BIOLOGICAL NEUROTOXINS

CLINICAL NEUROBEHAVIORAL TOXICOLOGY

0733-8619/00 $15.00

+ .OO

BIOLOGICAL NEUROTOXINS Christopher G. Goetz, MD, and Ethan Meisel

Biologic toxins are divided into three classes, animal, plant, and bacterial, each with a long history that includes medical, historical, and literary sources. In many cases, the best clinical descriptions date from early sources, but advances in biochemistry and molecular biology have offered new insights on mechanistic issues. With these advances, there are new developments that address target-specific neurologic involvement. Pure neurotoxins also offer important research tools for studies of subcellular control processes in the central, peripheral, and autonomic nervous systems and muscles. ANIMAL TOXINS

Most animal toxins of neurologic significance affect the cholinergic system, either through enhancement or blockade. There is strong seasonal variation in toxin-related incidents, and injuries from snakes, scorpions, and ticks are more common during summer months when campers and vacationers may inadvertently encounter these animals. In the case of snakes, it is especially important to attempt to identify the snake species, because potent antivenoms have been developed against specific poisons. The exotic marine toxins are not discussed, but exhaustive reviews are available.6 Snake Venoms

Venomous snakes of the world belong to three primary groups. The Viperidae encompass true vipers as well as pit vipers, a subgroup that From the Department of Neurological Sciences, Rush-Presbyterian-St. Luke’s Medical Center (CGG), Rush Medical College (EM), Chicago, Illinois NEUROLOGIC CLINICS VOLUME 18 NUMBER 3 AUGUST 2000

719

720

GOETZ & MEISEL

dominates the population of venomous snakes in the New World and includes various rattlesnakes. The Elapidae, found on every continent except Europe, include cobras, kraits, mambas, and American coral snakes. The Hydrophiodae, or sea snakes, are found chiefly in Asian and Australian waters. Snakebites constitute a significant health hazard that continues in the modern era. Worldwide every year, as many as 2.5 million people are victims of envenomation, with mortality as high as 125,000.2*In the United States there are an estimated 45,000 snakebites yearly. Although in this country the mortality is extremely low, children, the elderly, and patients with comorbid conditions have increased risk.% Snake venoms affect cardiac muscle, coagulant pathways, and the neurologic system. The specific neurotoxicity of these venoms relates primarily to their action on the peripheral neuromuscular junction, a nicotinic cholinergic system. Snake neurotoxins may act either presynaptically or postsynaptically, and most venoms are chemically composed of both types. Presynaptic toxins (P-bungarotoxin,notexin, and taipoxin) alter the normal release of acetylcholine from the presynaptic cell of the neuromuscular junction. Initially, there is augmentation of acetylcholine release followed by presynaptic depletion of the ne~rotransmitter.9~ Postsynaptic neurotoxins produce a nondepolarizing neuromuscular block of nicotinic receptors. Both types of toxins depress cholinergic function at the neuromuscular junction. Recent amino acid sequencing attributes the high affinity of the more potent toxins to the presence of a fifth disulfide bond .25,35,67,86 Pre- and postsynaptic effects of a given snake toxin can be differentiated physiologically. In pure form, the postsynaptic toxin causes a nondepolarizing neuromuscular blockade, a diminished amplitude but normal frequency of miniature end-plate potential (MEPPs) occurs on intracellular recordings and a decremental compound muscle action potential (CMAP) is seen on extracellular recordings. In some instances, this blockade may be reversed by cholinesterase inhibitors, but with others, there is no effect.= The presynaptic cholinergic-depletingeffects cause an exhaustion of MEPPs and an early incremental CMAP with rapid repetitive stimulation due, at least in part, to the facilitation of acetylcholine release. These effects are not reversed by cholinesterase inhibitor^.^^ There is little evidence that snake venoms act directly on the central nervous system (CNS).17 Clinical Features. Local pain and swelling are especially common with viper, rattlesnake, and cobra bites. Swelling increases over 24 hours and may extend over the entire bitten limb or trunk. Sanguinous blistering and local gangrene are secondary local complications.*0A preparalytic phase follows that includes headache, vomiting, local paresthesias and loss of consciousness. Ptosis and external ophthalmoplegia resembling myasthenia gravis herald more generalized weakness.85The latent period between snakebite and the development of paralytic signs and symptoms may vary from 1 to 10 hours. After the extraocular muscle and eyelid

BIOLOGICAL NEUROTOXINS

721

levator weakness occur, facial and jaw paresis develops. Swallowing and mouth opening become progressively compromised over hours. Gradual development of diaphragmatic, intercostal, and limb weakness follows.1o5 Secretions pool in the pharynx, the weakened respiratory muscles fail, consciousness is lost, and convulsions may occur. No sensory disturbance occurs except at the area around the bite itself. The neurotoxins are not toxic to striated muscle, except for sea snake and tiger snake venom in which notexin is a component. Other systemic effects of neurologic importance, including blindness and intracranial hemorrhage, relate to coagulation deficits.105Pathologically, alterations seem confined to the muscles, except for secondary bleeding effects. Widespread hyaline necrosis in skeletal muscles is seen and varies from focal to massive and diffuse.83 Treatment. Antivenom use, which has been the traditional mainstay of treatment, carries the risk of adverse effects including fatal anaphylaxis. Specific antidotes and dosages can be found in reference sources.16Pretreatment with diphenhydramine, steroids, and adrenaline have all been advocated. One recent prospective and randomized study analyzed 105 patients who received 0.25 ml of adrenaline versus placebo before antivenom administration. Those patients who received the adrenaline showed a significant reduction in adverse effects without any significant side effects, including intracerebral h e m ~ r r h a g eSupportive .~~ treatment is the mainstay of care for most victims of coral snake bite. Scorpion Sting

The manifestations of scorpion sting depend on the species responsible and may include local and systemic complications.54In the United States, the Arizona bark scorpion, Centruroides sculpturatus, represents the greatest health risk.I3Early local changes include regional pain and swelling. Within hours of envenomation, systemic reactions occur, including excessive salivation, sweating, mydriasis, and abdominal pain. Hypertension, peripheral circulatory collapse, and cardiac failure are complications that may be fatal. Neurologic involvement includes skeletal muscle rigidity, fasciculations of the extremities and tongue, convulsions, and alteration of mentation; the latter two conditions probably occur as secondary complications of hypoxia. Scorpion venoms produce a variety of neurochemical effects because of the peptides they contain. By interacting with membrane ion channels, these toxins cause an enhanced presynaptic depolarization, resulting in neurotransmitter release from synaptic vesicles.lo6Treatment is nonspecific and focuses on maintaining respiratory, cardiac, coagulation functions.44Although antivenom use may be justified after envenomation in young children with life-threatening symptoms, antivenom use can be associated with adverse reactions, and supportive care is almost always sufficient. Anticonvulsant medications may be necessary to control seizures.I2

