CHAPTER CONTENTS Introduction 523 Aconitine 523 Anthracenones 525 Anticholinergics 526 Cardiac Glycosides 528 Cicutoxin 530 Grayanotoxins 532 Lathyrism 533 Nicotine and Related Compounds 535 Veratrum Alkaloids 537 INTRODUCTION Each year, hundreds of thousands of exposures to toxic plants occur around the world. Most of these exposures are of minimal toxicity largely because they involve pedi- atric ingestions that are of low quantity. The more seri- ous poisonings usually involve adults who have mistaken a plant for a food source or who have deliberately con- sumed it for its medicinal or toxic properties, such as hallucinogens or abortifacients. A poor correlation exists between taxonomy and tox- icity. Members of the same family of plants may have different toxic effects or, sometimes, no toxicity. Not infrequently, a single plant may contain several different toxins. In this discussion, plants are grouped by their toxins rather than on the basis of their taxonomy. Plant identification is often a difficult. If a specimen is available, local nurseries may be of help in identification. Poison centers are usually a good starting point in the identification of plants and management of their inges- tion. Most centers have botanical consultants and other resources that can assist in plant exposures. Few anti- dotes exist for plant exposures, and treatment is usually supportive. ACONITINE Members of the Aconitum genus grow throughout the world. Exposures are commonly associated with the over- zealous consumption of herbal preparations containing aconitine. Although fatal poisonings have been reported, aconitine is still readily available at many nutrition or herbal medicine stores. Plants Aconitum exposures are primarily to Aconitum napellus (monkshood; Figure 47-1) and Aconitum vulparia (wolfs- bane). Several species are also used in herbal preparations, including Aconitum carmichaeli (“chuanwu”) and Aconitum kusnezoffii (“caowu”). 1 The latter two appear to account for more fatalities than ingestion of monkshood. Delphinium species (larkspur) have similar toxicity. 2 Location A. napellus and A. vulparia grow in meadow areas of the mountainous areas from Arizona into Canada. Aconitum species are cultivated as perennial ornamentals. Delphinium 47 CHAPTER Neurotoxic Plants Brent Furbee
Transcript
CHAPTER CONTENTS
Introduction 523
Aconitine 523
Anthracenones 525
Anticholinergics 526
Cardiac Glycosides 528
Cicutoxin 530
Grayanotoxins 532
Lathyrism 533
Nicotine and Related Compounds 535
Veratrum Alkaloids 537
INTRODUCTION
Each year, hundreds of thousands of exposures to toxic plants occur around the world. Most of these exposures are of minimal toxicity largely because they involve pedi-atric ingestions that are of low quantity. The more seri-ous poisonings usually involve adults who have mistaken a plant for a food source or who have deliberately con-sumed it for its medicinal or toxic properties, such as hallucinogens or abortifacients.
A poor correlation exists between taxonomy and tox-icity. Members of the same family of plants may have different toxic effects or, sometimes, no toxicity. Not infrequently, a single plant may contain several different toxins. In this discussion, plants are grouped by their toxins rather than on the basis of their taxonomy.
Plant identifi cation is often a diffi cult. If a specimen is available, local nurseries may be of help in identifi cation. Poison centers are usually a good starting point in the identifi cation of plants and management of their inges-tion. Most centers have botanical consultants and other resources that can assist in plant exposures. Few anti-dotes exist for plant exposures, and treatment is usually supportive.
ACONITINE
Members of the Aconitum genus grow throughout the world. Exposures are commonly associated with the over-zealous consumption of herbal preparations containing aconitine. Although fatal poisonings have been reported, aconitine is still readily available at many nutrition or herbal medicine stores.
Plants
Aconitum exposures are primarily to Aconitum napellus (monkshood; Figure 47-1) and Aconitum vulparia (wolfs-bane). Several species are also used in herbal preparations, including Aconitum carmichaeli (“chuanwu”) and Aconitum kusnezoffi i (“caowu”).1 The latter two appear to account for more fatalities than ingestion of monkshood. Delphinium species (larkspur) have similar toxicity.2
Location
A. napellus and A. vulparia grow in meadow areas of the mountainous areas from Arizona into Canada. Aconitum species are cultivated as perennial ornamentals. Delphinium
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species are found throughout the United States and Canada, where they are also grown as ornamentals.
Description
Aconitum plants grow to 3 to 4 feet. The leaves are palmately divided into fi ve lobes, which are divided into narrow segments. Flowers, which are dark blue to purple or purple and white, are composed of fi ve petal-like sepals, one of which covers the top of the fl ower. The latter forms a hoodlike structure over the fl ower, hence the name. These plants, although peren-nial, dry up and appear dead soon after the onset of summer heat.
Toxic Parts
All parts of Aconitum plants are toxic, with toxicity greatest in roots and decreasing through fl owers, through leaves, and to the lowest toxicity in stems.3
Mechanism of Toxicity
Like grayanotoxins and veratrum alkaloids, aconitine effects its toxicity through action on sodium channels. Aconitine appears to increase sodium entry into muscle, nerve, baroreceptors, and Purkinje fi bers to produce a positive inotropic effect, enhanced vagal tone, neuro-toxicity, and increased automaticity and torsade de pointes.4 During late repolarization of the Purkinje fi ber (late phase 4), aconitine attaches to a limited number of the sodium channels and increases Na� infl ux,5–7 caus-ing late (or delayed) afterdepolarizations and increased automaticity (e.g., premature ventricular beats). How-ever, aconitine-induced sodium accumulation may also lead to early afterdepolarization during late phase 2 or early phase 3 of the action potential. These early after-depolarizations produce lengthening of the QT interval and are thought to explain reports of torsade de pointes in patients poisoned with aconitine.5,7–9 Bifascicular ven-tricular tachycardia, a dysrhythmia most often associated with digitalis toxicity, has also be reported in patients poisoned with aconitine.10
Clinical Presentation
Most case reports of aconitine poisoning have come from ingestion of herbs containing aconitine.1,11 Follow-ing exposure, onset of symptoms has been reported in one series of cases to occur between 3 minutes to 2 hours, with a median of 30 minutes.9 Symptoms may persist for 30 hours.12 Neurological complaints include initial visual impairment, dizziness, limb paresthesias, weakness,13 and ataxia.3 Coma may follow. Chest dis-comfort, dyspnea, tachycardia, and diaphoresis may also occur.13 Hyperglycemia, hypokalemia, bradycardia (with hypotension), atrial and nodal ectopic beats, supra-ventricular tachycardia, bundle branch block, intermittent bigeminy, ventricular tachycardia, ventricular fi brillation, and asystole have been reported.3,5,13,14 Death is usually due to ventricular arrhythmia.13,15 Ingestion of delphin-ium root has also resulted in ventricular dysrhythmias and cardiac arrest.2,13,15
Laboratory Studies
The presence of aconitine has been demonstrated by high-performance liquid chromatography at autopsy.15
Management
Neurological complaints related to aconitine require supportive care. The paramount concern is management of lethal arrhythmias. Ventricular tachycardia has failed to respond to several antiarrhythmic agents, including lido-caine, disopyramide, bretylium, amiodarone, potassium,
Figure 47-1. Aconitine. Aconitum napellus (see color plate).
