SEMINARS I N NEUROLOGY-VOLUME
10, NO. 1 MARCH 1990
Neurotoxic Snake Envenoming
The Ebers Papyrus (ca. 1550 BC) records neurotoxic symptoms reported by a patient bitten by a snake, probably the Egyptian cobra, "I am as cold as water and then again as hot as fire. All my body sweats, and I tremble. My eyesight is not steady, and I cannot see for the sweat pours over my face." Central American folklore says the bite of the tropical rattlesnake (Crotalus durissus) (Fig. 1) will break a person's neck wherever inflicted, thus reflecting the flaccid paralysis that may follow envenoming by this snake in some parts of its range. Early British accounts of snakebite in India mention inability to speak or swallow with foaming at the mouth, ptosis, fixed pupils, and other signs of cranial nerve palsies, as well as cyanosis from progressive respiratory failure. Numbness, cramps, difficult. in speaking and swallowing, and respiratory para ysis were described in early accounts of fatal coral snake poisoning in Florida. Nineteenth century research on chemistry of snake venoms established their protein nature and enzymatic activity. The first protein toxin from a snake venom to be isolated and characterized was crotoxin from venom of the Brazilian rattlesnake (C. durissus terrificus).' It had neurotoxic activity and was subsequently shown to consist of a basic subunit with phospholipase A activity and a smaller acidic subunit. At about the same time, a neurotoxin with curare-like activity was isolated from Indian cobra venom.' In the mid-1960s, by using ion exchange chromatography, postsynaptic neurotoxins were isolated from cobra and sea snake venoms. About 80 neurotoxins of this group have subsequently been isolated and sequenced. Synthesis of a peptide with the sequence and activity of one of the cobra neurotoxins has been acc~mplished.~
I
Figure 1. Tropical rattlesnake (Crotalus durissus sp.) The only rattlesnake found in most parts of Central and South America. The dark neck stripes are characteristic. In many parts of its range, venom of this snake has powerful neurotoxic activity. Crotoxin, the first snake venom toxin to be characterized, was isolated from venom of this species.
A second group of snake venom neurotoxins with presynaptic activity similar to that of botulinum toxin was defined in 1963 with the isolation of P-bungarotoxin from venom of the krait, Bungurus multicznctus4 (Fig. 2). Toxins in this group have phospholipase A, activity. They occur in a variety of snake venoms. Other neurotoxins from snake venoms have been described but are not
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana Reprint requests: Dr. Minton, Department of Microbiology and Immunology, Indiana University School o f Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46223 Copyright O 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Sherman A. Mznton, M.D.
Snakes of these families have tubular or deeply grooved fangs at the anterior end of a maxilla that is not greatly reduced in size and capable of slight to moderate movement. With few exceptions, their fangs are shorter than those of vipers of comparable size and the storage capacity of their venom glands is less. Cobras are the best known elapid snakes (Fig. 3). Strictly speaking, they comprise six species of the genus Naja, but the name is often applied to other snakes of cobralike habitus. Four species of Naja are restricted to Africa; the Egyptian cobra ( N . haje) also occurs in the western part of the Arabian peninsula. Asian cobras are considered a single species, N . naja, although they show considerable geographic variation. Spreading the neck to form a hood is the hallmark of cobras, although it is by no means restricted to them. The African N . mossambica, N . nigm'collis, and the related genus Hemachatus have fangs modified for ejecting jets of Figure 2. Many-banded krait (Bungarus multjcjnctus). venom anteriorly and somewhat upward; these are Kraits are south Asian snakes with strongly neurotoxic the "spitting cobras." Cobras are large snakes, venoms. Alpha- and beta-bungarotoxins are derived from those of the genus Naja ranging from 1.2 to 2.5 m venom of this species. in length. The king cobra (Ophiophagus) is much larger, sometimes reaching a length of 5 m, and is restricted to forest areas of southeast Asia. T h e fully characterized with respect to structure and other cobras occur in a wide variety of habitats and adapt well to agricultural and suburban situations. site of activity. The four species of tropical African mambas (Dendroaspis) are large, slender snakes usually 1.5 to 2.2 m long, although the black mamba (D. polySNAKES WHOSE VENOMS lepzs) is reported to reach a length of 4 m. They are CONTAIN NEUROTOXINS at least partially arboreal, very alert and active, and Snakes as a group are readily recognized, but aggressive under some circumstances. their classification at the family level and below has Kraits (Bungarus)are south Asian elapids with always presented problems to taxonomists. A sum- short fangs but highly toxic venom. Although they mary of the important snake families is given in are often thought of as small snakes, their average Table 1. All species in the families Viperidae, Elap- lengths are 1 to 1.5 m with two species reaching 2 m. idae, Hydrophiidae, and Atractaspididae plus an They are nocturnal and often found close to human unknown but significant number in the family dwellings. Colubridae are venomous. By no means are all speThe family Elapidae is represented in the cies dangerous to man. In some the quantity of ven- Americas by the coral snakes (Micrurus) with about om is very small, the toxicity low, or the injecting 50 species, most of which are in the 0.6 to 1.2 m mechanism inefficient. Others, because of their distri- size range. Most have tricolor patterns of red, yelbution and habits, have minimal contact with man. low, and black. They are secretive and not often Venoms of many species of snakes have been encountered. Elapid snakes reach their greatest variety in reported to have neurotoxic activity; however, there has been a tendency to consider those snakes Australia and New Guinea, where they are the whose bite is lethal but does not produce marked dominant snake family. They range in size from swelling, hemorrhage, or shock as having neuro- small (40 to 60 cm) burrowers that are essentially toxic venom. Moreover, snake venoms have multi- innocuous to the coastal taipan (Oxyuranus scutellaple deleterious effects; a purely neurotoxic or tus), which may reach a length of 3.3 m and may n ~ &re dangerous largk hematotoxic venom probably does not exist. Neu- be aggressive. ' ~ m o the rotoxins have been found most frequently in ven- species are the tiger snakes (Notechis), which may oms of snakes of the family Elapidae and their be plentiful in the well-populated eastern coastal close relatives the sea snakes, family Hydrophiidae. districts of Australia, the brown snakes (Pseudo-
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N E U R O T O X I C SNAKE ENVENOMING--MINTON
SEMINARS I N NEUROLOGY VOLUME 10, NUMBER 1 MARCH 1990 Table 1. Major Groups of Snakes Distribution
Remarks
Tropical and warm temperate zones
Very small, wormlike snakes. None venomous
Boas and pythons Family Boidae
Mostly tropical and warm temperate zones. Pythons in Old World only
Includes both large and small species. None venomous
"Typical" snakes Family Colubridae
Almost worldwide except for Arctic, Antarctic, South Australia, and certain islands
Large and extremely varied family. Many species with venom glands and posterior maxillary fangs, but few capable of causing clinically significant envenomation
Mole vipers Family Atractaspididae
Africa, limited areas of Middle East
About 15 species, all venomous. Rather small burrowers. Large maxillary fangs often used singly with backward, stabbing motion
Cobras, mambas, coral snakes, kraits, and others Family Elapidae
Tropical and warm temperate zones
About 180 species, all venomous. Fangs at anterior end of maxillae
Sea snakes Family Hydrophiidae
Mostly southeast Asian and Australian coastal waters
About 50 species, all venomous. Fangs similar to those of Elapidae. Venoms highly toxic
Pit vipers Family Viperidae, subfamily Crotalinae
The Americas and much of Asia
About 120 species, all venomous. Highly movable fangs on much reduced maxillae. Heat-sensing pits between eyes and nostrils
Old World vipers Family Viperidae, subfamily Viperinae
Africa, Europe, and Asia
About 40 species, all venomous. Fangs like those of pit vipers. No heat-sensing pits
naja), which are very quick and may be dangerous if cornered, and snakes of the genus Pseudechzs, which tend to frequent damp habitat throughout most of Australia and New Guinea. The death adder (Acanthophis antarcticus) is short and thick, with a wide head. Venoms of all these snakes are highly toxic. The 50 or so species of sea snakes (family Hydrophiidae) for the most part inhabit tropical and subtropical sections of the western Pacific and Indian Oceans over the continental shelves. One species reaches Hawaii and western coasts of Mexico and Central America. Although highly specialized for marine life, these snakes are closely related to Australian elapids, as shown by similarity in plasma and venom proteins. A practical aspect of' this is that tiger snake antivenom is quite effective in treatment of sea snake bites. Few neurotoxins have been identified in venoms of vipers (family Viperidae), a family of about 160 species. Most have been described from venoms of rattlesnakes, a group of 3 1 pit viper species comprising the genera Sistrurus and Crotalus. RatFigure 3. Chinese cobra (Naja naja atfa) This variety of tlesnakes occur from southern Canada to northern the Asian cobra occurs in south China and Taiwan. Its and Uruguay and are highly variable in venom has been extensively studied and is the source of size* with the smallest species reaching a length of cobrotoxin, cardiotoxin, complement factor, and other bioabout 55 cm and the largest occasionally exceeding logically active substances. 54
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Group Blind snakes Families Typhlopidae and Leptotyphlopidae
2 m. They cause most of the serious or fatal snakebites seen in the United States and northern Mexico. Neurotoxins have not been detected in venoms of Asian pit vipers, but a few have been reported in Old World vipers that lack loreal sensory pits.