722

GOETZ & MEISEL

Tick Paralysis

Tick paralysis, a flaccid ascending paralysis, results from the toxin of in 1824 certain female ticks. This disease was first reported by H0ve11~~ and has now been described in many parts of the world. In North American, Dermacentor andersoni, D. variabilis, D. occidentalis, Amblyomma americanum,and A. muculutum are responsible. In Europe and the Pacific, Ixodes ricinus and I. cornuatus are also c a ~ s i t i v eTick . ~ ~paralysis is most common in the Rocky Mountains and Northwestern states and in British Columbia and Alberta, Canada.lWThe toxin producing this disease is presumably excreted in saliva of the mature female tick. Children under the age of 10 years are most commonly affected. Most often, the tick is found on the patient's head, behind the ear or on the neck.41There is some indication of an association between the proximity of the site of attachment to the brain and the severity of clinical disability. Neither the nature of the neurotoxin nor the exact mechanism of its action is understood. The toxin may cause a failure in the liberation of acetylcholine at the neuromuscular junction or may cause a generalized depression of all excitable tissues, including the neurons of the spinal cord and brain stem." Clinical Features. Vague complaints such as restlessness, irritability, fatigue, and muscular pain occur days after the tick attaches to the person. Over the next day, unsteady gait develops followed by a symmetric ascending flaccid paralysis associated with a loss of deep tendon reflexes." This constellation of symptoms can be confused with the Guillain-Barre If the tick is not found and syndrome, myasthenia gravis, and b~tulism.'~ removed, clinical weakness may progress to involve muscles innervated by cranial nerves and cause paralysis of the sternocleidomastoid, facial, ocular, and lingual musculature, resulting clinically in dysphagia, dysarthria, facial paralysis, and ocular weakness. Mortality occurs in 10% of patients and is a result of respiratory paralysis. Secondary convulsions may occur terminally and are believed to be caused by hypoxia.lo7 The sensorium and consciousness are spared. There are no signs of systemic involvement such as alterations in the temperature, blood profiles, and sedimentation rate. The cerebrospinal fluid is also characteristically normal, aiding in distinguishing the syndrome from other entities. Cerebellar involvement and ataxia of all limbs have been described,&and focal paralysis of a single limb can occasionally occur. The electromyographic findings from tick-related meningoradiculitis include evidence of denervation with normal motor conduction velocities, prolonged distal latencies, and low sensory amplitudes, suggesting an axonal neuropathy. In addition, a study reviewing nerve conduction results of six patients demonstrated normal motor conduction velocities and a marked reduction in size of the compound motor action potential. The nerve conduction abnormalities rapidly returned to normal after the tick was removed.43Sural nerve biopsy specimens confirmed the axonal disease. Infiltrates of lymphocytes and plasma cells were numerous throughout the endoneurium, perineurium, and epineurium.lolThe similarity of

BIOLOGICAL NEUROTOXINS

723

this intoxication with Guillain-Barre syndrome and Lyme disease raises the possibility of overlap among immunologic, infectious, and toxic causes of neuropathic disorders. The course of tick paralysis depends on how quickly the tick is found and removed. The recovery pattern also may be species specific. Improvement usually occurs within hours of tick removal, but in Australia, symptoms may worsen in the first 24 to 48 hours, followed by improvement. In North America, the presence of bulbar symptoms generally confers a more grave prognosis, whereas this pattern is not true in Australia, where cranial nerve involvement occurs earlier in the disease progression.43Animal studies have shown that the clinical weakness may be dose related in that the most pronounced weakness occurs in animals challenged with the most Ciguatera Toxin

Ciguatera toxin (ciguatoxin) is a widespread toxin in the Pacific and Caribbean regions. Unlike the other major fish toxin, tetrodotoxin, ciguatoxin is carried by a number of different species of fish that cannot be identified as toxic by any outward appearance. The toxin is unpredictable in its distribution, so that a species may be poisonous on one side of an island and perfectly harmless on the other. Furthermore, the geographical areas in which poisonous fish are found are constantly changing, making the risk of poisoning high even to indigenous people.92Ciguatoxin poisoning is the most common food-borne illness caused by a chemical toxin reported to the Centers for Disease Control and Prevention. The responsible agent is a lipid-soluble, heat-resistant, and acid-stable toxin with a molecular weight of 1000 to 1500 daltons. It is produced by a marine dinoflagellate known as Gumbierdiscus toxicus. The one-celled animal attaches to algae and is passed up the food chain through larger and larger fish, becoming concentrated. Humans seem to be the only species adversely affected. The action of ciguatoxin relates primarily to its effects on the tetrodotoxin-sensitivesodium channel. The toxin causes spontaneous opening of the channels at resting potential, resulting in membrane depolarizat i ~ nIn. ~vitro ~ studies demonstrate that the toxin also causes swelling of the nodes of Ranvier. The proposed toxic mechanism is water influx as a result of the increased sodium ~ermeability.~ Symptoms of toxicity usually begin 3 to 5 hours after ingestion of contaminated food, but can be delayed by several days. Perioral and distal paresthesias usually initiate the toxic syndrome, followed by weakness, myalgias, dizziness, and dry mouth. Ptosis, dilated pupils, photophobia, and even transient blindness are among the neuroophthalmologic findi n g ~Clinical . ~ ~ morbidity usually relates to respiratory compromise, hypotension, and generalized weakness. Minimal and often undiagnosed intoxication with perioral dysesthesias and a sense of vague weakness that resolves over hours is probably common in such places as the Virgin Is-

724

GOETZ & MEISEL

lands and other sea areas.33It has been suggested that more severe neurologic sequelae are associated with a significantly longer delay in onset of ~yrnptoms.~ Treatment has been primarily supportive. Although many of the symptoms are anticholinergic in nature, atropine has not been found to be useful in treating symptoms other than cardiac or gastrointestinal symptoms. Calcium gluconate, pralidoxine chloride, neostigmine, and glucocorticoids also have been used, but without controlled efficacy studies.74 Amitriptyline has been advocated for the management of pruritic and dysesthetic symptoms (25 mg bid).28Although it carries the risk of hypotension, mannitol may be helpful, putatively reversing the swelling that occurs at the nodes of R a n ~ i e r . ~ Paralytic Shell Fish

Several types of shell fish, including clams and mussels, can be contaminated with toxins that include saxitoxin, a heat- and acid-stable toxin similar in action and structure to the sodium channel blocker tetradotoxin. This toxin is produced by marine dinoflagellates of the genus G ~ n y u u Z u x . ~ ~ Patients, often tourists, develop an acute paralytic illness within 30 minutes to 2 hours after ingestion of contaminated food. Most common neurologic symptoms include paresthesias, perioral and extremity tingling, and cerebellar ataxia. Respiratory depression is the most serious compliElectrophysiologic evidence shows cation, and mortality is 1% to normal motor and sensory conduction velocities and amplitudes with delayed proximal conduction timesz9In addition, domoid acid, a compound structurally related to the excitatory amino acid glutamate, has been the source of intoxications that are characterized by seizures, ophthalmoplegia, severe agitation, and subsequent coma.95 Black Widow Spider Bites

Volume for volume, the venom of the black widow spider is more potent than pit viper venom.79The acute symptoms include severe pain with local muscle spasm, and prolonged neurologic signs include headache, generalized fatigue,’ paresthesias, weakness, photophobia, and insomnia. The spider’s sharp fangs, or chelicerae, inject the venom, and its primary action involves forced release of acetylcholine from the presynaptic neuromuscular junction. Additionally, sympathetic and parasympathetic cholinergic systems are stimulated, then blocked. The venom appears to cause a channel for monovalent cation exchange to remain open,3O apparently by binding to a recently described guanosine triphosphate (GTP)-binding protein coupled receptor, l a t r ~ p h i l i n Severe . ~ ~ cramping ensues, but depolarization blockade follows, resulting in global weakness. Mortality from envenomation is likely to be less than 1 %, without a significant increase of mortality in the pediatric p o p ~ l a t i o n ? Antivenom ~,~~~

BIOLOGICALNEUROTOXINS

725

is effective with rapid resolution of symptoms, but because reactions are a risk, its use is controversial. Some authors suggest administration over 1 to 2 hours with cardiorespiratory monitoring.l1° Calcium gluconate infusion does not appear to alter the course of symptoms. Other treatment includes supportive care, muscle relaxants, sedative-hypnotic agents, narcotic analgesics and tetanus i m m u n i z a t i ~ n . ~ ~ , ~ ~ BOTANICAL TOXINS