and phenytoin. Tai et al. reported successful use of fl ecainide following lidocaine failure in a single case.10 Yeih et al. reported successful use of amiodarone follow-ing lidocaine failure in a case report.16 No antiarrhythmic agents have demonstrated clear superiority. In animal studies, Adaniya et al. demonstrated the ability of magne-sium to suppress early afterdepolarizations and polymor-phic ventricular tachycardia.5 It should be noted that while some authors17 differentiate between polymorphic ventricular tachycardia and torsade de pointes, Adaniya et al. seem to use the two terms interchangeably.5
ANTHRACENONES
Toxicity of Karwinskia humboldtiana was fi rst reported by Clavijero in 1769.5a In 1917, Castillo-Najera reported poisoning in 106 soldiers of whom 20% died. 5b Autopsies indicated peripheral nerve damage. Since that time, the consumption of berries of tullidora also known as coyotillo has been reported to cause paralysis. More recently, with ventilatory support, death occurs considerably less often. The plant is also toxic to sheep, goats, hogs, birds, and cattle.18
Plants
Toxic exposure of Karwinskia species (Figure 47-2) most often involves K. humboldtiana and less often involves Karwinskia mollis, Karwinskia parvifolia, Karwinskia johnstonii, Karwinskia rzedowskii, and others.
Location
Karwinskia species is found throughout Mexico, in the southern United States (primarily southwest Texas and southern California), in Central America, in Caribbean countries, and in northern Columbia. In Mexico, plants are found in areas of scrub vegetation at altitudes under 1000 meters above sea level with a dry climate.19
Description
Karwinskia species have several common names, among which coyotillo and tullidora are the most used. It is an evergreen shrub growing from 3 to 21 feet in height. It has deeply veined, oblong, smooth edged, dark green leaves up to 7 inches long. The leaves have an opposite attachment to the stem. The fruit is a small berry that is green to red to black (mature) and about 1 centimeter in diameter.
Toxic Parts
Highest concentration of Karwinskia toxin is in the seeds of the berry. The fruit is most toxic when unripe.
Mechanism of Toxicity
Several toxins classifi ed as anthracenones have been identifi ed. T-544 is thought to be the cause of paralysis. T-496 causes diarrhea, and T-514 causes hepatic and pulmonary damage in animal models.20 Axonal swelling has been observed in humans and is thought to be sec-ondary to Schwann cell injury.21 Wheeler and Camp described uncoupling of oxidative phosphorylation as a result of application of Karwinskia extracts.22 Thus, decreasing adenosine triphosphate production23 and the formation of reactive oxygen species appear to be re-sponsible for the cellular damage.
Clinical Presentation
Ingestion of multiple Karwinskia berries may initially produce vomiting and diarrhea in some cases. Onset of a distal, ascending fl accid paralysis begins within 2 to 3 weeks and may progress to bulbar paralysis that can be fatal in the absence of respiratory support. Symptoms are symmetrical with absent tendon refl exes. Surviving patients usually have full recovery if complications such as anoxia do not occur. The latency period between in-gestion and onset of symptoms makes this a diffi cult di-agnosis that is compounded because it occurs most often in children. Differential diagnosis includes Guillain-Barré syndrome and poliomyelitis.18,24 Pulmonary hemorrhage and renal failure may occur. About 40 cases are reported each year in Mexico, with up to fi ve fatalities annually.24
Laboratory Studies
Bermudez et al. described the use of thin-layer chro-matography to identify the Karwinskia toxins in the blood of patients with acute fl accid paralysis.24a Elec-tromyography demonstrates a peripheral polyneuropa-thy with segmental demyelinization. Cerebrospinal fl uid is normal. Sural nerve biopsy has demonstrated Figure 47-2. Anthracenones. Karwinskia species.
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demyelinization without infl ammatory infi ltrate or ax-onal degeneration.
Management
Supportive care and physical rehabilitation are the only therapies for anthracenone exposure. With ventilatory support, patients can survive, and most recover within a year. A few patients are left with residual effects.
ANTICHOLINERGICS
Numerous plants and mushrooms exhibit anticholinergic properties. The best known of these are the members of the Solanaceae family. Of the anticholinergic plants, the genera Atropa, Datura, and Hyoscyamus produce hyoscyamine (atropine). Other members of this group produce scopolamine. The members of both groups are listed here, but for this discussion Datura species are the primary focus because they account for more hospitaliza-tions than the other plants.
The fi rst recorded Datura poisoning occurred in 1676 during the Bacon Rebellion, when soldiers under Captain John Smith made a salad of Datura stramonium leaves and began to hallucinate. The name “Jamestown weed” was given to this plant, and its name has been corrupted over the years to “Jimson weed.”
Plants
Anticholinergic properties are found in Atropa belladonna (deadly nightshade), Datura meteloides (sacred datura; Figure 47-3), Datura stramonium (Jimson weed), Datura arborea (trumpet lily), Datura candida, Datura suaveolens (angel trumpet), other Datura species, Hyoscyamus niger (henbane), Lycium barbarum (matrimony vine), and Man-dragora offi cinarum (mandrake).
Location
D. meteloides is a perennial southwestern plant that grows well in desert areas. D. stramonium grows as an annual on recently disturbed ground throughout the United States. It is often found in soybean fi elds.
A B
Figure 47-3. Anticholinergics. (A) Datura meteloides (see color plate). (B) Datura metalloids seed pod (see color plate).
D. meteloides is a stout bushy plant with thick stems. The large leaves are oval with wavy edges. The foliage has a pungent odor. Seeds are found in spiney pods about 1.5 inches long. The fl owers are 6 to 8 inches long and white with purple edges. D. stramonium is similar to D. meteloides; Jimson weed has a dark purple stem and is a taller plant.
Toxic Parts
The entire Datura plant is toxic. The fl owers, fruits, and seeds are especially toxic.
Mechanism of Toxicity
The members of the genus Datura contain varying amounts of hyoscyamine and scopolamine. Young plants tend to contain mostly scopolamine, but as they mature, hyoscyamine predominates. The toxicity of these com-pounds results from competitive blockade of acetylcholine at peripheral and central muscarinic receptors.