SNAKE VENOMS Snake venoms are colorless to dark amber liquids containing 18 to 67% solids of which some 90% are proteins. Pharmacologically active substances include enzymes, polypeptide toxins, glycoproteins, and low molecular weight compounds such as nucleotides, biogenic amines, and small peptides. Many of the enzymes and toxins are very stable. Dried snake venoms retain lethality and some enzyme activities after storage for 25 to 50 years. The postsynaptic neurotoxins are probably the best understood snake venom toxins. They bind to the nicotinic acetylcholine receptors competitively with acetylcholine and produce a nondepolarizing neuromuscular block. These toxins fall into two groups, one with 60 to 62 amino acids and four disulfide bridges, the other with 71 to 74 amino acids and five disulfide bridges. Molecular weights are 7000 to 8000 d.j Alpha-bungarotoxin from venom of the krait, R . multicinctus, is prototype of this class of neurotoxins. It is typical of the long chain toxins, and its amino acid sequence and primary structure have been r e p ~ r t e d .It~ combines irreversibly with the cholinergic receptor and blocks the binding of decamethonium without affecting the catalytic site for acetylcholinesterase. It thus serves as a specific reagent for the physiologic receptor of acetyl~holine.~.~ The three-dimensional shape of erabutoxin b (and probably other short toxins) has been described as "that of a shallow saucer with footed stand." There are two reactive site l ~ o p sThe . ~ prime competitive binding site for both long and short postsynaptic toxins has been identified.9hort neurotoxins have been identified in a variety of elapid and sea snake venoms and may be present in all; long neurotoxins are present in many elapid venoms and a few sea snake venoms. Some venoms contain both long and short neurotoxins. l o Presynaptic neurotoxins inhibit release of acetylcholine at the myoneural junction and are more often lethal than postsynaptic neurotoxins. Those that have been described have the structure of a basic phospholipase A, or have a subunit of that type." The best known toxins in this group are P-bungarotoxin from venom of the many-banded krait (B. multicinctus), notexin from the tiger snake
(Notechis scutatus), taipotoxin from the taipan (0. scutellatus), and crotoxin from the Brazilian rattlesnake (C. durissus terrificus). However, the myotoxins of Enhydrina schistosa and some other sea snakes are quite similar and the distinction between neurotoxin and myotoxin may be illusory. Most of these toxins have molecular weights of 13,500 to 22,000 d except for those, such as taipotoxin and textilotoxin, that have multiple subunits and a correspondingly higher weight. The phospholipase A's in venom have 110 to 125 amino acids with six or seven disulfide bonds and are broadly homologous with pancreatic enzymes. Their neurotoxicity and myotoxicity are not related to hydrolytic activity. The nonenzymatic subunits are nontoxic but apparently serve to stabilize the enzyme in tiss u e ~ . ~ ~ . ~ ~ Toxic phospholipase As are known for venoms of several vipers. In addition to crotoxin, Mojave or K' toxin, originally isolated from the Mojave rattlesnake and subsequently found in venoms of some other North American rattlesnakes, belongs to this group.I3 Immunologically, it is related to c r o t o ~ i n . 'A ~ chemically and pharmacologically similar but immunologically distinct toxin is in venom of the Palestine horned viper (Pseudocerastes persicus fieldi)." Viperotoxin from venom of the Palestine viper (Vipera palaestinae) has 108 amino acids and three disulfide bonds and has an acidic rather than basic phospholipase A subunit.15 Its site and manner of action are poorly known. Single chain basic phospholipase A neurotoxins have been reported from venoms of the long-nosed viper (Vipera ammodytes), horned puff adder (Bitis caudalis), and Pallas' viper (Agkistrodon halys)." Some additional, poorly known snake neurotoxins of uncertain clinical significance include the K-neurotoxins from venoms of some kraits (Bungurus), which are selective for neuronal nicotinic receptors and have little action on muscle nicotinic receptors.16 Vipotoxin from venom of Russell's viper (Vipera russelli) blocks biogenic amine receptors but has little toxicity for mice.I7Dendrotoxin from venom of the mamba Dendroaspis angusticeps blocks potassium channels and facilitates acetylcholine release at the myoneural junction with an increase in skeletal muscle response to stimulation.ls
CLINICAL MANIFESTATIONS The clinical course of snakebite is variable and unpredictable because of factors that involve both the biting snake and the bitten human. The two most important factors are the intrinsic toxicity of the venom for man and the amount injected. The
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N E U R O T O X I C SNAKE ENVENOMING-MINTON
VOLUME 10, NUMBER 1 MARCH 1990
former can only roughly be estimated from data drome may be as soon as 3 minutes after a bite or obtained from animal experiments. Even among as late as 24 hours.21Some aspects of it have been mammals, there is wide variation among species in reported following bites of all groups of elapid susceptibility to snake venoms as well as infraspe- snakes. Both the presynaptic and postsynaptic neucific variation. The amount of venom injected is rotoxins apparently are involved. There is evihighly variable and at least partly under the snake's dence that the presynaptic neurotoxins are associcontrol. Herpetologists and snake keepers have re- ated with delayed onset, prolonged symptoms, and peatedly observed that snakes use different meth- poor response to antivenoms, whereas the postsynods in handling relatively large, active prey (an aptic toxins account for early paralytic symptoms, adult rat or mouse) and helpless prey (nestling such as ptosis and ophthalmoplegia.ll Cobra bites are reported more frequently than birds or rodents) and may use still different techniques when confronted by an enemy. Experimen- bites by other elapid snakes; however, there is a tal attempts to verify this have not been conclusive tendency in south Asian countries to ascribe all but do show that the amount of venom injected by venomous snakebites to "cobras," particularly if neurotoxic symptoms are present. Cobra bites are a snake in a given bite is extremely variable-from none to half of the venom available in the glands. almost invariably painful and accompanied by Evaluation of snakebite cases from various parts of some degree of local swelling, which may progress the world indicates that 20 to 60% result in little or to involve an entire extremity. Local necrosis inno envenoming even though the bites may have volving skin and subcutaneous tissues may occur been inflicted by large snakes with highly toxic and may be extensive, involving much of the bitten venom. Such bites are particularly common with limb. The onset is characteristically delayed 2 to 4 some snakes such as coral snakes and sea snakes. days after the bite and often is preceded by discolSnake venoms also show clinically significant geo- oration of the skin and blistering. Necrosis has graphic variation (neurotoxic symptoms are often been reported frequently following bites by Afriseen with Russell's viper bites in Sri Lanka but not can spitting cobras and the cobras of Malaysia, in Burma, whereas the opposite is true of pituitary Thailand, and Taiwan but is uncommon in the hemorrhageIg) and ontogenic variation (bites by Philippine~.~l-'"t has been ascribed to the broadyoung diamondback rattlesnakes [Crotalus atrox] spectrum cell membrane toxin, often referred to as are more likely to be followed by coagulopathy cardiotoxin or direct lytic factor, which is a major than bites by adults2'). Variation in human re- component of all cobra venoms.24Cobra venom nesponse to snake venom has been little investigated, crosis is difficult to induce in experimental animals, which usually die of neurotoxic manifestaalthough anaphylaxis has been reported. The numerous toxins present in snake venoms tions first. On the other hand, necrosis is often virtually guarantee that any serious snakebite will seen as the chief or only manifestation of cobra enshow evidence of injury to several organ systems. venoming in man. I t has been demonstrated that Nearly all physicians experienced in treating snake- some cobra postsynaptic neurotoxins bind weakly bites stress the folly of clinical classification of bites to the human myoneural junction.Weurotoxic as neurotoxic, hematotoxic, myotoxic, or other. symptoms in cobra bites can sometimes be detected However, a common theme in the clinical picture in 3 minutes and rarely are delayed more than 6 of envenoming by snakes whose venoms contain hours in untreated cases. Respiratory paralysis can neurotoxins is the development of cranial nerve develop in 15 minutes and lead to death within 2 palsies (Table 2). These are characteristically man- hours. There are anecdotal reports of deaths ifested as ptosis and ophthalmoplegia with blurred within an hour. With or without antivenom treatvision or diplopia, difficulty in swallowing with an ment, the neurotoxic manifestations of cobra bite inability to handle oral secretions, slurred speech, resolve completely in nonfatal cases within a week. Bites by the African spitting cobras, N. nigriweakness of facial muscles (Fig. 4), and occasionally loss of the sense of taste or smell. The pupils collis and N. mossambica, present a distinctly differusually are dilated and respond sluggishly to light. ent picture. Although venoms of these snakes conThis syndrome is often accompanied by drowsi- tain postsynaptic neurotoxins, the clinical picture ness, sometimes with mental confusion and eu- is one of marked local swelling often accompanied phoria. Flaccid paralysis (Fig. 5) affects all muscle by blistering and necrosis. Platelets and complegroups in no particular sequence and is accompa- ment are reduced and hemorrhages occur. Evinied by loss of tendon reflexes. There is no pain dence of neurotoxicity other than drowsiness has on passive movement or pressure. Breathing be- not been rep~rted.~~l~"hereare not many wellcomes shallow and diaphragmatic; coma a r d con- documented clinical reports of bites by the king vulsions may precede death. The onset of this syn- cobra. Ophiophagus, but the picture seems to be
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SEMINARS IN NEUROLOGY
f
?O 0 0
?O 0 0 0 +
0
to++ 0 0 0 0
+to++
-C
+to++
+to +to ?O
+
++
++
++ ++
+to++
Asian, Most African Cobras: Naja spp.