A wide variety of plants contain toxins of neurologic importance. The ingestion of colorful but dangerous berries and flowers is especially common in young children. Adults are regularly victims of inadvertent mushroom toxicity. A number of hazardous plants are associated with specific neurologic complications and, especially in the case of psychotropic compounds, botanical-based toxins are the foundation of synthetically prepared illicit drugs. Many plants, including deadly nightshade and jimson weed, with high concentrations of atropine induce symptoms comparable to those that occur with anticholinergic drug overdose.47 Mushrooms Mushroom poisoning has been described since ancient history. The wife and children of Euripides and Emperor Claudius were probable victims of lethal intoxication. Poisonous mushrooms may be divided into two groups, those that cause early (within 6 hours after ingestion) and .those that cause late (6 to 40 hours) toxic signs. Mushrooms that cause early signs of toxicity induce a variety of clinical syndromes. Amanita (A. muscaria and A. pantherina) has strong anticholinergic effects because of its concentrations of ibotenic acid, muscazon, and muscimol. Clinically, intoxication causes agitation, muscle spasms, ataxia, mydriasis, myoclonus, and even convulsion^.^^ The gammaamino butync acid (GABA)-ergic action of these compounds accounts for part of the psychoactive response encountered. No specific antidote is available, and atropine is contraindicated. A. pantherine carries a mortality rate of 10% to 20% after i n g e ~ t i o n . ~ ~ The genera Inocybe and Clitocybe contain muscarine, a compound that stimulates parasympathetic nerve endings in a manner that mimicks acetylcholine. Atropine treatment has decreased mortality and the recommended starting dose is 2 rng.3l Coprinus atrarnentarius, generally considered edible, contains coprine, an amino acid that inhibits the enzyme acetaldehyde dehydrogenase. When consumed in combination with alcohol, a syndrome closely resembling that caused by disulfiram ingestion results and causes facial flushing, paresthesias, and severe nausea and vomiting with hyperventilation.” Psilocybe, a mushroom often consumed for it’s psychoactive effects, contains psilocybin and psilocin, two compounds with strong hallucinogenic proper tie^.^^ Furthermore, the pres-

726

GOETZ & MEISEL

ence of phenylethylamine may be responsible for the adverse effects such as tachycardia.8 Two major groups of mushrooms cause intoxication with delayed neurologic responses. Gyromitra causes neurologic symptoms probably as a result of direct neurotoxic effects, and A. phalloides causes neurologic symptoms secondary to hepatic damage. Gyromitra esculenta, or false morel, results in fatality rates ranging from 15% to 35%.40Therapy has traditionally been symptomatic with attention to electrolyte management, however, when the clinical picture is complicated by specific neurologic features, treatment includes pyridoxine hydrochloride.48A. phalloides causes neurologic symptoms as a secondary effect of hepatic damage, causing patients to die in hepatic coma. These Amanita mushrooms are responsible for about 95%of fatalities associated with mushroom ingestion, and reach several hundred per year globallyMThe clinical course begins 6 to 8 hours after ingestion. Symptoms include massive emesis and bloody choleralike diarrhea. Although patients often die during this phase from electrolyte imbalance, the most dangerous phase of hepatorenal failure does not occur until 3 to 5 days after mushroom ingestion.&Secondary neurologic manifestations include a gradual decline of mental status with confusion, asterixis, and eventually hepatic coma and death.31Treatment is mainly supportive and includes careful regulation of fluid status and electrolyte balance, correction of hypoglycemia, and monitoring of coagulation and renal and liver function.48 Jamaican Vomiting Sickness

Unripe ackee, a fruit indigenous to West Africa and first brought to Jamaica in 1778, is the causative agent involved in Jamaican vomiting sickness, a clinical syndrome resembling Reye’s syndrome. Until 1970, canned ackee was available in the United States. The responsible toxin is believed to be hypoglycine A, which inhibits several short-chain acetylcoenzyme A (acetyl CoA) dehydrogenases, thereby altering glycolysis and gluconeogenesis, amino acid metabolism, and fatty acid oxidation. Neurotoxicity appears to relate to hypoglycemia and the central accumulation of short-chain fatty acidsa9 Clinical Features. Intoxication after ingestion of unripe ackee causes severe vomiting and hypotonia without fever, followed by body twitching, which progresses to generalized seizures, coma, and death within 2 to 48 hour^.^^,^^ Young children are most commonly affected, and subjects who are malnourished are at increased risk for toxic signs. Intoxication is unusual in adults, and usually presents differently, with signs of agitation and delirium, ataxia, nystagmus, ptosis, and diffusely increased tendon reflexes. Neuropathologic changes include marked cerebral edema and hyperemia of the brain and meninges without specific microscopic changes.51 Treatment. Electrolyte management and rapid administration of glucose correct the severe hypoglycemia. Mortality before the introduction

BIOLOGICAL NEUROTOXINS

727

of glucose administration was 80%.a9Although the ability to control hypoglycemia has decreased the number of deaths, a report of 29 cases of endemic fatal encephalopathy in a small area in West Africa in 1998 demonstrates the significant mortality still associated with this illness.71 Glycine administration has been effective in reversing toxicity in hypoglycin A-treated rats and has been suggested to enhance conjugation of toxic metabolites.”* More recently, methylene blue has been used to treat ackee poisoning because of its ability to reoxidize nictotinamideadenine dinucleotide (NADH), thus allowing gluconeogenesis to continue.63Neither of these treatments has yet to be tested extensively in humans. Chickpea (Lathyrism)

In areas in Europe and India, spastic paraplegia has developed in humans and animals after consumption of different varieties of the chickpea, Lathyrus. Three potent neurotoxins, amino-0-oxalylaminopropionic acid, amino-oxalylaminobutyric acid, and 0-N-oxalylamino-L-alanine (LBOAA) seem to be involved in the pathogenesis of human l a t h y r i ~ mL.~~ BOAA likely induces neurodegeneration through excitotoxicactions at the AMPA glutamate receptor. L-BOAA has been shown to inhibit mitochondrial complex 1in a dose-dependent manner in male, but not female, mice and is thiol reversible, implying oxidation as the inciting mechanism. In experimental animals, these actions were limited to areas in the CNS similar to the primary areas affected in humans.91 Men are seven times more likely than women to be affected by intoxication, possibly a result of antioxidant characteristics of female hormones. Furthermore, there is great variability in who is affected even after consumption of similar amounts of ~hickpea.4~ The onset of neurotoxic signs can be acute or progressive. Lumbar pain and lower extremity weakness and stiffness are usually the first effects and occur after awakening in the morning. A low-grade fever may accompany these symptoms. Decreased strength, often associated with paresthesias, develops within several days, and leg spasticity and clonic tremor follow. Greatly increased tone in the thigh extensors, adductors, and the gastrocnemius muscles develops, so that the severely affected patient characteristically walks on the balls of the feet with a lurching, scissoring gait. Extensor plantar responses are typical as evidence of myelopathyF If the condition is severe, the upper extremities also may be involved. With disease progression, there may be muscle atrophy and a marked sensory deficit with paresthesias; lightning pains reminiscent of tabes dorsalis; and decreased sensitivity to touch, heat, and pain. Ataxia, with eventual loss of tendon jerks, is infrequent. Sphincter control is usually retained unless the involvement is extensive. Within 1 to 2 weeks, the pain and paresthesias usually disappear leaving a pure motor syndrome.68There may be some recovery of muscle power after the initial attack, but the spastic gait and secondary pes cavus tend to persist. In some instances relapses occur. Although spas-

728

GOETZ 81 MEISEL

tic paraplegia is the most common neurotoxic effect, polyneuropathy or mononeuropathy may be present.” Neuropathologic findings involve primarily anterolateral sclerosis in the thoracolumbar cord with loss of axons and m ~ e l i nCortical . ~ ~ lesions, including senile plaques and neurofibrillary tangles in Ammon’s horn, may be found, although whether they are pathophysiologicallyrelated to the chickpea or incidental findings is not known. Experimentally, lesions of large blood vessels similar to those that occur in copper deficiency have been produced; peripheral neuropathic lesions also have been seen.38 Khat