Clinical Presentation
Onset of anticholinergic symptoms is usually within 30 to 60 minutes of ingestion and may last for 24 to 48 hours. Both central and peripheral syndromes may be seen. Levy described 27 cases in which every patient had altered mental status and mydriasis.25
Central Anticholinergic Syndrome
Central nervous system (CNS) excitation often manifests as agitation and hallucinations. CNS depression and coma may follow. Hallucinations are generally visual but may be auditory. Speech has a characteristic mumbling quality and is often incomprehensible. Patients often an-swer questions with appropriate one-word answers, but if prompted (and able) to speak in sentences, the fragmented speech pattern becomes obvious. Undressing behavior is not uncommon.
Peripheral Anticholinergic Syndrome
Tachycardia and mydriasis are common fi ndings of pe-ripheral anticholinergic syndrome. Flushed skin may be more diffi cult to detect. Fever is occasionally noted. Bowel sounds may be depressed or absent but are usually persist. Bladder motility may be decreased as well. Al-though dry mucous membranes may be associated with hyperventilation, dry axillae, in association with the other signs, indicate anticholinergic poisoning and help distinguish it from increased adrenergic activity.
Datura accounts for many admissions to critical care units each year. Although children are occasionally
poisoned, most exposure occurs in patients who have ingested seeds or a tea brewed from the seeds in an attempt to induce hallucinations. Death is rare and may occur more as the result of impaired judgment than direct toxicity. A few death reports do seem to indicate potentially fatal toxicity in high-dose expo-sures.26,27 Petechial hemorrhages of the endocardium and hyperemia and edema of the lungs were reported in both cases.
Laboratory Studies
Atropine may be detected by radioimmunoassay, gas chromatography–mass spectrometry, thin-layer chroma-tography,28 and liquid chromatography. Scopolamine has been analyzed in plasma and urine by radioreceptor assay and gas chromatography–mass spectrometry.29
Management
Anticholinergic decontamination is best accomplished with the administration of activated charcoal if the inges-tion has occurred within the previous 2 hours. The rec-ommended dose of activated charcoal is 0.5 to 1g/kg in children or 25 to 100g in adults. Tachycardia rarely re-quires treatment. Patients should be monitored for urine output and bladder distention. A nasogastric tube should be inserted in patients with decreased gut motility. Hypotension should be treated with intravenous isotonic fl uids. Dopamine may be used if hypotension persists after the patient’s intravascular volume has been re-stored, but this is unusual. The combination of impaired diaphoresis with agitation may lead to severe hyperther-mia, which must be aggressively treated with sedation or paralysis and active cooling. Rhabdomyolysis is common and explains renal failure and other complications seen in severe Datura toxicity. Because of their anticholinergic activity, phenothiazines and diphenhydramine should be avoided. Haloperidol does not appear to be effective for resolution of central anticholinergic effects.30 Benzodiazepines are, on the other hand, effective in the treatment of agitation.
Several authors have advocated the use of intrave-nous physostigmine for patients with central anticho-linergic effects.25,30,31 Physostigmine inhibits acetylcho-linesterase, thus increasing the amount of acetylcholine available to the muscarinic receptors. While benzodiaz-epines may be used to sedate agitated patients, phy-sostigmine may restore the patient’s level of conscious-ness to its baseline. It is particularly helpful in differentiating anticholinergic poisoning from other causes of altered mental status. It should not be used unless peripheral anticholinergic signs accompany a clinical picture of central anticholinergic poisoning. Seizure activity, bradycardia, heart blocks, and asystole
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have followed use of physostigmine.32,33 Potential ben-efi t should be weighed against risk before use.
CARDIAC GLYCOSIDES
The medicinal properties of the cardiac glycosides were known to the ancient Egyptians, as well as the Romans, who used it as an emetic, heart tonic, and diuretic.34 In 1785, William Withering published An Account of the Foxglove and Some of Its Medical Uses: With Practical Re-marks on Dropsy and Other Diseases, thus popularizing its use.34a In 1890, Sir Thomas Fraser introduced Strophanthus and its digitalis-like effects. Worldwide, these plants have been used as abortifacients; in the treatment of leprosy, venereal disease, and malaria; and as a suicide agent.35 More than 200 naturally occurring cardiac glycosides have been identifi ed to date. Digitalis species ingestion is seldom re-ported. Convallaria majalis (lily of the valley) exposures are associated with minimal morbidity and, in a recent review of 10 years of data from regional poison centers, have had
no associated mortality.36 Of the many plants containing cardiac glycosides, Nerium oleander is responsible for the greatest number of toxic exposures each year.37
Plants
Plants known to contain cardiac glycosides include Digi-talis purpurea, Digitalis lanata (foxglove; Figure 47-4A), Nerium oleander (oleander; Figure 47-4B), Strophanthus gratus (ouabain), Thevetia peruviana species (yellow oleander); Convallaria majalis (lily of the valley), Urginea maritima, and Urginea indica (squill). Other plants thought to contain cardiac glycosides are Asclepias (milk-weed), Calotropis (crown fl ower),38 Euonymus europaeus (spindle tree), Cheiranthus and Erysimum (wall fl ower), and Hellaborus niger (henbane).
Toxic Parts
All parts of plants containing cardiac glycosides are toxic. Seeds are said to contain more glycoside than other parts of the plant.
A B
Figure 47-4. Cardiac glycosides. (A) Digitalis species (see color plate). (B) Nerium oleander (see color plate).
Oleander is a native of the Mediterranean and Asia but grows in tropical and subtropical areas around the world. It is grown as an ornamental across the southern part of the United States. It does not tolerate freezing tempera-tures. Digitalis spp. and Convallaria majalis may be found throughout North America.
Description
N. oleander can grow to 30 feet. The leaves are leathery and have a lanceolate shape. They may be six or more inches long in mature plants. Thevia peruviana is a small tree with similarly shaped but smaller leaves. Its fl owers are yellow-orange. All parts of these plants, including the seeds, are toxic.
Mechanism of Toxicity
The glycoside toxin attaches to the �-subunit of the Na�/K�-ATPase pump to inhibit its action. Because this pump exchanges intracellular sodium ions for extracellu-lar potassium ions, inhibition leads to an overall increase in intracellular sodium ions. Rises in intracellular sodium concentration result in secondary rises in intracellular calcium levels, explaining the positive inotropic effect of cardiac glycosides. In toxic amounts, the rises in intracel-lular sodium and calcium depolarize the cell following repolarization to cause late afterdepolarizations and in-creased automaticity typical of cardiac glycoside poison-ing. Depolarization of baroreceptors innervated by the ninth cranial nerve triggers afferent refl exes, which in-crease vagal tone and produce bradycardia and heart blocks.39 Severe poisoning results in hyperkalemia as the ability to pump potassium into the muscle is curtailed.