?O 0 0 0
+to++
Oto + +to++
e
?O 0 0 0
?to++
0 *to++
+
Spitting Cobras: Naja Coral nigricollis, Mambas: Kraits: Snakes: Dendroaspis Bungarus Micrurus N. mossambica spp. spp. SPP.
+ + k
+to ++ Oto + + 0 0
?to++
0 +to++
Oto
++
++
to
+
+
+
Oto
+
* to +
+
Oto
to
+ to +
+
South American Rattlesnakes: Crotalus durlssus
Oto + Oto + +to++ ?to++
0
*
+to++ Oto
+to++
North American Rattlesnakes: Crotalus spp.
+ ?O Oto + + +to++ ?to++
Oto
*to++ Oto + +
+to++
Old World Vipers: Echis, Bitis, Vipera, Others
+ : slight and not clinically significant; 0: absent or not reported.
+
Oto++ Oto + 0 Oto
?to++
Oto *to++
0 to
Australian Elapids: Notechis, Sea Snakes: Pseudonaja, Enhydrina, Oxyuranus, Hydrophis, Others Acanthophis
Important Clinical Manifestations of Snakebite Produced by Venoms Known to Contain Neurotoxins*
'Based on reports of cases of moderate to severe envenoming. + + : prominent and severe, sometimes life-threatening; + : consistently present, clinically significant;
Local pain and swelling Local necrosis Cranial nerve palsies Respiratory paralysis Rhabdomyonecrosis Renal failure Hypovolemic shock Coagulopathy
Table 2.
Figure 4. Ptosis and moderate facial paresis following the bite of an Australian tiger snake. (Photograph copyright Julian White. Reprinted with permission.)
58
similar to that of envenoming by Asian Naju. Because of the potentially large amount of venom the king cobra can inject, deal11 may occur quickly. Although mamba venoms are quite different from other elapid venorris, the corriparatively k w clinical reports of mamba envenoming are not markedly differenr from accounts of severe cobra bites. 1,ocal pain and swelling are less pronounced than in cobra bites, and if necrosis occurs, it is confined to the immediate vicinity 01' the bite. Neurotoxic symptoms may develop within 5 minutes, and the onset of respiratory paralysis can be rapid. Vomiting, abdominal pain, diarrhea, and parestliesias are mentioned as early symptoms more frequently in mamba than in cobra en~enorning.~' Krait bites usually occur at night and may be inflicted on sleeping persons. Local pain is present but usually not severe; swelling is moderate to minimal. There is usually a period of at least an hour and sometimes as much as 12 hours between the bite and onset of systemic symptoms. Paresthesias, abdominal pain, and fjsciculations may precede or accompany onset of cranial nerve palsies and respiratory paralysi~.'~~~!' Most reported cases are 01' bites by thc closely related Blrngarw rrieruleus, B. mz~lticinctu.s,and l3. rm(li(lus.A report of poisoning by R . Jascialu.\ was rriarkcd by rapid onset of symptonis and death in less than 2 hours.'"' I here are few case reports of coral snake poisoning and most refer to bites by the Uriited Slates species :l.licruru;, f : fulvius. About half the bites are fdlowed by no syrnptonls of poisoning or by only minor pain and swelling. As with krait envenoming. several hours may elapse 1)etwet.n the bite and
VOLUME 10. NCMBEK 1 M A R C H 1990
Figure 5. Muscular weakness with inability to raise the head seen following a cobra bite in Malaysia. This is the "broken-neck effect" reported following bites by several species of snakes with neurotoxic venoms. (Photograph by H. Alistair Reid, courtesy Mrs. Reid, R.D.G. Theakston, and the Liverpool School of Tropical Medicine. Reprinted with permission.)
onset of neurotoxic manifestations, which may include paresthesias and fasciculations. Crcatine kiriase lcvcls may be elevated. Paralysis may last 6 to 14 days and muscular strength may not be fully regained for 6 to 8 t ~ e e k s . ~ ' . ~ ~ I11 rnarked contrast with bites by most North American rattlesnakes, bites by the Brazilian rattlesnake show very little edema or ecchymosis. However, cranial nerve palsics, rnyalgia, muscle weakness, son~nolence,and vomiting are cornnion. although life-threatening respiratory failure is not. Most deaths result from renal failure sec:ond;iry to massive rhabdornyonecrosi~."'~~"~ Bites by the hlojavc rattlesnake may show slight local edema, ecchymosis, arid necrosis but oi'ten are accompar~iedby pronounced systemic manifestations such as hypotension, vomiting, disigns arrhea, and pulmonary edcrria."U~ncc~uivoc:;il of r~curotoxicenvenoming are rare. In the region of T L I C S O Arizona, ~, where h e makes do not have Mojave toxin in their venom, bites are much like those of other ratt1csn;ikcs.:'" The berg adder (Bilis u/ropo.s) is a small South African snake belonging to a genus whose rrlcrrlhers typically inflict bites characterized by iri~ense local srvclling, blistering;, ecchymosis, and' liypovolelnic shock (Table 2). berg adder bites produce a moderate local reaction lmt also are followecl by ptosis, oplithalmoplegia, loss o f taste and smell, and other signs of cranial nerve involverncrit. Respirarory paralysis has not been observed, and no Fdtalities havc heen reported."' .rhe toxin responsible has riot been itlontified.
