doses as needed, or phenobarbital 20 mg per kg IV at rate of 25 to 50 mg per minute.
6. Adenosine antagonists.
a. Sources. Theophylline, caffeine, theobromine, pentoxifylline, and carbamazepine.
b. Mechanism of action. Antagonism of presynaptic A1 receptors preventing inhibition of glutamatergic neurons, and A2 receptors causing cerebral vasoconstriction. Theophylline may decrease GABA levels by decreasing pyridoxal-5-phosphate levels.
c. Other clinical features.
(1) The manifestations of theophylline toxicity are similar to those of sympathomimetic syndrome (see II.A.2.).
(2) The manifestations of carbamazepine toxicity are similar to those of anticholinergic syndrome (see II.A.1.).
d. Treatment.
(1) Phenobarbital 20 mg per kg IV at rate of 25 to 50 mg per minute for altered mental status, CNS agitation, theophylline levels >100 μg per ml, or seizures, additionally may use repeated doses of diazepam 10 mg or lorazepam 2 mg as needed.
(2) Hemodialysis for theophylline or caffeine overdose with seizures.
7. Withdrawal seizures.
a. Sources. Ethanol, benzodiazepines, barbiturates, and baclofen.
b. Mechanism of action. Prolonged use of GABA agonists results in decreased activity at GABA receptors and increased activity at glutamate receptors.
c. Other clinical features. Delirium, hallucinations, tachycardia, hypertension, fever, autonomic instability, and hypertonicity (baclofen).
d. Treatment.
(1) Diazepam 10 mg or lorazepam 2 mg IV for seizures, repeat doses as needed, or phenobarbital 20 mg per kg IV at rate of 25 to 50 mg per minute.
(2) For baclofen withdrawal oral baclofen should be restarted at the previous rate, or the baclofen pump should be refilled.
Recommended Readings
Albers J. Toxic neuropathies. Continuum. 1999;5:27–50.
Albin RL. Basal ganglia neurotoxins. Neurol Clin. 2000;18(3):665–680.
Dobbs MR. Clinical Neurotoxicology. Syndromes, Substances, Environments. Philadelphia, PA: Saunders Elsevier; 2009.
Flomenbaum NE, Goldfrank LR, Hoffman RS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. New York, NY: McGraw-Hill; 2006.
Ibrahim D, Froberg B, Wolf A, et al. Heavy metal poisoning: clinical presentations and pathophysiology. Clin Lab Med. 2006;26(1):67–97, viii.
Kao LW, Nanagas KA. Carbon monoxide poisoning. Med Clin North Am. 2005;89(6):1161–1194.
O’Connor AD, Rusyniak DE, Bruno A. Cerebrovascular and cardiovascular complications of alcohol and sympathomimetic drug abuse. Med Clin North Am. 2005;89(6):1343–1358.
Rusyniak DE, Nanagas KA. Organophosphate poisoning. Semin Neurol. 2004;24(2):197–204.
Rusyniak DE, Sprague JE. Hyperthermic syndromes induced by toxins. Clin Lab Med. 2006;26(1):165–184, ix.
Spencer PS, Schaumburg HH, eds. Experimental and Clinical Neurotoxicology. 2nd ed. New York, NY: Oxford University Press; 2000.
Walsh RJ, Amato AA. Toxic myopathies. Neurol Clin. 2005;23(2):397–428.
Wills B, Erickson T. Drug- and toxin-associated seizures. Med Clin North Am. 2005;89(6):1297–1321.