Neurotoxicity is also thought to occur as a result of Na�/K�-ATPase pump inhibition. Marx et al.39a proposed that this occurred in both neurons and astrocytes. While this would directly affect impulse transmission of neurons, the effect on astrocytes might also adversely affect neuro-nal activity. A major function of the astrocyte is to take up glutamate and convert it to glutamine, which in turn, is converted to both glutamate and �-aminobutyric acid (GABA). Inhibition of the glutamate transporter GLT-1 would lead to an increase of the excitatory neurotransmit-ter, glutamate, and a decrease in the inhibitory GABA. Excitotoxicity would occur, eventually leading to neuronal and astrocyte death.40 Evidence also indicates that seroto-nergic transmission may play a role.41 It should be noted that signifi cant interspecies variation occurs in physiologi-cal response to cardiac glycosides. Rodents, for example, tend to be resistant to cardiac effects, while neurotoxicity is more apparent than in humans. Care should be taken in extrapolating from rodent studies to humans.42,43
Clinical Presentation
Gastrointestinal irritation is common with ingestion of cardiac glycosides, particularly N. oleander or T. peruviana. The latter was studied as a potential antiarrhythmic agent in the 1930s but was not marketed because it caused more gastrointestinal irritation than digitalis.44 Saravanapavanan-than et al. reviewed 170 cases of T. peruviana ingestion and found that vomiting was the most common presenting complaint (68.2%).45 Other symptoms are shown in Table 1.
Electrocardiographic effects have occurred in up to 61.8% of patients in one study.45 They include, in order of frequency, atrioventricular block, bradycardia, T wave changes, ST depression, ventricular ectopy, and atrial ectopy. PR prolongation, QT shortening, and P or T wave fl attening may also occur.46 Hyperkalemia is reported in more serious acute poisonings.46–48 Normal or decreased serum potassium levels are commonly found in chronic poisoning if renal function is normal.
Neurological affects have occurred with plant inges-tions and are similar to those associated with therapeutic use of digitalis. Visual abnormalities include scotomas, hazy vision, fl ickering halos, and yellow–green–tinted vision (chromatopsia).49,50 Nonspecifi c symptoms such as malaise, fatigue, drowsiness, restlessness, and agita-tion have all been reported.51 While vague symptoms occur at lower doses, more severe symptoms are often associated with cardiotoxicity. CNS depression may occur as a direct effect of the toxin48 but is often associ-ated with bradycardia and hypotension. Death has been reported.45,46
Although rare, neuropsychiatric changes are also ob-served. They are associated with high-dose exposures. Delirium, hallucinations, and psychosis have been reported and may occur early.51–53 The administration of digoxin immune Fab therapy has been reported to result in rapid reversal.53
Symptom Percentage (%)
Dizziness 35.9
Diarrhea 38.0
Abdominal pain 5.9
Pain or numbness in tongue, throat, lips 4.1
No symptoms 12.9
Table 1: Relative Frequency of Signs and Symptoms Associated with Oleander Poisoning
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Laboratory Studies
Osterloh et al. described cross-reactivity of oleander glycosides on radioimmunoassay for digoxin.47 The test may serve as confi rmation of the presence of cardiac glycosides; however, clinical symptoms are more indica-tive of toxicity. Postmortem serum concentrations are known to increase and do not predict the premortem levels.46
Management
In general, management of cardiac glycoside toxicity from plants is the same as for digitalis toxicity. Airway control and other basic life support measures are the fi rst concern. Gastric decontamination with activated charcoal should follow those measures. The recom-mended dose of activated charcoal is 0.5 to 1g/kg in children or 25 to 100g in adults. Hyperkalemia may be treated with such agents as insulin and dextrose infusions or sodium bicarbonate infusion. Ventricular tachyar-rhythmias may be managed with lidocaine, and brady-rhythmias may respond to atropine or ventricular pacing. Large doses of Fab-antidigoxin antibodies correct both rhythm and hyperkalemia in dogs poisoned by olean-der.54 Shumaik et al. reported the use of digoxin-specifi c Fab fragments in the treatment of a 37-year-old man who had ingested N. oleander leaves.55 Other reports of their use have supported those fi ndings.48,56
CICUTOXIN
The fi rst reports of toxic effects from Cicuta species occurred in 1697. Stockbridge reported the fi rst case of poisoning in the United States in 1814.57 In a review of deaths reported to poison centers between 1986 and 1996, Krenzelok et al. found reports of 19 deaths. Of these, Cicuta species accounted for more deaths than did any other plant.58 Exposure to Cicuta and Oenanthe spe-cies may be accidental, as in most pediatric cases, but more commonly, the fatal cases involve misidentifi cation of the plant as a foodstuff or as a hallucinogen.
Plants
Cicutoxin is found in Cicuta maculata (water hem-lock) and Cicuta douglasii (western water hemlock; Figure 47-5). The related oenanthotoxin is found in Oenanthe crocata (hemlock water dropwort).
Location
Water hemlock grows in the eastern half of the United States and Canada. C. douglasii grows in the western United States. O. crocata is considered to be a European plant but is reported to have been transplanted into the Washington, DC, area.59 These plants are found in or immediately adjacent to water. They are most often
A B
Figure 47-5. Cicutoxin. (A) Cicuta douglasii (see color plate). (B) Water hemlock root (see color plate).
encountered in lakes or streams but may be found in marshy areas.
Description
Plants of the Cicuta and Oenanthe species are generally found growing out of the water or close enough for their roots to make contact with the water. Both varieties form a low-growing bush that may be 3 to 4 feet tall. Stems are hollow and have a carrot-like odor. Flowers, which occur during the summer months, are small and white in fl at-topped clusters or umbels. Leaves are compound and toothed. Both plant species have thick whitish roots that, when sliced sagittally, possess transverse stripes. The stripes may form small chambers late in the growing season. The roots have been mistaken for wild carrots. They are 5 to 6 inches long and white, and when cut they have a strong carrot-like odor. Although the roots are characterized as having transverse chambers, they are often solid. Roots of Oenanthe species are also said to secrete a yellowish sap when cross sectioned.60 Water hemlock bears a striking resemblance to other umbelli-fores, which are nontoxic. Heracleum lanatum (cow parsnip) and Daucus carota (Queen Anne’s lace) may be distinguished by their location and physical differences in the stem. Mistaking a toxic member of the Apiaceae family for a nontoxic one has been a fatal error for nu-merous foragers over the years.61–64 Almost yearly, one to two deaths are reported to poison centers in the United States due to the ingestion of these plants.
Toxic Parts
All parts of plants of the Cicuta and Oenanthe species are toxic, especially the roots.