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SEMINARS I N NEUKOLQGY
Kussell's viper is a leading cause of fatal snakebites in southeast Asia, and its venom typically causes hemorrhages, disseminated intravascular coagulation, shock, and renal failure. However, cranial nerve palsies and respiratory distress regularly accompany envenoming in Sri Lanka.lg Since the elapid snakes of Australia and New Guinea are a large and diverse lot, it is not surprising that clinical envenomation shows considerable variation, although the constellation of cranial nerve involvement and respiratory paralysis is seen with nearly all the more dangerous species. Local pain and swelling are slight to moderate and sometimes most marked with bites by species whose venoms rarely cause systemic effects. Neurotoxic symptoms rarely appear less than 1 hour after a bite, but violent headache, abdominal pain, vomiting, and hypotension leading sometimes to syncope may occur within a few minutes. Rhabdomyonecrosis with hyperkalemia and myoglobinuria can lead to death from cardiac arrest or renal failure. Coagulopathy may be seen particularly following bites by Pseudechis and Pseudonaja species but is not often a serious clinical problem. Residual paralysis and muscle weakness may require up to 17 weeks to r e ~ o l v e . ~ ~ . ~ ~ The close relationship between Australian elapids and sea snakes is also reflected in the symptomatology of envenomation. Sea snake bites are almost painless and produce little or no swelling. Approximately 60% of those bitten develop no significant poisoning. In others, the onset of symptoms is usually within a 30- to 120-minute period and begins with myalgia and pain on passive movement. Pseudotrismus may be seen. Dark urine indicating myoglobinuria is evident in about 3 hours. Cranial nerve palsies and respiratory paralysis may become superimposed on the myotoxic syndrome after several hours." However, in the only adequate series, cases of sea snake bite were nearly all caused by one species, the beaked sea snake, E. schistosa. Bites of other species may differ. ' h o patients bitten by Stokes' sea snake (Astrotia stoke~i) showed primarily neurotoxic symptoms, one becoming unconscious 20 minutes after being bitten and developing respiratory paralysis within 1 hour. There was little clinical evidence of myonecrosis, but creatine kinase levels were e l e ~ a t e d . ~ ' . ~ '
DIAGNOSIS AND TREATMENT Differential diagnosis in snakebite involves ruling out injuries by inanimate objects, injuries by other venomous animals, and bites by nonvenomous snakes. Additionally, venomous snakebites that
need only conservative management must be differentiated from those requiring more aggressive management. Often the nature of the wounds and presence of local pain, swelling, and discoloration permit early recognition of a venomous snakebite. Many snakes with predominantly neurotoxic or myotoxic venoms, such as coral snakes and sea snakes, however, have small fangs whose punctures may be difficult to find and venoms that cause little pain or swelling. Also, these bites may be followed by a symptom-free latent period lasting several hours. If the snake is positively identified as a dangerous species, it is often advisable to initiate treatment during this period. Ptosis, external ophthalmoplegia, and difficulty in opening the mouth and protruding the tongue are usual early signs of neurotoxic envenomation. They may be preceded by headache, vomiting, and abdominal pain. Tenderness of regional lymph nodes may be observed early even though the reaction at the site of the bite is minimal. Periodic measurements of circumference of a bitten limb are usually necessary to determine presence and progression of swelling. Enzyme-linked immunosorbent assay (ELISA) for detection of snake venoms is generally available in Australia and has been developed for use in other nations. Venom antigen levels in plasma and urine are most significant in determining severity of envenoming, whereas aspirate from the bite site or venom deposited on skin or clothing is better for identification of the snake species. Current ELISA cannot usually distinguish venoms of closely related snakes. ELISA can also be used to detect venom antibodies in epidemiologic studies of snakebite. A coagulation profile should be obtained on all patients hospitalized for snakebite and repeated in 6 to 8 hours in all but clearly trivial envenoming. Creatine kinase and lactic dehydrogenase levels are markedly elevated in patients bitten by snakes with myotoxic venoms, and this is sometimes of help in diagnosis. Examination of urine and plasma for myoglobin may also be helpful. Complement levels may be decreased in cobra envenoming. Antivenoms in adequate dosage usually neutralize life-threatening systemic effects of snake venoms; they are less effective against local effects. Antivenoms are produced by about 50 laboratories worldwide and vary greatly in neutralizing ability, degree of refinement, and potential for producing undesirable side effects. All are produced in horses. Some antivenoms are specific for venom of one snake species, whereas others are polyvalent against venoms of all snakes of a particular geographic area. T h e degree of para-specific protection afforded is unpredictable. Tiger snake antivenom protects against venoms of many Australian
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NEUROTOXIC SNAKE ENVENOMING--MINTON
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SEMINARS I N NEUROLOGY VOLUME 10, NUMBER 1 MARCH 1990
60
considered. When intense swelling involves the hand, digit dermotomy often is beneficial in preventing impairment of function. 'The local necrotizing effect of cobra and some other venoms is difficult to counteract with available treatment. ACKNOWLEDGMENT I wish to acknowledge the valued assistance of Sherry1 Riley for typing and other clerical assistance.
REFERENCES 1. Slotta K, Fraenkel-Conrat H. 'l'wo active proteins from rattlesnake venom. Nature 1938; 142:2 13 2. Ghosh B, De SS, Chowdhuri DK. Separation of the neurotoxin from crude cobra venom and study of the action of a number of reducing agerlts o n it. Indian J Med Kes 194 1;29:367-73 3. Yang CC. Crystallization and properties of cobrotoxin from Formosan cobra venom. J Biol Chem 1965;240: 1616-8 4. Charrg CC, Lee CY. Isolation of neurotoxins from the venom of Bungarus multicinctus and thrir modes of neurornuscular blocking action. Arch I n t Pharrnacodyn 1963; l44:241-57 5. Lee CY. Chemistry and pharmacology of' polypeptide toxins in snake venoms. Annu Rev Pharmacol 1972; 12:256-86 6. Narita K, Mebs D, Iwanaga S, et al. Primary structure of cx-bungarotoxin from Bungarus mu,lticinctus venom. J Formosan Med Assoc 1972;7 1:336-43 7. Changeaux JP, Kasai M, Lee CY. Use of a snake venom toxin to characterize the cholinergic receptor protein. Proc Natl Acad Sci USA 1970;67:1241-7 8. Low BW. T h e three-dimensional structure of postsynaptic snake neurotoxins: consideration of structure and function. In: Snake Venoms Lee CY, ed: Handbook of' Experimental Pharmacology, vol 52. Berlin: SpringerVerlag, 1979:213-57 9. Low BW, Corfield PWR. Acetylcholirie receptor a-toxin binding site-theoretical a n d model studies. Asia Pac J Pharmacol 1987;2:1 15-27 10. Endo T, Tamiya N. Current view on the structurefunction relationship of postsynaptic ncurotoxins from snake venoms. Pharmacol T h e r 1987;34:403-51 11. Chang CC. Ncurotoxins with phospholipase A, activity in snake venoms. Proceedings of the National Science Council (Taiwan) Part B. Lii'e Science, 1985;9: 126-42 2. Rosenbcrg P. T h e relationship between enzymatic activity and pharmacological properties of phospholipases in natural poisons. In: Harris JB, ed: Natural toxins: animal plant, and microbial. Oxford: Clarendon Press, 1986: 129-74 3. Johnson JK, Bieber AL. Mojave toxin: rapid purification. heterogenicity and resistance to denaturation by urea. Toxicon 1988;26:337-51 4. Weinstein SA, Minton SA, Wilde CE. T h e distribution among ophidian venoms of a toxin isolated from the venom of' the Mqjave rattlesnake (C~.otalusscutulatw scutulatus). Toxicon 1985;23:825-44 5. Moroz C, DeVries A, Sela M. Isolation and characterization of a neurotoxin from Vapera palacstinae venom. Biochim Biophys Acta 1966; 124: 136 6. Harris J B . Phospholipases in snake venoms and their effects o n nerve and muscle. Pharmacol T h e r 1985;31: 79-102.