Khat is a naturally growing shrub of East Africa and Yemen. The leaves are chewed by millions for their amphetamine-like effects on the central dopaminergic receptors. Although not yet common in the United States, khat can be grown easily or transported by air resulting in an increase in this form of toxicity among immigrants, college students, and visitors returning from areas where the plant is widely grown. Khat induces central stimulant and sympathomimetic effects, including hypertension, fever, insomnia, and a gregarious, often pressured speech.62With chronic use, decreased economic productivity and impotency can occur, and with abrupt withdrawal, severe depression ensues. In addition, a toxic psychosis consisting of manic symptoms, paranoid delusions, and auditory hallucinations can develop that resembles toxicity from amphetamine, cocaine, and other centrally active sympathomimetic products.”’ The major active component of khat is the amphetamine-like compound, S-cathinone, which reaches peak concentrations 1.5 to 3.5 hours after onset of chewing and is undetectable by 24 hours.61 Spanish Rapeseed Oil

The ingestion of denatured rapeseed oil caused an epidemic of neurotoxic signs in Spain. The implicated oil contained high concentrations of oleyl anilide.77Over 300 deaths were attributable to the oil, over 20,000 people were variably affected, and 80% had neurologic manifestation^.^^ Three hundred twenty-two patients have been prospectively followed2 over 12 years, revealing a multiphasic clinical picture consisting of four stages. A 1- to 2-month acute phase was characterized by pulmonary edema, myalgias, rash, and other nonspecific symptoms. The intermediate phase followed, lasting 1 to 2 months and consisting primarily of severe myalgias. The early chronic phase, which lasted up to 2 years after toxin exposure, included a mixed symmetric polyneuropathy. The polyneuropathy, initially present in 68% of cases, remained in a significant number of patients at the end of follow-up. The late chronic phase consisted of tremor, myokymia, carpal tunnel syndrome, chronic musculoskeletal pain and muscle cramps that were the most common complaint at the end of the follow-up period. Other chronic problems included

BIOLOGICAL NEUROTOXINS

729

scleroderma-like lesions, Raynaud's syndrome, and weight Fewer than 10% of identified patients achieved complete remission after the acute phase, and more than 80% of patients developed chronic complaints.2 Detailed muscle and nerve biopsy specimens were analyzed in affected patients, and the major site of involvement was the peripheral nerve. Perineuritis and later fibrosis of the perineurium were distinctive. Demyelination of axons occurred in some cases, with distal nerves affected more widely than proximal onesn Whereas the predominant neurologic deficits were related to the peripheral nervous system, 3% of patients showed added clinical signs of central nervous system dysfunction; encephalopathy with either depressed level of consciousness or focal hemispheric signs occurred in half of these patients. In the other instances, increased intracranial pressure signs predominated. In those cases in which the CNS was examined, anterior horn cells in the spinal cord and cranial nerve nuclei showed marked chromatolysis.81 Botanical Depressants and Convulsants

Andromedotoxin, veratrine, solanine, and taxine are the most important depressant compounds found in such plants as death camas, lambkill, sheep laurel, mountain laurel, and calico bush. A peaceful progressive drowsiness and eventual coma without convulsion or mental irritability follows ingestion. No specific antidotes are known, and the neuropharmacologic mechanisms of action of these agents are not well delineated. The convulsant plants cause both acute and chronic toxic signs. The Cicuta genus includes the most toxic plant native to North America, water hemlock, which has a case-fatality rate of 30% and is responsible for the majority of deaths related to misidentification of plants.*O The toxin, an unsaturated aliphatic alcohol, causes nausea, abdominal pain, and epigastric distress within 15 minutes of ingestion, followed by general cholinergic symptoms and respiratory distress. Within 1 hour after ingestion, severe, typically generalized, seizures develop, often progressing to status epilepticus in fatal cases. Death occurs as a result of respiratory failure, anoxia and cardiac arrhythmias. There is no antidote, and therapy consists of supportive measures. Thiopentane sodium, a short-acting barbiturate, has been recommended because of its rapid action and its anticholinergic effect." Other plants with convulsant compounds include various berry plants such as chinaberry, moonseed, pinkroot, and Carolina allspice, a plant containing calycanthine, which is similar to strychnine. Again, no specific antidotes are available, and identification and respiratory support are the basic therapeutic aims. In the case of strychnine-like toxins, isolation of the patient from external stimuli is important. Convulsant plant toxins are also found in plant extracts or various aqueous decoctions of juniper, white cedar, and cypress. Single ingestion of these decoctions, even in a large dose, rarely causes neurologic signs

730

GOETZ & MEISEL

but chronic toxicity after daily ingestion of teas or brews is more clinically important. Personality changes and progressive seizure disorders have been described.15 BACTERIAL TOXINS

Three clinical syndromes are remarkable for the direct role of exotoxins on the nervous system. Two of these, diphtheria and tetanus, result from exotoxin production as part of a systemic infection, whereas botulism results from the ingestion of pre-formed exotoxin produced anaerobically. With current vaccination programs and careful regulation of food packaging, these syndromes are relatively unusual in urban American society and therefore diagnosis depends on sensitivity to the clinical history and recognition of characteristic presentations. Diphtheria

Corynebacterium diphtheriue, an anaerobic spore-formingbacteria, produces a powerful circulating exotoxin that preferentially affects muscle and myelin.14Diphtheria, which is transmitted by respiratory secretions, appears in two clinical forms, oropharyngeal and cutaneous. Both forms are associated with neurologic complications. Although rare in industrialized countries, there have been recent diphtheria outbreaks. In the Soviet Union, an epidemic between 1990 and 1996 consisted of 150,000 cases and resulted in 5000 deaths.18 In the United States, between 1980 and 1995, there were 41 diphtheria cases reported and 7% had neurologic features. Almost all diphtheria cases were the result of travel outside of the United States.'O Neurologic complications are the result of either direct damage to muscle and peripheral nerve or to indirect damage from cardiac emboli, metabolic encephalopathy, or hypoxia and airway obstruction. Because the exotoxin does not penetrate the blood-brain barrier appreciably, direct CNS involvement is uncommon.'04 The first neurologic symptoms consist of palatal paralysis occurring within the first 4 weeks of disease. Ocular involvement with accommodation dysfunction usually occurs 5 to 7 weeks after the initial symptoms. Neuropathies of cranial nerves nine through eleven also may be seen at this time. Peripheral neuropathy characteristically occurs between the eighth to twelfth week, but can occur as early as the sixth week. At that time, a predominant sensory polyneuropathy or a proximal motor neuropathy that extends distally can be obAutonomic dysfunction, predominantly affecting the parasympathetic system, can be detected?* The picture of a Guillain-Bar& syndrome with visual blurring and palatal involvement should immediately suggest diphtheria, especially in a patient who has recently traveled outside the United States. Pathologically, a noninflammatory demyelination of the peripheral nervous system predominates. The ganglia of the peripheral nervous sys-

BIOLOGICAL NEUROTOXINS

731

tem are the most affected, with adjacent segmental demyelination in peripheral nerves and roots. Cranial and somatic nerves are similarly affected. Specifically, the area of the node of Ranvier is preferentially altered, correlating experimentally with slowing of conduction velocities. The distribution of the lesions likely relates to the existence of a blood-nerve barrier that prevents access to nerve parenchyma of negatively charged proteins like diphtheria toxin.Io4 In the rare event that CNS signs develop, the pathophysiology is thought to relate to focal embolization to the CNS from mural thrombi in the diseased heart or to nonspecific systemic effects of a toxic or hypoxic encephalopathy. The former may give signs of hemiparesis or hemicho~ea.~J6 The toxic encephalopathy is characterized by alterations in mental status, drowsiness, and, on occasion, c0nvulsions.4~Diphtheritic meningitis is rare.59Diffuse cerebral damage after airway obstruction and hypoxia are not distinctive for this condition and appear microscopically the same as in other situations. Treatment of diphtheria focuses on rest, antitoxin administration, and maintenance of proper airway and cardiac function. Since the introduction of antitoxin, the mortality from severe disease has been reduced from upwards of 50% to 5% to 10%.I8Mildly symptomatic cases are usually treated with 10,000 to 20,000 units of antitoxin, moderate cases (pharyngeal membrane present) with twice that dose, and severe cases (laryngeal involvement) with 50,000 to 100,000 units all given at a single dose. Because the antitoxin binds and inactivates toxin already in the blood or extracellular fluid, the rapid administration of antitoxin is paramount.