Mechanism of Toxicity
Although nausea and vomiting are considered to be the most consistent fi ndings, seizure activity followed by cardiac arrest is the common sequence in fatal cicutoxin or oenanthotoxin exposures.65 An exact mechanism for the proconvulsant activity of cicutoxin has not been determined. Starreveld and Hope suggested that seizure activity might be due to cholinergic overstimulation of the reticular formation or basal ganglia.66 Nelson et al. performed a series of experiments in mice to explore the effi cacy of anticholinergic agents in the prevention of cicutoxin-induced seizures. They found that anticholin-ergic agents failed to protect the animals while pretreat-ment with cholinergic agents did not appear to lower the seizure threshold.67
By 1979, a more appealing theory for cicutoxin’s proconvulsant activity had arisen. Carlton et al. sug-gested that cicutoxin is structurally similar to picrotoxin,
an indirect antagonist at GABAA receptors.68 GABA re-ceptors serve as ion channels to allow the passage of chloride ions into the neuron. This hyperpolarizes the neuron moving it away from its threshold for fi ring. Many anticonvulsants such as the benzodiazepines and barbiturates act as indirect agonists at the GABA receptor. By preventing the action of GABA, picrotoxin hyperpolarizes the neuron, moving it closer to its threshold for fi ring. If cicutoxin acts on the GABA receptor at the picrotoxin site, seizure activity would be expected as it is with picrotoxin. This would also be consistent with Nelson’s fi ndings that seizures were better controlled in animals treated with diazepam or barbiturates than with other agents.67,69
Clinical Presentation
Case reports of Cicuta species61,65,66,70–72 and Oenanthe species60,73–76 ingestions are similar in presentation. In-gestion is followed by nausea, vomiting, and diaphoresis. While these signs and symptoms have led some authors to speculate about increased cholinergic activity as the mechanism for seizure activity,66 the frequent reports of mydriasis70–72 detract from this theory. The initial con-vulsion often occurs within the fi rst hour. Repeated convulsions, with intermittent lethargy, ensue for the next several hours. Fatalities usually occur within about 10 hours and are almost invariably associated with repeated seizure activity. O. crocata poisoning has been estimated to be 70% fatal in one small series.75
Rhabdomyolysis and renal failure have been reported.68 Although some toxins may cause rhabdomyolysis directly, the presence of prolonged seizure activity that was reported in this patient may well be the etiology.
Laboratory Studies
Although clinically useful means of determining cicutoxin or oenanthotoxin are not available, methods of identifi ca-tion are described by King et al. for the latter.74 These methods included ultraviolet absorption, thin-layer chro-matography, high-performance liquid chromatography, and mass spectrometry, which may be useful for later confi rmation of exposure.
Management
Asymptomatic patients should be given activated charcoal and observed for 4 hours after ingestion. If no cicutoxin or oenanthotoxin symptoms occur, they may be released. The recommended dose of activated charcoal is 0.5 to 1g/kg in children or 25 to 100g in adults. This should be given orally or through a nasogastric tube. Activated charcoal should not be given to a comatose patient until the patient’s airway is protected.
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Symptomatic patients often arrive after seizures have occurred. The patient’s airway should be secured fi rst. Diazepam or phenobarbital are most appropriate for sei-zure control and should be used aggressively. Phenytoin has no clear role in management of cicutoxin-induced seizures. Because of vomiting and, occasionally, diarrhea, fl uid replacement is often required. Creatine phosphoki-nase should be monitored because of the possibility of rhabdomyolysis. In addition to maintaining urine output, urine alkalinization may be benefi cial patients with rhab-domyolysis.77 Hemodialysis plus charcoal hemoperfusion has been performed in one case36; however, clearance of cicutoxin was not measured and the favorable outcome is consistent with many of the cases managed without extracorporeal elimination.71 At this time, hemodialysis or hemoperfusion have not been shown to be benefi cial. Seizure control and supportive care are the most effective therapies.
GRAYANOTOXINS
Rhododendrons and azaleas were introduced into Europe from Asia in the mid-1700s to early 1800s. Both are parts of the 500 to 1000 natural species with numer-ous hybrids. Exact species identifi cation can be diffi cult. The toxic components of this genus vary, and their presence in a given plant is diffi cult to predict. Although ingestion of leaves, fl owers, or nectar or use of the leaves in the production of tea produces toxicity, most poison-ings result from consuming honey made from nectar collected from these plants. Honey poisonings are less common today because honey from several sources is combined before marketing. The earliest description of poisoning by these plants appears in the anabasis, a description of the unsuccessful military expedition of Cyrus the Younger to overthrow Artaxerxes II (401 to 400 BC). The following is an account of the incident that took place in what is now northeastern Turkey on the coast of the Black Sea:
The number of bee hives was extraordinary, and all of the soldiers that ate of the honey combs lost their senses, vomited, and were affected with purging, and none of them was able to stand upright; such as had eaten only a little were like men greatly intoxicated, and such as had eaten much were like mad men and some like persons at the point of death. They lay upon the ground, in consequence, in great numbers, as if there had been a defeat; and there was general dejection. The next day, no one of them was found dead; and they recovered their senses about the same hour they had lost them on the preceding day.
Several other accounts of the toxicity of “mad honey” are available.78
Plants
Grayanotoxins are found in Rhododendron species (rho-dodendrons, azaleas; Figure 47-6), Kalmia angustifolia (sheep laurel), Kalmia latifolia (mountain laurel), and Pieris species (Andromeda). Grayanotoxin I may also be found in honey made from the nectar of these plants.
Location
Native to the temperate parts of the world, rhododendrons are grown widely as ornamentals. Rhododendron occiden-tale, Rhododendron macrophyllum, and Rhododendron albifl orum are of special interest on the West Coast in the production of honey. Reports of contaminated honey have also occurred in the eastern United States, where rhodo-dendrons as well as K. latifolia and K. angustifolia may serve as a source of grayanotoxin.
Description
Rhododendron leaves are evergreen, oblong, and leath-ery and have a smooth margin. They appear in whorls about the branch. Because of the many species, the leaf size is variable but generally ranges from 1 to 5 inches. The fl owers are white to pink (rhododendrons) and white, pink, magenta, crimson, or orange (azaleas).
Toxic Parts
The entire rhododendron plant is toxic.
Figure 47-6. Grayanotoxins. Rhododendron species (see color plate).
In 1955, it was discovered that the members of the Erica-ceae family contained structurally similar compounds that were responsible for their toxicity. These compounds, which were formerly known as andromedotoxin, acety-landromedol, and rhodotoxin, are now termed grayano-toxin I.79 Grayanotoxin II and III are toxic derivatives of grayanotoxin I. Animal studies initially indicated that these toxins were capable of producing respiratory depression, bradycardia, hypotension, and seizure activity.80 Subse-quent studies in squid axons have shown that grayanotoxin I acts by attaching to the sodium channels of cell mem-branes and changing both open and closed channels to a modifi ed open state. This increases sodium conductance dramatically and leads to cellular depolarization.81,82 It appears that a single molecule of grayanotoxin is suffi cient to activate a sodium channel.83 This effect is thought to explain, in part, the CNS and cardiac manifestations of grayanotoxin poisoning. Masutani et al. noted in their study of grayanotoxin effects on frog skeletal muscle that grayanotoxin appears to contain four hydroxyl groups essential for its biological activity. These are also present in veratridine (false and white hellebore), batrachotoxin (poison dart frog), and aconitine (monkshood).84
The increases in intracellular sodium concentrations in the heart, baroreceptor cells, and brain cells mimic the effects of cardiac glycosides to produce increased auto-maticity, enhanced vagal tone (heart blocks, bradyrhyth-mias, etc.), and CNS changes. Because Na�/K�-ATPase is not inhibited, hyperkalemia is notably absent.