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snakes, most sea snakes, and many cobras and kraits; however, antivenoms against Asian sawscaled vipers (Echis) are ineffective against African snakes of the genus and vice versa. There are no firm indications for initiating antivenom therapy. Ptosis, oculomotor palsy, slurred speech, and dysphagia are common early signs of neurotoxic envenoming and are indications for antivenom therapy. However, with coral snake and krait bites, antivenom should be started before signs of envenomation appear, because these venoms are difficult to neutralize after they have been bound at the myoneural junction. Antivenom is administered intravenously diluted with crystalloid or glucose solution. Antivenom is most effective if begun within 4 hours after a bite, however some venom effects such as coagulopathy may be reversed even after 24 hours. Total response of the patient rather than a single parameter should determine the quantity of antivenom given. Doses of 400 to 500 ml may be needed. Acute anaphylaxis is an ever present danger of antivenom therapy, and appropriate precautions should be taken. Some 70 to 80% of patients who receive antivenom develop serum sickness. Edrophonium hydrochloride counteracts the neuromuscular blocking action of cobra venom more rapidly than antivenom, although its action is temporary. Antivenom may be administered c o n c ~ m i t a n t l ~ . ~ ~ e o s t i g mmethyl i n e sulfate has been used in krait and cobra envenomation with variable r e ~ u l t s . ~ ~ ~respiratory ~ V h e paralysis caused by venom neurotoxins may be difficult to reverse with antivenom. Intermittent positive pressure ventilation with or without tracheostomy is often needed and may be lifesaving. It may be used alone or combined with antivenom and neostigmine-atropine.28~46~47 Artificial respiratory support often is needed for 14 to 48 hours in cases of krait and cobra bites and was required for more than 10 weeks in an Australian snakebite case; the patient eventually rec~vered."~ Of the other life-threatening complications of snakebite, hypovolemic shock usually responds to antivenom in adequate dosage plus intravenous fluids. Coagulopathy also usually responds favorably to antivenom. Supplemental fresh-frozen plasma, cryoprecipitate, and platelets may be helpful. Renal failure requires correction of electrolyte imbalance and often dialysis. Bacterial infections are uncommon. Culture and sensitivity tests should guide antibiotic therapy. Local tissue damage may result from impairment of circulation or the direct effect of the venom on tissues or both. If intracompartment pressure reaches 30 mmHg, fasciotomy should be
17. Chiappinelli VA. Actions of snake venom toxins on neuronal nicotinic receptors and other neuronal receptors. Pharmacol Ther 1985;3 1: 1-32 18. Harvey AL, Anderson AJ. Dendrotoxins: snake toxins that block potassium channels and facilitate neurotransmitter release. Pharmacol Ther 1985;3 1:33-55 19. Warrell DA. Tropical snake bite studies. In: Harris JB, ed: Natural toxins: animal, plant and microbial. Oxford: Clarendon Press, 1986:25-45 20. Reid HA, Theakston RDG: Changes in coagulation effects by venoms of Crotalus atrox as snakes age. Am J Trop Med Hyg 1978;27:1053-7 21. Watt G, Padre L, Tuazon ML, et al. Bites by the Philippine cobra (Naja naja philippinensis): prominent neurotoxicity with minimal local signs. Am J Trop Med Hyg 1988;39:306-ll 22. Trishnananda M, Oonsombat P, Dumavibhat B, et al. Clinical manifestations of cobra bite in the Thai farmer. Am J Trop Med Hyg 1979;28:165-6 23. Reid HA. Cobra-bites. Br Med J 1964;2:540-5 24. Karlsson E. Chemistry of protein toxins in snake venoms. In: Lee CY, ed: Snake Venoms, vol. 52. Handbook Experimental Pharmacology. Berlin: Springer-Verlag, 1979;159-212 25. Warrell DA, Greenwood BM, Davidson NM, Ormerod LD. Necrosis, hemorrhage, and complement depletion following bites by the spitting cobra (Naja nigricollis). Q J Med l976;45: 1-22 26. Tilbury CR. Observations on the bite of the Mozambique spitting cobra (Naja mossambica mossambica). S Afr Med J 1982;61:308-13 27. Visser J , Chapman DS. Snakes and snake-bite. Cape Town: Purnell & Sons, 1978 28. Karalliedde LD, Sanmuganthan PS. Respiratory failure following envenomation. Anaesthesia 1988;43:753-4 29. Looareesuwan S, Viravan C, Warrell DA. Factors contributing to fatal snake bite in the rural tropics: analysis of 46 cases in Thailand. Trans R Soc Trop Med Hyg 1988;82:930-4 30. Viravan C, Veeravat U, Warrell MJ, et al. ELISA confirmation of acute and past envenoming by the monocellate Thai cobra (Naja kaouthia). Am J Trop Med Hyg 1986;35: 173-81 31. Parrish HM, Khan M. Bites by coral snakes: reports of 11 representative cases. Am J Med Sci 1967;253:561-6 32. Kitchens CS, Van Mierop LHS. Envenomation by the Eastern coral snake (Micrurus fulvius fulvius). JAMA 1987;258: 1615-8 33. Azevedo-Marques MM, Hering SE, Cupo P. Evidence
34.
35. 36. 37. 38. 39.
40. 41. 42. 43.
44.
45.
46. 47. 48.
that Crotalus durissus ternficus (South American rattlesnake) envenomation in humans causes myolysis rather than hemolysis. Toxicon 1987;25:1163-8 Cupo P, Azevedo-Marques MM, Hering SE. Clinical and laboratory features of South American rattlesnake (Crotalus durissw temficus) envenomation in children. Trans R Soc Trop Med Hyg 1988;82:924-9 Rothan WB, Gennaro JF. Treatment of the bite of a Mojave rattlesnake. J Fla Med Assoc 1968;55:324-7 Hardy DL. Envenomation by the Mojave rattlesnake (Crotalus scutulatus scutulatw) in southern Arizona. Toxicon 1983;21:11 1-8 Ellis CG. The berg adder: a unique snake. Practitioner 1979;223:544-7 Sutherland SK. Australian animal toxins. Melbourne: Oxford University Press, 1983 White J. Elapid snakes: venom toxicity and actions; aspects of envenomation; management of bites. In: Covacevich J , Davie P, Pearn J, eds: Toxic plants & animals, a guide for Australia. Brisbane: Queensland Museum, 1987:369-457 Reid HA. Epidemiology and clinical aspects of sea snake bites. In: Dunson WA, ed: The biology of sea snakes. Baltimore: University Park Press, 1975:417-62 Mercer HP, McGill JJ, Ibrahim RA. Envenomation by sea snake in Queensland. Med J Aust 1981; 1: 130-2 Audley I. A case of sea snake envenomation. Med J Aust 1985;143:582 Watt G , Theakston RDG, Hayes CG, et al. Positive response to edrophonium in patients with neurotoxic envenoming by cobras (Naja naja philippinensis): a placebo-controlled study. N Engl J Med 1986;315: 1444-7 Warrell DA, Looareesuwan S, White NJ, et al. Severe neurotoxic envenoming by the Malayan krait, Bungarus candidus; response to antivenom and cholinesterase. Br Med J 1982;286:678-82 Mitrakul C, Dhamkrong-at A, Futrakul P, et al. Clinical features of neurotoxic snake bite and response to antivenom in 47 children. Am J Trop Med Hyg 1984; 33: 1258-66 Pawar DK, Singh H. Elapid snake bite. Br J Anaesth 1987;59:385-7 Casale FF, Patel SM. Elapid snake bite: a report of two cases. Br J Anaesth 1974;46: 162 Patten BR, Pearn JH, DeBuse P, et al. Prolonged intensive therapy after snake bite: a probable case of envenomation by the rough-scaled snake. Med J Aust 1985; 142:467-9
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NEUROTOXIC SNAKE ENVENOMING--MINTON
10, NO. 1 MARCH 1990
Neurotoxic Snake Envenoming
The Ebers Papyrus (ca. 1550 BC) records neurotoxic symptoms reported by a patient bitten by a snake, probably the Egyptian cobra, "I am as cold as water and then again as hot as fire. All my body sweats, and I tremble. My eyesight is not steady, and I cannot see for the sweat pours over my face." Central American folklore says the bite of the tropical rattlesnake (Crotalus durissus) (Fig. 1) will break a person's neck wherever inflicted, thus reflecting the flaccid paralysis that may follow envenoming by this snake in some parts of its range. Early British accounts of snakebite in India mention inability to speak or swallow with foaming at the mouth, ptosis, fixed pupils, and other signs of cranial nerve palsies, as well as cyanosis from progressive respiratory failure. Numbness, cramps, difficult. in speaking and swallowing, and respiratory para ysis were described in early accounts of fatal coral snake poisoning in Florida. Nineteenth century research on chemistry of snake venoms established their protein nature and enzymatic activity. The first protein toxin from a snake venom to be isolated and characterized was crotoxin from venom of the Brazilian rattlesnake (C. durissus terrificus).' It had neurotoxic activity and was subsequently shown to consist of a basic subunit with phospholipase A activity and a smaller acidic subunit. At about the same time, a neurotoxin with curare-like activity was isolated from Indian cobra venom.' In the mid-1960s, by using ion exchange chromatography, postsynaptic neurotoxins were isolated from cobra and sea snake venoms. About 80 neurotoxins of this group have subsequently been isolated and sequenced. Synthesis of a peptide with the sequence and activity of one of the cobra neurotoxins has been acc~mplished.~
I
Figure 1. Tropical rattlesnake (Crotalus durissus sp.) The only rattlesnake found in most parts of Central and South America. The dark neck stripes are characteristic. In many parts of its range, venom of this snake has powerful neurotoxic activity. Crotoxin, the first snake venom toxin to be characterized, was isolated from venom of this species.
A second group of snake venom neurotoxins with presynaptic activity similar to that of botulinum toxin was defined in 1963 with the isolation of P-bungarotoxin from venom of the krait, Bungurus multicznctus4 (Fig. 2). Toxins in this group have phospholipase A, activity. They occur in a variety of snake venoms. Other neurotoxins from snake venoms have been described but are not
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana Reprint requests: Dr. Minton, Department of Microbiology and Immunology, Indiana University School o f Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46223 Copyright O 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Sherman A. Mznton, M.D.