Botulism Botulinum toxin, the most potent poison known, is produced by the spores of Clostridium botulinum. Inhibition of acetylcholine release is the underlying mechanism that accounts for the clinical spectrum of the disease.42Although the pathophysiology of the toxin-induced paralysis is well understood, the exact mechanism is still being delineated. The first step involves the internalization of the exotoxin across the membrane of ganglionic synapses, postganglionic parasympathetic synapses, and the neuromuscular junction. In the CNS, this process appears to occur by endocytosis in a mechanism independent of synaptic vesicle recycling. The mechanism of toxin internalization at the neuromuscular junction is still not clear, but it is possible that synaptic vesicle recycling is involved, thus suggesting a receptor-mediated mechanism.102Once inside the neuron, the toxin, which requires zinc for both enzymatic and structural functi0n,3~cleaves a group of proteins involved with vesicle docking and fusion collectively referred to as SNARE proteins, thus inhibiting release of the neurotransmitter.” There is evidence to suggest that botulinum toxin requires tyrosine phosphorylation within the neuron to become active.36 Classically, there are three forms of botulinum toxicity. Food-borne and infantile botulism, which occur with an annual incidence of 24 and 71 cases a year, respectively, are by far more common than is the third

732

GOETZ & MEISEL

form, wound botulism.87Food-borne botulism occurs primarily after the ingestion of contaminated home-canned fruits and vegetables. Toxicity develops as a result of consumption of toxin that is formed in the anaerobic environment of the sealed cans or jars. As a result, in this form of botulism, the toxic signs appear rapidly within hours or at most by 1week after ingestion. Infantile botulism, which occurs in the first 6 months of life, appears to relate to the absorption of living C. botulinum from the gastrointestinal tract. Wound botulism occurs after inoculation of a contaminated wound and results in both infection and intoxication.88Although wound botulism used to be extremely rare, there has been a modest increase within the last decade, likely associated with the injection of black tar heroin imported from Clinical Features. In both food-borne and wound botulism, cranial nerve signs, especially eye symptoms, appear early. Patient complaints include eye strain, blurry vision, and diplopia. The examination may reveal both an internal and external ophthalmoplegia. Rapid involvement of other cranial nerves produces vertigo, deafness, and dysphagia. Swallowing ultimately becomes impossible, and liquids are regurgitated through the nose. The voice often has a nasal quality and may be hoarse. Muscular weakness is characteristic of botulinum intoxication and typically appears on the second to fourth day after intoxication as either a descending symmetric paralysis or generalized weakness. Paresis may become so severe that moving about or even turning in bed is impossible. Often this muscular involvement particularly affects the neck muscles, so that the patient is unable to raise the head or needs to use the hands to turn the head. Acute muscular weakness may occasionally be the presenting symptom, and patients may suddenly fall down and be unable to raise themselves.’ Although there is no objective sensory involvement in Consciousbotulism, paresthesias may occur in as many as 14%of ness is maintained, although restlessness, agitation, and autonomic dysfunction are characteristic. The course of botulism is highly variable, ranging from rapid decline terminating in death to mild cases with minimal transient neurologic disturbances that often overlooked clinically. Terminally, the illness is characterized by labored respirations intermixed with prolonged periods of apnea and a gradual change from restlessness to somnolence. If the patient survives, recovery begins within a few weeks, although full strength returns very slowly, and muscular fatigability often persists long after resolution of the other symptoms. The differential diagnosis of botulism includes myasthenia gravis, Guillain-Barre syndrome, tick paralysis, chemical intoxication (e.g., carbon monoxide, belladonna, barium carbonate, methyl chloride, methyl alcohol, organic phosphorus compounds, and atropine), trichinosis, diphtheritic polyneuritis, psychiatric syndromes, and the Lambert-Eaton myasthenic syndrome. Although botulism toxicity is similar to atropine toxicity, the absence of hallucinosis and pupillary alterations in botulism is striking and may be helpful in distinguishing between the two entities. Mushroom and various marine toxins also are often anticholinergic, but

BIOLOGICAL NEUROTOXINS

733

sensory complaints and violent vomiting and diarrhea are present. The absence of fever in botulism helps to exclude poliomyelitis. Infantile botulism is a different clinical syndrome from other forms of botulism. In this disorder, spores actually germinate in the infant’s intestine and produce the toxin in vivo. The disease may be a mild outpatient illness or progress to fulminant, sudden death. Weakness and hypotonia are the prominent features of the severe form of illness, and infantile botulism is part of the differential diagnosis for any hypotonic infant? The early manifestations are usually constipation and an increasing inability to suck or swallow. In affected infants, the results of serum assays for toxin usually are negative but both toxin and spores can be found in stool. With proper life support, the disease appears to be selflimited even without antibiotic and antitoxin administration. Botulism has been offered as a possible explanation for sudden infant death syndrome (SIDS, crib death) with asphyxia ascribed to upper airway or tongue flac~idity.~ Treatment. Confirmation of the diagnosis depends on detection of the toxin in the patient or in implicated food. The patient and all exposed subjects should be hospitalized for antitoxin therapy and observation. Respiratory monitoring is crucial, and intensive care facilities usually are required. Trivalent ABE antitoxin has been recommended, one vial given intravenously and one administered intramuscularly. The dose is to be repeated once in 2 to 4 hours if symptoms persist. Guanidine, which enhances acetylcholine release from presynaptic terminals, has been used with experimental success, but this treatment remains controversial in humans.*l Because there is a small possibility that spores may still be releasing toxin within the gastrointestinal tract, penicillin has been advocated, .although definite penicillin efficacy has been established only for woundrelated botulism. Tetanus

Clostridiurn tetani produces a powerful exotoxin under the anaerobic conditions of wounds or soil-contaminated injuries. Less common sources of disease are vaccinations and unclean needles used by drug addicts. Although neonatal tetanus is primarily of historical interest in the United States, worldwide it remains the second leading cause of vaccine-preventable death among children.10g The mechanism by which tetanus toxin exerts its effect is similar in many ways to botulinum toxin. The first step involves the uptake of toxin into the host cell through synaptic vesicle recycling, implying that the receptor for the toxin on the nerve terminal is a component of the synaptic vesicle lumen. This finding also implies an activity-dependent mechanism. The L chain of the toxin is then translocated to the cytosol under acidic condition^.^^ Once inside the cytosol, the toxin interacts with its target, synaptobrevin, a protein involved in the neuroexcytosis apparatus, blocking the release of neurotransmitters from inhibitory interneurons.”