Clinical Presentation
While most grayanotoxin exposures are of little conse-quence,85 serious cardiotoxicity has been reported. Vomit-ing, loss of consciousness, and seizure were observed in a 27-year-old female who had ingested 75 mL of honey she had purchased in Turkey. She was hypotensive and bradycardic. Her only laboratory abnormality was a mild leukocytosis. Dysrhythmias included sinus node arrest, atrioventricular-escape beats, second-degree atrioventricu-lar block, and intraventricular conduction block. The pa-tient recovered after insertion of a cardiac pacemaker.86
Laboratory Studies
Thin-layer chromatography has been used to identify grayanotoxin compounds.87
Management
Initial grayanotoxin management should include the administration of activated charcoal if the ingestion has occurred within the last 2 hours. The recommended
dose of activated charcoal is 0.5 to 1g/kg in children or 25 to 100g in adults. Supportive care is usually suffi cient for management. Signifi cant bradycardia may be treated with atropine or cardiac pacemaker. Although experi-mental agents such as tetrodotoxin88 have been used to reverse the effects of grayanotoxin I, no clinically avail-able antidote exists. Lidocaine or other sodium chan-nel–blocking antiarrhythmics (group I) would seem appropriate for ventricular arrhythmias.
LATHYRISM
As far back as Hippocrates, the toxicity of a diet of Lathyrus sativus was known to cause illness in animals and people. In fact, in the early 1800s, Francisco Goya painted Gracias a la Almorta (Thanks to the Grasspea) depicting a woman dispensing bowls of the legumes to the people surrounding her. As has occurred over the years, war had produced a need for alternative sources of cereals and fl our. While intermittent ingestion of Lathyrus species did not cause illness, the need for fre-quent consumption resulted in two forms of illness, neurolathyrism and osteolathyrism. In 1942, 1200 Romanian Jewish males were interred in a German forced-labor camp where they received a diet of ap-proximately 400 grams of grass peas a day. By December of that year, 800 of the inmates were showing signs of spastic paraparesis.89 Seyle is credited for coining the terms neurolathyrism to describe the disorder of the nervous system and osteolathyrism to denote the con-nective tissues.90 In the mid-1950s, �-aminopropion-itrile had been identifi ed as the toxic component of Lathyrus odoratus causing bone lesions and aneurysms in animals. In 1964, Rao et al. reported the isolation of �-N-oxalyl-L-�,�-diaminopropionic acid, also known as �-oxalyamino-L-alanine (L-BOAA). In the last 50 years, most cases have been found in Bangladesh, India, China, Chile, Ethiopia, and Nepal.89,91
Plants
Lathyrism primarily results from L. sativus exposure (Figure 47-7); however, other implicated species include Lathyrus cicera, Lathyrus ochrus, and Lathyrus clymenum. Lathyrus odoratus (sweet pea), a common ornamental, has been reported to cause osteolathyrism.
Location
While the Lathyrus genus may grow worldwide, cases of lathyrism are usually confi ned to Bangladesh, India, China, Chile, Ethiopia, and Nepal. There are 60 species of Lathyrus. In the United States, L. sativus grows in California, Oregon,
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Maryland, and Washington, DC. All states in the United States have some species of Lathyrus.92
Description
Lathyrus is a low-growing vine with small blue fl owers producing approximately 1 centimeters long. It is drought resistant, which contributes to its use in times of famine.
Toxic Parts
Toxicity is primarily in the Lathyrus seeds. Of interest, efforts have been under way to produce a toxin-free cul-tivar of L. sativus.93
Mechanism of Toxicity
Lathyrism is a disease of the upper motor neurons. The primary injury is degeneration of the corticospinal tract. Swelling of the anterior horn cells and diminished Nissl substance with Hirano bodies were reported by Streifl er et al.94 At a cellular level, it appears that L-BOAA acts on non-N-methyl-d-aspartate receptors such as a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid or kainic
acid receptors. Both ion channel receptors allow the in-fl ux of sodium ions, leading to membrane depolarization. Calcium ion infl ux causes long-term changes in synaptic connections and leads to cellular degeneration. Initial changes may be reversible but become permanent if exposure is not stopped.
Clinical Presentation
Onset of lathyrism symptoms is often associated with heavy exertion. Leg weakness is the most common ini-tial complaint. Neurological signs include increased deep tendon refl exes of the knee and ankle, sustained patellar clonus, bilateral extensor plantar refl exes, and spasticity of lower extremity adductors and extensors.89 Drory et al. conducted a nearly 50-year follow-up study of eight randomly selected men from the Wapniarka forced-labor camp mentioned earlier.95 The patients had spastic paraparesis and scissors gait requiring aid from one or two canes. Tendon refl exes in the lower extremities were increased, and bilateral extensor plantar refl exes were evident. Upper limbs were normal, and sensory defi cits were absent. All nerve conduction velocities were normal. Electromyography studies
A B
Figure 47-7. Lathyrus species (A) Lathyrus sativus fl ower (see color plate). (B) Lathyrus sativus seeds (see color plate).
showed abnormalities of the lower limbs in fi ve of the eight patients, but the authors speculated that some changes may have been due to aging. They found wide-spread neurogenic pathology in the lower limb muscles of two of the eight patients.95
Spencer et al. studied lathyrism in a population of Ethiopians between 1988 and 1990. They estimated the prevalence to be from 1 to 75 per 10,000 population. Men were affected 2.6 times more often than women. Onset of symptoms occurred between 1 to 6 months of regular grass pea consumption.89 Haque et al. found a prevalence rate of 14 per 10,000 in two northwestern districts of Bangladesh.96
Osteolathyrism presents as bone pain and deformity usually found as a separate population but occasionally found in those suffering from neurolathyrism.97 The pri-mary toxin appears to be �-aminopropionitrile. Dawson et al. found that semicarbazide, thiosemicarbazide, and aminoacetonitrile may also induce bony deformities with lysyl oxidase, a cofactor.98 Cohn and Streifl er described clinical signs including the absence of ossifi cation centers of the ischial tuberosities and ileac crest, as well as bowing and thickening of the femoral shaft. Before that, osteo-lathyrism had been considered a separate entity from neurolathyrism.99
Laboratory Studies
Diagnostic studies of lathyrism are not clinically avail-able. Diagnosis is based upon physical examination, his-tory of exposure, and exclusion of other neuropathies.