Snakes of these families have tubular or deeply grooved fangs at the anterior end of a maxilla that is not greatly reduced in size and capable of slight to moderate movement. With few exceptions, their fangs are shorter than those of vipers of comparable size and the storage capacity of their venom glands is less. Cobras are the best known elapid snakes (Fig. 3). Strictly speaking, they comprise six species of the genus Naja, but the name is often applied to other snakes of cobralike habitus. Four species of Naja are restricted to Africa; the Egyptian cobra ( N . haje) also occurs in the western part of the Arabian peninsula. Asian cobras are considered a single species, N . naja, although they show considerable geographic variation. Spreading the neck to form a hood is the hallmark of cobras, although it is by no means restricted to them. The African N . mossambica, N . nigm'collis, and the related genus Hemachatus have fangs modified for ejecting jets of Figure 2. Many-banded krait (Bungarus multjcjnctus). venom anteriorly and somewhat upward; these are Kraits are south Asian snakes with strongly neurotoxic the "spitting cobras." Cobras are large snakes, venoms. Alpha- and beta-bungarotoxins are derived from those of the genus Naja ranging from 1.2 to 2.5 m venom of this species. in length. The king cobra (Ophiophagus) is much larger, sometimes reaching a length of 5 m, and is restricted to forest areas of southeast Asia. T h e fully characterized with respect to structure and other cobras occur in a wide variety of habitats and adapt well to agricultural and suburban situations. site of activity. The four species of tropical African mambas (Dendroaspis) are large, slender snakes usually 1.5 to 2.2 m long, although the black mamba (D. polySNAKES WHOSE VENOMS lepzs) is reported to reach a length of 4 m. They are CONTAIN NEUROTOXINS at least partially arboreal, very alert and active, and Snakes as a group are readily recognized, but aggressive under some circumstances. their classification at the family level and below has Kraits (Bungarus)are south Asian elapids with always presented problems to taxonomists. A sum- short fangs but highly toxic venom. Although they mary of the important snake families is given in are often thought of as small snakes, their average Table 1. All species in the families Viperidae, Elap- lengths are 1 to 1.5 m with two species reaching 2 m. idae, Hydrophiidae, and Atractaspididae plus an They are nocturnal and often found close to human unknown but significant number in the family dwellings. Colubridae are venomous. By no means are all speThe family Elapidae is represented in the cies dangerous to man. In some the quantity of ven- Americas by the coral snakes (Micrurus) with about om is very small, the toxicity low, or the injecting 50 species, most of which are in the 0.6 to 1.2 m mechanism inefficient. Others, because of their distri- size range. Most have tricolor patterns of red, yelbution and habits, have minimal contact with man. low, and black. They are secretive and not often Venoms of many species of snakes have been encountered. Elapid snakes reach their greatest variety in reported to have neurotoxic activity; however, there has been a tendency to consider those snakes Australia and New Guinea, where they are the whose bite is lethal but does not produce marked dominant snake family. They range in size from swelling, hemorrhage, or shock as having neuro- small (40 to 60 cm) burrowers that are essentially toxic venom. Moreover, snake venoms have multi- innocuous to the coastal taipan (Oxyuranus scutellaple deleterious effects; a purely neurotoxic or tus), which may reach a length of 3.3 m and may n ~ &re dangerous largk hematotoxic venom probably does not exist. Neu- be aggressive. ' ~ m o the rotoxins have been found most frequently in ven- species are the tiger snakes (Notechis), which may oms of snakes of the family Elapidae and their be plentiful in the well-populated eastern coastal close relatives the sea snakes, family Hydrophiidae. districts of Australia, the brown snakes (Pseudo-
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N E U R O T O X I C SNAKE ENVENOMING--MINTON
SEMINARS I N NEUROLOGY VOLUME 10, NUMBER 1 MARCH 1990 Table 1. Major Groups of Snakes Distribution
Remarks
Tropical and warm temperate zones
Very small, wormlike snakes. None venomous
Boas and pythons Family Boidae
Mostly tropical and warm temperate zones. Pythons in Old World only
Includes both large and small species. None venomous
"Typical" snakes Family Colubridae
Almost worldwide except for Arctic, Antarctic, South Australia, and certain islands
Large and extremely varied family. Many species with venom glands and posterior maxillary fangs, but few capable of causing clinically significant envenomation
Mole vipers Family Atractaspididae
Africa, limited areas of Middle East
About 15 species, all venomous. Rather small burrowers. Large maxillary fangs often used singly with backward, stabbing motion
Cobras, mambas, coral snakes, kraits, and others Family Elapidae
Tropical and warm temperate zones
About 180 species, all venomous. Fangs at anterior end of maxillae
Sea snakes Family Hydrophiidae
Mostly southeast Asian and Australian coastal waters
About 50 species, all venomous. Fangs similar to those of Elapidae. Venoms highly toxic
Pit vipers Family Viperidae, subfamily Crotalinae
The Americas and much of Asia
About 120 species, all venomous. Highly movable fangs on much reduced maxillae. Heat-sensing pits between eyes and nostrils
Old World vipers Family Viperidae, subfamily Viperinae
Africa, Europe, and Asia
About 40 species, all venomous. Fangs like those of pit vipers. No heat-sensing pits
naja), which are very quick and may be dangerous if cornered, and snakes of the genus Pseudechzs, which tend to frequent damp habitat throughout most of Australia and New Guinea. The death adder (Acanthophis antarcticus) is short and thick, with a wide head. Venoms of all these snakes are highly toxic. The 50 or so species of sea snakes (family Hydrophiidae) for the most part inhabit tropical and subtropical sections of the western Pacific and Indian Oceans over the continental shelves. One species reaches Hawaii and western coasts of Mexico and Central America. Although highly specialized for marine life, these snakes are closely related to Australian elapids, as shown by similarity in plasma and venom proteins. A practical aspect of' this is that tiger snake antivenom is quite effective in treatment of sea snake bites. Few neurotoxins have been identified in venoms of vipers (family Viperidae), a family of about 160 species. Most have been described from venoms of rattlesnakes, a group of 3 1 pit viper species comprising the genera Sistrurus and Crotalus. RatFigure 3. Chinese cobra (Naja naja atfa) This variety of tlesnakes occur from southern Canada to northern the Asian cobra occurs in south China and Taiwan. Its and Uruguay and are highly variable in venom has been extensively studied and is the source of size* with the smallest species reaching a length of cobrotoxin, cardiotoxin, complement factor, and other bioabout 55 cm and the largest occasionally exceeding logically active substances. 54
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Group Blind snakes Families Typhlopidae and Leptotyphlopidae
2 m. They cause most of the serious or fatal snakebites seen in the United States and northern Mexico. Neurotoxins have not been detected in venoms of Asian pit vipers, but a few have been reported in Old World vipers that lack loreal sensory pits.