734

GOETZ & MEISEL

Pathology. Histopathologic changes within the CNS may be extensive and permanent. Usually when death occurs before the fifth day of illness, very few lesions are visible. The first elements to become involved are the nerve cells, which are irregularly damaged and present a swelling and perinuclear chromatolysis. The most severe changes occur within the nerve cells of the cortex and the brain stem. If the illness lasts longer than 5 days, many other changes appear, consisting primarily of perivascular areas of demyelination and gliosis. Clinical Features. The central and the peripheral nervous systems and the muscular system are involved in tetanus toxicity. Centrally, the predominant effect is disinhibition related to a toxic effect on gray matter gangliosides and possibly a presynaptic antagonism of amino acid putative transmitters in interneuron function (GABA and possibly glycine)j6 Both the a- and y-motoneuron systems are disinhibited by the toxin.94 Tetanus toxin enters the nervous system through retrograde axonal transport from the site of inoculation.34The incubation period is usually from 5 to 25 days, but may be as short as a few hours. In most cases, the clinical onset of neurotoxic symptoms is characterized by a seemingly preferential affinity of the toxin for the facial and bulbar muscles. Initial signs may consist of a chill, headache, and restlessness, with pain and erythema at the site of injury. A sensation of tightness in the jaw and a mild stiffness and soreness in the neck are usually noticed within a few hours. Pain between the shoulder blades also may be present. These early complaints, though vague and indistinct, are followed within a day or two by the more definite symptoms that characterize this disease. The jaw becomes stiff and tight; trismus results. This muscular involvement soon spreads to the throat muscles, producing dysphagia, and, when the facial muscles are involved, facial asymmetry and a fixed smile (risus sardonicus) results. As the disease progresses, muscular hypertonicity may spread and become generalized, with involvement of the trunk and extremity muscles. Opisthotonos results from rigidity of the back muscles that produces an arching of the spine along with retraction of the head. The abdominal muscles gradually assume a boardlike rigidity, and this development causes a forward arching of the back in some cases (emprosthotonos). Spasms or tonic contractions can occur in any muscle group and, although they may occur spontaneously, they are especially precipitated by the slightest stimulus, such as noises, touching the patient, or even touching the bed. The tetanic contractions are usually periodic and are associated with agonizing pain. During these episodes, the jaws are usually rigidly locked, the back arched, the limbs extended and stiff, the fingers clenched, and the abdomen boardlike. These episodes are exhausting and often terrifying to the patient. Flaccid tetraplegia and long-lasting muscle weakness may be seen in the post-tetanic phase and are believed to be caused by the peripheral action of the toxin.60In some of the more severe cases, marked dyspnea, poor respiratory function, and cyanosis also occur and may end in asphyxia and sudden death. The toxin has no direct effect on CNS centers involved with consciousness or mentation.

BIOLOGICAL NEUROTOXINS

735

Localized, relatively benign, forms of tetanus may rarely occur in partially immunized patients and may be confined to a wounded extremity or the head (cephalic tetanus).'" The latter condition is characterized by a short incubation period, facial paralysis, and dysphagia associated with infection of the face or head. Localized tetanus, however, is unusual and should generally be thought of as only the earliest manifestation of more extensive disease. Another tetanus syndrome seen in partially immune patients is generalized but nonfulminant disease after a minor injury. Resembling traditional tetanus with generalized muscle stiffness, spasms, and even risus sardonicus and trismus, this syndrome may be prolonged and last for many months. The history of a prior wound several months before the initial presentation, the high titer of serum antibody to tetanus, the history of partial immunization, and the clinical signs of nonfulminant tetanus solidify the diagnosis. The major entity that must be distinguished is stiffperson or Moersch-Woltman syndrome.82 An interesting hypothesis links opportunistic intestinal colonization by Clostridium tetani with autism. According to this theory, neurotoxin is released in the intestine and then transported directly to the CNS by the vagus nerve, thus bypassing the spinal cord and hence avoiding the characteristic features of tetanus." Treatment. The three main objectives of therapy in tetanus are to provide supportive care until fixed neurotoxin can be metabolized, neutralize circulating toxin, and remove the source of toxin. Respiratory intensive care is essential and often requires a ventilator. Tracheostomy is indicated in heroin addicts because of the high incidence of cardiac arrhythmias and hyperthermia in such cases.1o6 Diazepam, a relatively safe tranquilizer, also has muscle relaxant properties. In those patients with autonomic hyperactivity, propranolol has been helpfu1.Io0Circulatingneurotoxin is neutralized by the intramuscular administration of 3000 to 6000 units of human tetanus immune globulin (TIG) into three sites simultaneously. There is no need for repeated doses. Dkbridement of any nonviable tissue and antibiotic administration must be performed to remove any on-going sources of toxin. Occasionally, after the use of tetanus antitoxin, particularly as a prophylactic agent, serum reaction develops, involving primarily the peripheral nervous system but occasionally involving the CNS. In most cases there appears to be a selective action on the cervical spinal cord and its branches, involving mainly the fifth and sixth cervical segments. Approximately 10 days after the inoculation, severe pain develops in the shoulder girdle, radiating to the neck. This pain persists and is soon accompanied by weakness, primarily in abduction of the upper extremity. Atrophy of the involved muscles, especially the supraspinati and infraspinati, the rhomboids and the deltoids, may develop.27In most cases the prognosis is good, with complete recovery generally occurring within 6 months. About 20% of the affected patients show some residual weakness and atrophy, especially in the deltoid muscles. Although other serums and

736

GOETZ & MEISEL

vaccines may cause this condition, most cases of residual weakness and atrophy are associated with tetanus antitoxin. Treatment is symptomatic.

FUTURE PERSPECTIVES

In addition to more clear delineation of clinical syndromes and treatments, future neurotoxicological studies offer the potential to study the molecular biology of toxins as important research tools that examine nervous system function. As an example, the identification of the cobra venom, a-bungarotoxin, allowed researchers to investigate the function of the neuromuscular junction and develop not only an animal model for myasthenia gravis, but also important therapeutic conclusions on treatments aimed at the nicotinic receptors of the neuromuscular junction. With increasing appreciation of ion channel physiology, biological neurotoxins that can be synthesized and purified offer tools to study the normal function of neurons and their subcomponents.

References 1. Allen RW, Ecklund AW Botulism in North Dakota. JAMA 99:557-559,1932 2. Alonso-Ruiz A, Calabozo M, Perez-Ruiz F, et a1 Toxic oil syndrome: A long-term follow-up of a cohort of 332 patients. Medicine 72:285-295,1993 3. Arnon SS, Chin J: The clinical spectrum of infant botulism. Rev Infect Dis 1:614-624, 1979 4. Amon SS, Midura TF, Damus K, et a1 Honey and other environmental risk factors for infant botulism. J Pediatr 94:331-336,1979 5. Angibaud G, Rambaud S Serious neurological manifestations of ciguatera: Is the delay unusually long? J Neurol Neurosurg Psychiatr 64:688-694,1998 6. Baden DG, Fleming LE, Bean J A Marine toxins. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, Elsevier, 1995, pp 141-175 7. Baker AB, Nolan HH: The central nervous system in diphtheria. J Nerv Ment Dis 10024-28,1944 8. Beck 0, Helander A, Karlson-Stiber C, et a1 Presence of phenylethylamine in hallucinogenic Psilocybe mushroom: Possible role in adverse reactions. J Anal Toxic01 22:4549,1998 9. Benoit E, Juzans P, Legrand A-M, et a1 Nodal swelling produced by ciguatoxin-induced selective activation of sodium channels in myelinated nerve fibers. Neuroscience 71~1121-1131,1996 10. Bisgard KM, Hardy IR, Popovic T, et al: Respiratory diphtheria in the United States, 1980 through 1995. Am J Public Health 88787-791,1998 11. Bolte ER: Autism and Clostridium tetuni. Medical Hypotheses 51:133-144, 1998 12. Bond GR Antivenom administration for Centruroides scorpion sting: Risks and benefits. Ann Emerg Med 21:788-791,1992 13. Bond GR: Snake, spider and scorpion envenomation in North America. Pediatr Rev 20147-150,1999 14. Bowman CG, Bonventre P F Studies on the mode of action of diphtheria toxin. J Exp Med 131:659-674,1970 15. Brauch F Das klinische bild der thujaver giftung. Z Kiln Med 19:86-92,1932 16. Buckley E, Porges N (eds): Venoms, Publication No. 44.Washington, DC, American Association for Advancement of Science, 1956