Management
Beyond removal of exposure, treatment of lathyrism is supportive. Many patients improve after exposure ends, but most have some permanent sequelae, including permanent spastic paraplegia.
NICOTINE AND RELATED COMPOUNDS
The pyridine and piperidine alkaloids—nicotine, coniine, anabasine, cystisine, arecoline, lobeline, and many others—have a similar mechanism of action. Plants containing these alkaloids are widely distributed today but are thought to have originated in South America. Nicotiana rustica, which contains up to 18% nicotine, is thought to have been the fi rst tobacco export from the New World. Much more potent than Nicotiana tabacum (0.5% to 9% nicotine), it is still smoked in Turkey and serves as a source for commercial nicotine produc-tion.100 N. tabacum is planted throughout the south-eastern United States as the source of cigar and cigarette
tobacco. Because the toxicity of smoked tobacco has been widely discussed elsewhere, only dermal and gas-trointestinal absorption is addressed in this chapter. Small quantities of nicotine are also found in plants from the Solanaceae family, such as tomatoes, potatoes, and eggplant. This is of little consequence in terms of poisoning.101,102 Several of the Nicotiana and Lobelia species are cultivated as fl owering plants. Of the uncul-tivated plants in this group, Nicotiana glauca (tree to-bacco) and Conium maculatum (poison hemlock) are the most common sources of poisoning.
Plants
Plants containing nicotine include N. tabacum (tobacco; Figure 47-8A), N. glauca (tree tobacco; Figure 47-8B), Nicotiana trigonophylla (desert tobacco), and Nicotiana attenuata (coyote tobacco). Coniine is primarily found in C. maculatum (poison hemlock; Figure 47-8C). Aethusa cynaprium (fool’s parsley) contains coniine. Lobeline and lobelamine are found in Lobelia infl ata (indian tobacco), Lobelia cardinalis, and other Lobelia species. Laburnum anagyroides (golden chain tree), Sophora secundifl ora (mescal bush bean), Sophora tomentosa (necklace pod Sophora), and Gymnocladus dioicus (Kentucky coffee bean) all contain cystisine. Areca catechu (betel palm or betel nut) contains arecoline.100
Location
Conium maculatum
Poison hemlock grows throughout the United States and southern Canada except in desert regions. It is often found along roadways or railroads.
Nicotiana glauca
Tree tobacco is common from the southeast to the southwest of the United States, where it may grow to 10 feet or higher. It grows in the desert but is commonly found along ditches in those areas. Where water is more plentiful, it has a wider range.
Description
Conium maculatum
The biennial C. maculatum may reach 10 feet in height. The leaves are pinnately divided three to four times and have a fernlike appearance similar to parsley, for which it is sometimes mistaken. The fl ower is umbrella shaped and strikingly similar to that of D. carota (Queen Anne’s lace) or Cicuta species (water hemlock). The stem is hollow and has red to purple speckles along its length. The crushed stems are said to smell like mouse urine; however, that observation is extremely subjective and should not be used to identify the plant. Its taproot is
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occasionally mistaken for parsnip. This plant is reputed to be the source of poison used in the execution of Socrates.69
Nicotiana glauca
Early N. glauca growth has a shrublike appearance and may be mistaken for collard greens due to the grayish cast of the green leaves. The leaves are oval with a smooth margin and a rubbery texture, and they grow up to 6 inches in length. The fl owers are approximately 2 inches long by 1⁄2 inch wide and bright yellow with a tubular shape.
Toxic Parts
All parts of both C. maculatum and N. glauca are poisonous. The seeds and roots of C. maculatum are especially toxic.
Mechanism of Toxicity
Nicotine, coniine, anabasine, lobeline, and related pyri-dine and piperidine alkaloids cause similar toxicity. Their primary action is activation and then blockade of nico-tinic acetylcholine receptors. Activation of nicotinic receptors in the cortex, thalamus, interpeduncular nu-cleus, and other locations in the CNS accounts for coma and seizures. Nicotine has been shown to enhance fast excitatory neural transmission in the CNS by triggering presynaptic cholinergic receptors, which increase pre-synaptic calcium and stimulate both cholinergic and
glutamatergic transmission.103 Nicotinic receptor activa-tion facilitates the release of many neurotransmitters, including acetylcholine, norepinephrine, dopamine, serotonin, and �-endorphins.104
Activation of nicotinic receptors at autonomic ganglia produces varied effects in the sympathetic and parasym-pathetic nervous system. These most commonly include nausea, vomiting, diarrhea, bradycardia, tachycardia, and miosis.105 Nicotine alkaloids act as depolarizing neuro-muscular blocking agents and produce fasciculations and paralysis.
Clinical Presentation
Ingestion or dermal exposure to nicotine and related compounds can result in any or all of the signs and symp-toms listed in Table 2.
Although rare, severe poisonings do occur.106 One of the more commonly reported poisonings results from the ingestion of cigarettes. The ingestion of a single cigarette is enough to cause symptoms in a small child. Smolinske et al. reported that 3 severely poisoned chil-dren had ingested a minimum of 1.4 mg/kg and 25 asymptomatic children ingested less than 1 mg/kg.107 Curry et al. reported nine cases of ingestion of N. glauca, which had been mistaken for collard and tur-nip greens.108 Three fatalities occurred. Symptoms in-cluded leg cramps, paresthesias, dizziness, and headache. Onset was within 1 hour, and resolution in the surviving patients ranged from 3 to several hours.108 Mellick et al. reported two cases of N. glauca ingestion resulting in
neuromuscular blockade and eventual complete recov-ery.109 Frank et al. reported a C. maculatum ingestion in a 4-year-old child that resulted in miosis, vomiting, and coma. The onset of symptoms was 30 minutes after in-gestion, with resolution in about 9 hours.110 Drummer et al. reported three fatalities from C. maculatum.102 Foster et al. reported the accidental ingestion of C. maculatum by a 14-year-old child that resulted in respi-ratory failure, asphyxia, and eventual death and that an-other child who ingested a smaller amount of the same C. maculatum plant had symptoms of nausea, malaise, and tingling of the extremities and survived.111 The 2002, the American Association of Poison Control Cen-ters annual report described a 13-year-old child who developed ascending paralysis, a seizure, and then death after ingestion of C. maculatum that was mistaken for parsley.112
Green tobacco sickness commonly occurs in the tobacco-growing states. Workers handling leaves can absorb nicotine through the skin. It occurs almost exclusively in workers who are cropping leaves from the plant.105 Symptoms comprise nausea, vomiting, diarrhea, diaphoresis, and weakness, which usually re-solve with symptomatic treatment.