SNAKE VENOMS Snake venoms are colorless to dark amber liquids containing 18 to 67% solids of which some 90% are proteins. Pharmacologically active substances include enzymes, polypeptide toxins, glycoproteins, and low molecular weight compounds such as nucleotides, biogenic amines, and small peptides. Many of the enzymes and toxins are very stable. Dried snake venoms retain lethality and some enzyme activities after storage for 25 to 50 years. The postsynaptic neurotoxins are probably the best understood snake venom toxins. They bind to the nicotinic acetylcholine receptors competitively with acetylcholine and produce a nondepolarizing neuromuscular block. These toxins fall into two groups, one with 60 to 62 amino acids and four disulfide bridges, the other with 71 to 74 amino acids and five disulfide bridges. Molecular weights are 7000 to 8000 d.j Alpha-bungarotoxin from venom of the krait, R . multicinctus, is prototype of this class of neurotoxins. It is typical of the long chain toxins, and its amino acid sequence and primary structure have been r e p ~ r t e d .It~ combines irreversibly with the cholinergic receptor and blocks the binding of decamethonium without affecting the catalytic site for acetylcholinesterase. It thus serves as a specific reagent for the physiologic receptor of acetyl~holine.~.~ The three-dimensional shape of erabutoxin b (and probably other short toxins) has been described as "that of a shallow saucer with footed stand." There are two reactive site l ~ o p sThe . ~ prime competitive binding site for both long and short postsynaptic toxins has been identified.9hort neurotoxins have been identified in a variety of elapid and sea snake venoms and may be present in all; long neurotoxins are present in many elapid venoms and a few sea snake venoms. Some venoms contain both long and short neurotoxins. l o Presynaptic neurotoxins inhibit release of acetylcholine at the myoneural junction and are more often lethal than postsynaptic neurotoxins. Those that have been described have the structure of a basic phospholipase A, or have a subunit of that type." The best known toxins in this group are P-bungarotoxin from venom of the many-banded krait (B. multicinctus), notexin from the tiger snake
(Notechis scutatus), taipotoxin from the taipan (0. scutellatus), and crotoxin from the Brazilian rattlesnake (C. durissus terrificus). However, the myotoxins of Enhydrina schistosa and some other sea snakes are quite similar and the distinction between neurotoxin and myotoxin may be illusory. Most of these toxins have molecular weights of 13,500 to 22,000 d except for those, such as taipotoxin and textilotoxin, that have multiple subunits and a correspondingly higher weight. The phospholipase A's in venom have 110 to 125 amino acids with six or seven disulfide bonds and are broadly homologous with pancreatic enzymes. Their neurotoxicity and myotoxicity are not related to hydrolytic activity. The nonenzymatic subunits are nontoxic but apparently serve to stabilize the enzyme in tiss u e ~ . ~ ~ . ~ ~ Toxic phospholipase As are known for venoms of several vipers. In addition to crotoxin, Mojave or K' toxin, originally isolated from the Mojave rattlesnake and subsequently found in venoms of some other North American rattlesnakes, belongs to this group.I3 Immunologically, it is related to c r o t o ~ i n . 'A ~ chemically and pharmacologically similar but immunologically distinct toxin is in venom of the Palestine horned viper (Pseudocerastes persicus fieldi)." Viperotoxin from venom of the Palestine viper (Vipera palaestinae) has 108 amino acids and three disulfide bonds and has an acidic rather than basic phospholipase A subunit.15 Its site and manner of action are poorly known. Single chain basic phospholipase A neurotoxins have been reported from venoms of the long-nosed viper (Vipera ammodytes), horned puff adder (Bitis caudalis), and Pallas' viper (Agkistrodon halys)." Some additional, poorly known snake neurotoxins of uncertain clinical significance include the K-neurotoxins from venoms of some kraits (Bungurus), which are selective for neuronal nicotinic receptors and have little action on muscle nicotinic receptors.16 Vipotoxin from venom of Russell's viper (Vipera russelli) blocks biogenic amine receptors but has little toxicity for mice.I7Dendrotoxin from venom of the mamba Dendroaspis angusticeps blocks potassium channels and facilitates acetylcholine release at the myoneural junction with an increase in skeletal muscle response to stimulation.ls
CLINICAL MANIFESTATIONS The clinical course of snakebite is variable and unpredictable because of factors that involve both the biting snake and the bitten human. The two most important factors are the intrinsic toxicity of the venom for man and the amount injected. The
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N E U R O T O X I C SNAKE ENVENOMING-MINTON
VOLUME 10, NUMBER 1 MARCH 1990
former can only roughly be estimated from data drome may be as soon as 3 minutes after a bite or obtained from animal experiments. Even among as late as 24 hours.21Some aspects of it have been mammals, there is wide variation among species in reported following bites of all groups of elapid susceptibility to snake venoms as well as infraspe- snakes. Both the presynaptic and postsynaptic neucific variation. The amount of venom injected is rotoxins apparently are involved. There is evihighly variable and at least partly under the snake's dence that the presynaptic neurotoxins are associcontrol. Herpetologists and snake keepers have re- ated with delayed onset, prolonged symptoms, and peatedly observed that snakes use different meth- poor response to antivenoms, whereas the postsynods in handling relatively large, active prey (an aptic toxins account for early paralytic symptoms, adult rat or mouse) and helpless prey (nestling such as ptosis and ophthalmoplegia.ll Cobra bites are reported more frequently than birds or rodents) and may use still different techniques when confronted by an enemy. Experimen- bites by other elapid snakes; however, there is a tal attempts to verify this have not been conclusive tendency in south Asian countries to ascribe all but do show that the amount of venom injected by venomous snakebites to "cobras," particularly if neurotoxic symptoms are present. Cobra bites are a snake in a given bite is extremely variable-from none to half of the venom available in the glands. almost invariably painful and accompanied by Evaluation of snakebite cases from various parts of some degree of local swelling, which may progress the world indicates that 20 to 60% result in little or to involve an entire extremity. Local necrosis inno envenoming even though the bites may have volving skin and subcutaneous tissues may occur been inflicted by large snakes with highly toxic and may be extensive, involving much of the bitten venom. Such bites are particularly common with limb. The onset is characteristically delayed 2 to 4 some snakes such as coral snakes and sea snakes. days after the bite and often is preceded by discolSnake venoms also show clinically significant geo- oration of the skin and blistering. Necrosis has graphic variation (neurotoxic symptoms are often been reported frequently following bites by Afriseen with Russell's viper bites in Sri Lanka but not can spitting cobras and the cobras of Malaysia, in Burma, whereas the opposite is true of pituitary Thailand, and Taiwan but is uncommon in the hemorrhageIg) and ontogenic variation (bites by Philippine~.~l-'"t has been ascribed to the broadyoung diamondback rattlesnakes [Crotalus atrox] spectrum cell membrane toxin, often referred to as are more likely to be followed by coagulopathy cardiotoxin or direct lytic factor, which is a major than bites by adults2'). Variation in human re- component of all cobra venoms.24Cobra venom nesponse to snake venom has been little investigated, crosis is difficult to induce in experimental animals, which usually die of neurotoxic manifestaalthough anaphylaxis has been reported. The numerous toxins present in snake venoms tions first. On the other hand, necrosis is often virtually guarantee that any serious snakebite will seen as the chief or only manifestation of cobra enshow evidence of injury to several organ systems. venoming in man. I t has been demonstrated that Nearly all physicians experienced in treating snake- some cobra postsynaptic neurotoxins bind weakly bites stress the folly of clinical classification of bites to the human myoneural junction.Weurotoxic as neurotoxic, hematotoxic, myotoxic, or other. symptoms in cobra bites can sometimes be detected However, a common theme in the clinical picture in 3 minutes and rarely are delayed more than 6 of envenoming by snakes whose venoms contain hours in untreated cases. Respiratory paralysis can neurotoxins is the development of cranial nerve develop in 15 minutes and lead to death within 2 palsies (Table 2). These are characteristically man- hours. There are anecdotal reports of deaths ifested as ptosis and ophthalmoplegia with blurred within an hour. With or without antivenom treatvision or diplopia, difficulty in swallowing with an ment, the neurotoxic manifestations of cobra bite inability to handle oral secretions, slurred speech, resolve completely in nonfatal cases within a week. Bites by the African spitting cobras, N. nigriweakness of facial muscles (Fig. 4), and occasionally loss of the sense of taste or smell. The pupils collis and N. mossambica, present a distinctly differusually are dilated and respond sluggishly to light. ent picture. Although venoms of these snakes conThis syndrome is often accompanied by drowsi- tain postsynaptic neurotoxins, the clinical picture ness, sometimes with mental confusion and eu- is one of marked local swelling often accompanied phoria. Flaccid paralysis (Fig. 5) affects all muscle by blistering and necrosis. Platelets and complegroups in no particular sequence and is accompa- ment are reduced and hemorrhages occur. Evinied by loss of tendon reflexes. There is no pain dence of neurotoxicity other than drowsiness has on passive movement or pressure. Breathing be- not been rep~rted.~~l~"hereare not many wellcomes shallow and diaphragmatic; coma a r d con- documented clinical reports of bites by the king vulsions may precede death. The onset of this syn- cobra. Ophiophagus, but the picture seems to be
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SEMINARS IN NEUROLOGY
f
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Asian, Most African Cobras: Naja spp.
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South American Rattlesnakes: Crotalus durlssus
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0 to
Australian Elapids: Notechis, Sea Snakes: Pseudonaja, Enhydrina, Oxyuranus, Hydrophis, Others Acanthophis
Important Clinical Manifestations of Snakebite Produced by Venoms Known to Contain Neurotoxins*
'Based on reports of cases of moderate to severe envenoming. + + : prominent and severe, sometimes life-threatening; + : consistently present, clinically significant;
Local pain and swelling Local necrosis Cranial nerve palsies Respiratory paralysis Rhabdomyonecrosis Renal failure Hypovolemic shock Coagulopathy
Table 2.
Figure 4. Ptosis and moderate facial paresis following the bite of an Australian tiger snake. (Photograph copyright Julian White. Reprinted with permission.)