BIOLOGICAL NEUROTOXINS

737

17. Campbell CH: The effects of snake venoms and their neurotoxins on nervous system of man and animals. In Hornabrook RW (ed): Topics on Tropical Neurology. Philadelphia, FA Davis, 1975, pp 259-293 18. Centers for Disease Control and Prevention: Diphtheria. Bulletin of the World Health Organization 76(supp1):129-130,1998 19. Centers for Disease Control: Tick Paralysis: Washington, 1995. JAMA 275:1470,1996 20. Centers for Disease Control and Prevention: Water Hemlock Poisoning-Maine, 1992. JAMA 271:1475,1994 21. Cherington M Botulism: Ten year experience. Arch Neurol30:432-437,1974 22. Chippaux JPSnake bites: appraisal of the global situation. Bulletin of the World Health Organization 76:515-524,1998 23. Clark RF, Wethern-Kestner S, Vance W ,et al: Clinical presentation and treatment of black widow spider envenomation: A review of 163 cases. Ann Emerg Med 21:782787,1992 24. Coldwell BB, Genest K, Hughes DW Effect of C. utrurnenturius on the metabolism of ethanol in mice. J Pharm Pharmacol21:176-179,1969 25. Connolly S, Trevett AJ, Nwokolo NC, et al: Neuromuscular effects of Papuan taipan snake venom. Ann Neurol38:916-920,1995 26. Critchley M Post-diphtheric chorea. Br J Child Dis 21:188-194, 1924 27. Davis LB: Paralysis from tetanus antitoxin. J Nerv Ment Dis 113:61-66, 1951 28. Davis RT, Villar LA: Symptomatic improvement with amitriptyline in ciguatera fish poisoning. N Engl J Med 315:65,1986 29. de Carvalho M, Jacinto J, Ramos N, et al: Paralytic shellfish poisoning: clinical and electrophysiological observations. J Neurol245:551-554, 1998 30. de Haro L, David, JM, Jouglard J: Le latrodectisme dan le sude de la France. La-Presse Medicale 23:1121-1123,1994 31. de Wolff FA, Pennings EJM:Mushrooms and hallucinogens: Neurotoxicologicalaspects. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, Elsevier, 1995, pp 35-60 32. Denny-Brown D Neurological conditions resulting from prolonged and severe dietary restrictions. Medicine 26:41-48, 1947 33. Engleberg NC, Morris JG, Lewis J: Cinguatera fish poisoning: A major common source outbreak in the US Virgin Islands. Ann Intern Med 98:336-337, 1983 .34. Eyrich K, Agostini B, Schulz A, et al: Clinical and morphological studies of skeletal muscle changes in tetanus. German Med Month 12:469-474,1967 35. Faure G, Bon C: Crotoxin, a phospholipase A2 neurotoxin from the South American rattlesnake Crotulus durissus terrificus: Purification of several isoforms and comparison of their molecular structure and of their biological activities. Biochem 27730-738,1988 36. Ferrer-Montiel AV, Canaves JM, DasGupta BR, et al: Tyrosine phosphorylation modulates the activity of clostridial neurotoxins. J Biol Chem 271:18322-18325, 1996 37. Fu F-N, Lomneth RB, Cai S, et al: Role of zinc in the structure and toxic activity of botulinum neurotoxin. Biochemistry 375267-5278,1998 38. Ganapathy KT, Dwivedi MP, Nagrajan V, et al: Experiments on chicks fed on Lathyrus sutivus. Indian J Med Res 51:865-867, 1963 39. Gessner BD, Middaugh JP Paralytic shellfish poisoning in Alaska: A 20-year retrospective analysis. Am J Epidemiol141:766-770, 1995 40. Giusti GV, Carnevale A: A case of fatal poisoning by Gyrornitru esculentu. Arch Toxicol 33:49-54,1974 41. Goetz CG: Neurotoxins in Clinical Practice. New York, SP Medical and Scientific Books, 1985 42. Goetz CG: Biological toxins. In Joynt RJ, Griggs RC (eds): Clinical Neurology. Philadelphia, Lippincott Williams & Wilkins, 1997 43. Grattan-Smith PJ, Morris JG, Johnston HM, et al: Clinical and neurophysiological features of tick paralysis. Brain 120:1975-1987, 1997 44. Gueron M, Ilia R, Sofer S The cardiovascular system after scorpion envenomation. J Toxicol Clin Toxicol 30:245-258, 1992 45. Gupta OK, Saksena PN, Gupta N N A clinical study of 856 patients with diphtheria. Indian J Pediatr 40:93-101,1973

738

GOETZ & MEISEL

46. Habermann E: Tetanus. In Vinken PJ, Bruyn GW (eds): Handbook Clinical Neurology. Amsterdam, North Holland Publishing Co., 1978, pp 491-510. 47. Hanna HP, Schmidley JW, Braselton WE: Datura delirium. Clin Neuropharm 15:109113,1992 48. Hanrahan JP, Gordon MA. Mushroom poisoning: Case reports and a review of therapy. JAMA 251~1057-1061,1984 49. Haque A, Hossain M, Wouters G, et al: Epidemiological study of lathyrism in northwestern districts of Bangladesh. Neuroepidemiology 15233-91, 1996 50. Hardman J, Limbird L, Molinoff F', et a1 (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996 51. Hill KR. Vomiting sickness of Jamaica: A review. West Indian Med J 1:243-246, 1952 52. Hogg RC, Lewis RJ, Adams DJ: Ciguatoxin (CTX-1) modulates single tetrodotoxinsensitive sodium channels in rat parasympathetic neurones. Neurosci Lett 252103-106, 1998 53. Holz GG, Habener J F Black widow spider a-latrotoxin: a presynaptic neurotoxin that shares structural homology with the glucagon-like peptide-1 family of insulin secretagogic hormones. Comp Biochem Physiol B Biochem Mol Biol121:177-184,1998 54. Horen WP: Insect and scorpion sting. JAMA 221:894-898,1972 55. Hovel1 WH, cited by Abbott KH. Tick paralysis: A review: I. Mayo Clin Proc 18:39-49, 1943 56. Hughes JM, Blumenthal JR, Merson MH: Clinical features of types A and B food borne botulism. Ann Intern Med 95:442-445,1981 57. Hughes JM, Merson MH: Current concepts fish and shell fish poisoning. N Engl J Med 2953117-1 120,1976 58. Idiaquez J: Autonomic dysfunction in diphtheritic neuropathy. J Neurol Neurosurg Psychiatr 55:159-161,1992 59. Jelsma F Cervical intramedullary cyst due to Corynebucterium diphtheriue gravis. J Neurosurg 3878-80,1973. 60. Kaeser HE, Miiller HR, Friedrich B: The nature of tetraplegia in infectious tetanus. Eur Neurol1:17-27,1968 61. Kalix P: Catha edulis, a plant that has amphetamine effects. Pharm World Sci 18(2):6973,1996 62. Kennedy JG, Teague J, Fairbanks L Qat use in North Yeman and the problem of addiction: A study in medical anthropology. Cult Wed Psychiatr 4311-344,1980 63. Kupfer A, Idle J R Methylene blue and fatal encephalopathy from ackee fruit poisoning. Lancet 353:1622-1623,1999 64. Lagos JC, Thies RE: Tick paralysis without muscle weakness. Arch Neurol21:471-474, 1969 65. Lampe KF, McCann MA: Differential diagnosis of poisoning by North American mushrooms, with particular emphasis on Amunitu phalloides-like intoxication. Ann Emerg Med 16~956-962,1987 66. Litten W The most poisonous mushrooms. Sci Am 232:90-101,1975 67. Loring RH, Andrews D, Lane W, et al: Amino acid sequence of toxin F, a snake venom toxin that blocks neuronal nicotinic receptors. Brain Res 385:30-37,1986 68. Ludolph AC, Spencer PS: Toxic models of upper motor neuron disease. J Neurol Sci 139(~~ppl.):53-59, 1996 69. Lupton MD, Klawans HL: Neurologic complications of diphtheria. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North Holland Publishing CO., 1978, pp 479-488 70. Matteoli M, Verderio C, Rossetto 0, et al: Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons. Proc Natl Acad Sci USA 9333310-13315,1996 71. Meda HA, Diallo B, Buchet JF', et al: Epidemic of fatal encephalopathy in preschool children in Burkina Faso and consumption of unripe ackee (Blighiu supidu) fruit. Lancet 353:536-540,1999 72. Misra UK, Sharma VP: Peripheral and central conduction studies in neurolathyrism. J Neurol Neurosurg Psychiatr 57572-577,1994