The use of betel quid which is popular in India, Southeast Asia, and the East Indies,100 has been reported in people who have immigrated to the United States from those countries. The quid is a betel nut wrapped in a betel vine leaf and smeared with a paste of burnt lime.113 It contains arecoline and several other choliner-gic pyridine alkaloids.
Rhabdomyolysis has been reported from the ingestion of C. maculatum, although the reports are somewhat confusing in that “hemlock poisoning” is attributed to exposure to both Cicuta and Conium species.114,115
Laboratory Studies
Nicotine, coniine, and other alkaloids may be measured in urine by various methods, including gas chromatog-raphy,29 mass spectrometry,102 and thin-layer chroma-tography.116
Management
Activated charcoal should be administered for ingestions of nicotine and related alkaloids have occurred in the previous 2 hours. The recommended dose of activated charcoal is 0.5 to 1g/kg in children or 25 to 100g in adults. Because vomiting is a common symptom, ipecac administration is not indicated, and lavage of plant materials is probably not as effective as the administra-tion of activated charcoal. In patients with dermal expo-sure, as in the case of green tobacco sickness, the skin should be thoroughly washed with soap and water. Atro-pine may be used to block muscarinic symptoms such as bronchospasm, vomiting, diarrhea, or bradycardia. There is no standard dose in this situation, and the amount given should be titrated to reverse muscarinic symptoms without inducing anticholinergic toxicity. Convulsions are best treated with benzodiazepines or barbiturates. Nicotinic symptoms such as weakness, fasciculations, or paralysis cannot be reversed, but supportive care is generally suffi cient to manage the patient, with some patients requiring ventilatory support. No clinically use-ful antidotes have been found for the nicotinic effects. Patients should be monitored for rhabdomyolysis and its subsequent renal impairment. Due to the usual rapid onset of symptoms, patients who present and remain asymptomatic and who are not suicidal may be released after 4 hours of observation.
VERATRUM ALKALOIDS
Veratrum alkaloids are found in the various species of Veratrum and Zigadenus throughout the United States and in parts of Canada. Historically, these plants have been used as sources of medicines and insecticide. Their toxicity was noted in sneezing powders, made from pulverized roots of these plants. Inhalation or ingestion has resulted in several signs and symptoms, including hypotension or bradyrhythmia. Teratogenicity in farm animals, particularly sheep, has been widely reported.
Muscarinic Nicotinic
Salivation Weakness
Lacrimation Fasciculations
Urination Paralysis
Gastroenteric cramping Tachycardia
Emesis Coma
Miosis Seizures
Bronchospasm
Bradycardia
Table 2: Muscarinic and Nicotinic Effects of Nicotine and Related Compounds
Chapter 47 • Neurotoxic Plants
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Plants
Veratrum alkaloids are found in Veratrum album (white hellebore; Figure 47-9A), Veratrum californicum (corn lily, skunk cabbage), Veratrum viride (false hellebore), and Zigadenus species (death camus; Figure 47-9B).117,118
Location
V. viride is found in Canada and the eastern United States from New England to Georgia. Related species are found in western United States (V. californicum), Alaska and Europe (V. album), and Asia (Veratrum japonicum).119 False hellebore tends to grow in low-lying, swampy areas, while white hellebore is found in alpine meadows.79
Description
Veratrum plants are tall (2 to 7 feet) perennial herbs. Broad, longitudinally plicated leaves are spirally arranged on a stout stem. White to yellowish-green pedicellate fl owers line the terminal 30 to 60 centimeters of the stem. These plants also contain a highly seeded fruit.79
Zigadenus is a genus of the lily family. It is found throughout the United States and Canada. Flowers are pale yellow, pink, or white. The leaves are long, thin, and grasslike. The root is a bulb, which is similar in
appearance to and often mistaken for wild onion. Zigadenus, however, lacks an onion-like odor.117,120
Toxic Parts
The entire veratrum plant contains toxic veratrum alka-loids; however, the bulb and fl owers most commonly cause poisoning. Fruit seeds and leaves rarely cause human toxicity.
Mechanism of Toxicity
The veratrum alkaloids, which are chemically similar to steroids, include protoveratrine, veratridine, and jervine.119 These agents were introduced in the 1950s as antihypertensive agents; however, they were found to have a narrow therapeutic index and their use was dis-continued.119,121 Of these steroidal alkaloids, veratridine is the most potent.83 The primary activity of these com-pounds is to attach to voltage-sensitive sodium channels in conductive cells and increase sodium permeability, raising intracellular sodium concentration like grayano-toxins. Veratrine affects only a limited number of the sodium channels, but those so affected reactivate 1000 times more slowly than the unaffected channels (i.e., slow recovery). These alkaloids also appear to block inactivation of sodium channels and change the
activation threshold of the sodium channels so that some remain open even at their resting potential.83 Again, the rise in intracellular sodium concentrations leads to increased automaticity, enhanced vagal tone without hyperkalemia, and occasional neurotoxicity. High doses given to animals result in cardiac arrest.6
Clinical Presentation
Poisoning with veratrum alkaloids most typically occurs after accidental ingestion of the plant secondary to con-fusion with an edible species.119 Toxicity also results from inhalation of sneezing powders prepared from pul-verized white hellebore root.122 Nausea and vomiting are most commonly seen after ingestion of the veratrum alkaloids. Clinically signifi cant bradycardia and hypoten-sion are also generally seen. Other reported toxic effects have included abdominal pain and distention, salivation, respiratory depression, yellow or green scotomata, pares-thesias, increased muscle tone, rigors, and rarely, sei-zures.119,121–124 Various electrocardiogram changes have also been reported with veratrum poisoning. Marinov et al. reported a characteristic electrocardiogram pattern in 10 of 12 patients poisoned with V. album that in-cluded PR and QT interval shortening, ST segment depression, T wave morphology changes, and bundle branch block.125 Quatrehomme et al. noted nausea and vomiting followed by hypotension. In contrast to the observations of Marinov and colleagues, Quatrehomme and colleagues reported QT prolongation.126
Characteristic facial deformities (cyclopia, cleft lip and palate, microphthalmia) and limb defects (bowed fi bulae, shortened tibia, excessive fl exure of the knees) occur in offspring of pregnant sheep who ingest plants containing veratrum alkaloids. Jervine and other steroidal alkaloids found in the Veratrum species are responsible for these birth defects.127
Laboratory Studies
No clinically useful laboratory studies confi rm veratrum alkaloid exposure.
Management
Initial management following veratrum alkaloid expo-sure should include the administration of activated char-coal if the ingestion has occurred within the last 2 hours. The recommended dose of activated charcoal is 0.5 to 1g/kg in children or 25 to 100g in adults. Bradycardia usually responds to atropine administration. Hypoten-sion may or may not respond to the atropine. Crystalloid fl uids or vasopressors such as dopamine have been used to support blood pressure. Symptoms generally resolve in 24 to 48 hours or less, and deaths are rare.119
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