BIOLOGICAL NEUROTOXINS

739

73. Montecucco C, Schiavo G, Rossetto 0 The mechanism of action of tetanus and botulinum neurotoxins. Arch Toxic01 Suppll8342-354,1996 74. Moms JG Jr, Lewin P, Hargrett NT, et a1 Clinical features of ciguatera fish poisoning: A study of the disease in the US Virgin Islands. Arch Intern Med 142:1090-1092,1982 75. Njau BC, Nyindo M, Mutani A: Immunological responses and the role of the paralyzing toxin in rabbits infested with Rhipicephalus evertsi. Am J Trop Med Hyg 35:1248-1255, 1986 76. Passaro DJ, Werner SB, McGee J, et al: Wound botulism associated with black tar heroin among injecting drug users. JAMA 279:859-863,1998 77. Posada de la Paz M, Philen RM, Abaitua Borda I, et a 1 A further study of factors associated with pathogenicity of oils related to the toxic oil syndrome epidemic in Spain. Epidemiology 5:404-409,1994 78. Premawardhena AP, de Silva CE, Fonseka MM, et a 1 Low dose subcutaneous adrenaline to prevent acute adverse reactions to antivenom serum in people bitten by snakes: Randomised, placebo controlled trial. Br Med J 318:1041-1043,1999 79. Reeves JA, Allison EJ, Goodman PE: Black widow spider bite in a child. Am J Emerg Med 14469-471,1996 80. Reid HA: Symptomatology, pathology, and treatment of land snake bite in India and Southeast Asia. In Bucherl W, Buckley EE, Deuiofeu V (eds): Venomous Animals and Their Venoms. New York, Academic Press, 1968, p 611-624 81. Ricoy JR, Cabello A, Rodriguez J, et al: Neuropathological studies of the toxic syndrome related to adulterated rapeseed oil in Spain. Brain 106:817-835, 1983 82. Risk WS, Bosch EP, Kimura J, et a 1 Chronic tetanus. Muscle Nerve 4:363,1981 83. Rowlands JB, Mastaglia FL, Kakulas BA, et a 1 Clinical and pathological aspects of a fatal case of mulga (Pseudechis australis) snakebite. Med J Aust 1:226-230, 1969 84. Russell FE: Snake venom poisoning in the United States. Annu Rev Med 31247-259, 1980 85. Sanmuganathan P S Myasthenic syndrome of snake envenomation: A clinical and neurophysiological study. Postgrad Med 876596-599,1998 86. Servent D, Winckler-Dietrich V, Hu HY, et a 1 Only snake curaremimetic toxins with a fifth disulfide bond have high affinity for the neuronal a7 nicotinic receptor. J Biol Chem 272~24279-24286,1997 87. Shapiro R, Hatheway C, Swerdlow DL: Botulism in the United States: A clinical and epidemiologic review. Ann Intern Med 129:221-228,1998 88. Simpson LL: The action of botulinal toxin. Rev Infect Dis 1:656-662, 1979 89. Sherratt HSA: Jamaican vomiting sickness. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, Amsterdam, Elsevier, 1995, pp 79-113 90. Spencer PS Lathyrism. In Vinken PJ, Bruyn GW (eds): Handbook of ClinicalNeurology. Amsterdam, Elsevier, 1995, pp 1-20 91, Sriram K, Shankar SK, Boyd MR, et a 1 Thiol oxidation and loss of mitochondria1 complex 1 precede excitatory amino acid-mediated neurodegeneration. J Neurosci 18: 10287-10296,1998 92. Starreveld E, Hope CE: Cicutoxin poisoning. Neurology 25:730-734, 1975 93. Swift TR Disorders of neuromuscular transmission other than myasthenia gravis. Muscle Nerve 4334-353,1981 94. Takano K, Kano M Gamma-bias of muscle poisoned by tetanus toxin. Arch Exp Pathol Pharmacol276:413-420,1973 95. Teitelbaum JS, Zatorre RJ, Carpenter S Neurological sequelae of domoid acid intoxication due to the ingestion of contaminated mussels. N Engl J Med 322:1781-1787,1990 96. Tibballs J, Cooper SJ: Paralysis with Ixodes cornuatus. Med J Aust 145:37-38, 1986 97. Timms PK, Gibbons RB: Latrodectism-effects of the black widow spider bite. West J Med 144:315-317,1986 98. Toxic Epidemic Syndrome Study Group: Toxic epidemic syndrome, Spain, 1981. Lancet 2697-702,1982 99. Trevino S ' Fish and shellfish poisoning. Clinical Laboratory Science 11:309-314,1998 100. Tsueda K, Oliver PB, Richter RW Cardiovascular manifestations of tetanus. Anesthesiology 40588-592,1974

740

GOETZ & MEISEL

101. Vallat JM, Hugon J, Lubeau M, et al: Tick-bite meningoradiuculoneuritis: Clinical, electrophysiologic, and histologic findings in 10 cases. Neurology 37749-753,1987 102. Verderio C, COCO S, Rossetto 0,et a1 Internalization and proteolytic action of botulinum toxins in CNS neurons and astrocytes. J Neurochem 73:372-379,1999 103. Vieira BI, Dunne JW, Summers Q: Cephalic tetanus in an immunized patient. Clinical and electromyographic findings. Med J Aust 145:156-157, 1986 104. Waksman BH: Experimental study of diphthetic polyneuritis. J Neuropathol Exp Neurol20:35-45, 1961 105. Warrell DA, Barnes HJ, Piburn M F Neurotoxic effects of bites by the Egyptian cobra (Naja huje) in Nigeria. Trans R SOCTrop Med Hyg 70:78-79, 1976 106. Warnick JE, Albuquerque EX, Diniz CR: Electrophysiologicalobservations on the action of the purified scorpion venom, Tityustoxin, on nerve and skeletal muscle of the rat. J Pharmacol Exp Therapeu 198:155-167,1976 107. Weingart JL: Tick paralysis. Minn Med 50:383-386, 1967 108. Weinstein L: Tetanus. N Engl J Med 289:1293-1296, 1973 109. WHO: Progress towards the global elimination of neonatal tetanus, 1990-1998. Weekly EpidemiologicalRecord 7473-80, 1999 110. Woestman R, Perkin R, Van Stralen D: The black widow: Is she deadly to children? Pediatr Emerg Care 12:360-364, 1996 Br J Hosp Med 111. Yousef G, Huq Z, Lambert T Khat chewing - as a cause of psychosis. _ _ 54:322-326,19$5 112. Yudkoff M. Cohn RM, Puschak R, et al: Glvcine therapv in isovaleric acidemia. J Pediatr 923813-817,1978 . I

'

Address reprint requests to Christopher G. Goetz, M.D. Department of Neurological Sciences Suite 755 Rush-Presbyterian-St. Luke's Medical Center 1725 W. Harrison Street Chicago, IL 60612