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similar to that of envenoming by Asian Naju. Because of the potentially large amount of venom the king cobra can inject, deal11 may occur quickly. Although mamba venoms are quite different from other elapid venorris, the corriparatively k w clinical reports of mamba envenoming are not markedly differenr from accounts of severe cobra bites. 1,ocal pain and swelling are less pronounced than in cobra bites, and if necrosis occurs, it is confined to the immediate vicinity 01' the bite. Neurotoxic symptoms may develop within 5 minutes, and the onset of respiratory paralysis can be rapid. Vomiting, abdominal pain, diarrhea, and parestliesias are mentioned as early symptoms more frequently in mamba than in cobra en~enorning.~' Krait bites usually occur at night and may be inflicted on sleeping persons. Local pain is present but usually not severe; swelling is moderate to minimal. There is usually a period of at least an hour and sometimes as much as 12 hours between the bite and onset of systemic symptoms. Paresthesias, abdominal pain, and fjsciculations may precede or accompany onset of cranial nerve palsies and respiratory paralysi~.'~~~!' Most reported cases are 01' bites by thc closely related Blrngarw rrieruleus, B. mz~lticinctu.s,and l3. rm(li(lus.A report of poisoning by R . Jascialu.\ was rriarkcd by rapid onset of symptonis and death in less than 2 hours.'"' I here are few case reports of coral snake poisoning and most refer to bites by the Uriited Slates species :l.licruru;, f : fulvius. About half the bites are fdlowed by no syrnptonls of poisoning or by only minor pain and swelling. As with krait envenoming. several hours may elapse 1)etwet.n the bite and
VOLUME 10. NCMBEK 1 M A R C H 1990
Figure 5. Muscular weakness with inability to raise the head seen following a cobra bite in Malaysia. This is the "broken-neck effect" reported following bites by several species of snakes with neurotoxic venoms. (Photograph by H. Alistair Reid, courtesy Mrs. Reid, R.D.G. Theakston, and the Liverpool School of Tropical Medicine. Reprinted with permission.)
onset of neurotoxic manifestations, which may include paresthesias and fasciculations. Crcatine kiriase lcvcls may be elevated. Paralysis may last 6 to 14 days and muscular strength may not be fully regained for 6 to 8 t ~ e e k s . ~ ' . ~ ~ I11 rnarked contrast with bites by most North American rattlesnakes, bites by the Brazilian rattlesnake show very little edema or ecchymosis. However, cranial nerve palsics, rnyalgia, muscle weakness, son~nolence,and vomiting are cornnion. although life-threatening respiratory failure is not. Most deaths result from renal failure sec:ond;iry to massive rhabdornyonecrosi~."'~~"~ Bites by the hlojavc rattlesnake may show slight local edema, ecchymosis, arid necrosis but oi'ten are accompar~iedby pronounced systemic manifestations such as hypotension, vomiting, disigns arrhea, and pulmonary edcrria."U~ncc~uivoc:;il of r~curotoxicenvenoming are rare. In the region of T L I C S O Arizona, ~, where h e makes do not have Mojave toxin in their venom, bites are much like those of other ratt1csn;ikcs.:'" The berg adder (Bilis u/ropo.s) is a small South African snake belonging to a genus whose rrlcrrlhers typically inflict bites characterized by iri~ense local srvclling, blistering;, ecchymosis, and' liypovolelnic shock (Table 2). berg adder bites produce a moderate local reaction lmt also are followecl by ptosis, oplithalmoplegia, loss o f taste and smell, and other signs of cranial nerve involverncrit. Respirarory paralysis has not been observed, and no Fdtalities havc heen reported."' .rhe toxin responsible has riot been itlontified.
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SEMINARS I N NEUKOLQGY
Kussell's viper is a leading cause of fatal snakebites in southeast Asia, and its venom typically causes hemorrhages, disseminated intravascular coagulation, shock, and renal failure. However, cranial nerve palsies and respiratory distress regularly accompany envenoming in Sri Lanka.lg Since the elapid snakes of Australia and New Guinea are a large and diverse lot, it is not surprising that clinical envenomation shows considerable variation, although the constellation of cranial nerve involvement and respiratory paralysis is seen with nearly all the more dangerous species. Local pain and swelling are slight to moderate and sometimes most marked with bites by species whose venoms rarely cause systemic effects. Neurotoxic symptoms rarely appear less than 1 hour after a bite, but violent headache, abdominal pain, vomiting, and hypotension leading sometimes to syncope may occur within a few minutes. Rhabdomyonecrosis with hyperkalemia and myoglobinuria can lead to death from cardiac arrest or renal failure. Coagulopathy may be seen particularly following bites by Pseudechis and Pseudonaja species but is not often a serious clinical problem. Residual paralysis and muscle weakness may require up to 17 weeks to r e ~ o l v e . ~ ~ . ~ ~ The close relationship between Australian elapids and sea snakes is also reflected in the symptomatology of envenomation. Sea snake bites are almost painless and produce little or no swelling. Approximately 60% of those bitten develop no significant poisoning. In others, the onset of symptoms is usually within a 30- to 120-minute period and begins with myalgia and pain on passive movement. Pseudotrismus may be seen. Dark urine indicating myoglobinuria is evident in about 3 hours. Cranial nerve palsies and respiratory paralysis may become superimposed on the myotoxic syndrome after several hours." However, in the only adequate series, cases of sea snake bite were nearly all caused by one species, the beaked sea snake, E. schistosa. Bites of other species may differ. ' h o patients bitten by Stokes' sea snake (Astrotia stoke~i) showed primarily neurotoxic symptoms, one becoming unconscious 20 minutes after being bitten and developing respiratory paralysis within 1 hour. There was little clinical evidence of myonecrosis, but creatine kinase levels were e l e ~ a t e d . ~ ' . ~ '
DIAGNOSIS AND TREATMENT Differential diagnosis in snakebite involves ruling out injuries by inanimate objects, injuries by other venomous animals, and bites by nonvenomous snakes. Additionally, venomous snakebites that
need only conservative management must be differentiated from those requiring more aggressive management. Often the nature of the wounds and presence of local pain, swelling, and discoloration permit early recognition of a venomous snakebite. Many snakes with predominantly neurotoxic or myotoxic venoms, such as coral snakes and sea snakes, however, have small fangs whose punctures may be difficult to find and venoms that cause little pain or swelling. Also, these bites may be followed by a symptom-free latent period lasting several hours. If the snake is positively identified as a dangerous species, it is often advisable to initiate treatment during this period. Ptosis, external ophthalmoplegia, and difficulty in opening the mouth and protruding the tongue are usual early signs of neurotoxic envenomation. They may be preceded by headache, vomiting, and abdominal pain. Tenderness of regional lymph nodes may be observed early even though the reaction at the site of the bite is minimal. Periodic measurements of circumference of a bitten limb are usually necessary to determine presence and progression of swelling. Enzyme-linked immunosorbent assay (ELISA) for detection of snake venoms is generally available in Australia and has been developed for use in other nations. Venom antigen levels in plasma and urine are most significant in determining severity of envenoming, whereas aspirate from the bite site or venom deposited on skin or clothing is better for identification of the snake species. Current ELISA cannot usually distinguish venoms of closely related snakes. ELISA can also be used to detect venom antibodies in epidemiologic studies of snakebite. A coagulation profile should be obtained on all patients hospitalized for snakebite and repeated in 6 to 8 hours in all but clearly trivial envenoming. Creatine kinase and lactic dehydrogenase levels are markedly elevated in patients bitten by snakes with myotoxic venoms, and this is sometimes of help in diagnosis. Examination of urine and plasma for myoglobin may also be helpful. Complement levels may be decreased in cobra envenoming. Antivenoms in adequate dosage usually neutralize life-threatening systemic effects of snake venoms; they are less effective against local effects. Antivenoms are produced by about 50 laboratories worldwide and vary greatly in neutralizing ability, degree of refinement, and potential for producing undesirable side effects. All are produced in horses. Some antivenoms are specific for venom of one snake species, whereas others are polyvalent against venoms of all snakes of a particular geographic area. T h e degree of para-specific protection afforded is unpredictable. Tiger snake antivenom protects against venoms of many Australian
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SEMINARS I N NEUROLOGY VOLUME 10, NUMBER 1 MARCH 1990
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considered. When intense swelling involves the hand, digit dermotomy often is beneficial in preventing impairment of function. 'The local necrotizing effect of cobra and some other venoms is difficult to counteract with available treatment. ACKNOWLEDGMENT I wish to acknowledge the valued assistance of Sherry1 Riley for typing and other clerical assistance.
REFERENCES 1. Slotta K, Fraenkel-Conrat H. 'l'wo active proteins from rattlesnake venom. Nature 1938; 142:2 13 2. Ghosh B, De SS, Chowdhuri DK. Separation of the neurotoxin from crude cobra venom and study of the action of a number of reducing agerlts o n it. Indian J Med Kes 194 1;29:367-73 3. Yang CC. Crystallization and properties of cobrotoxin from Formosan cobra venom. J Biol Chem 1965;240: 1616-8 4. Charrg CC, Lee CY. Isolation of neurotoxins from the venom of Bungarus multicinctus and thrir modes of neurornuscular blocking action. Arch I n t Pharrnacodyn 1963; l44:241-57 5. Lee CY. Chemistry and pharmacology of' polypeptide toxins in snake venoms. Annu Rev Pharmacol 1972; 12:256-86 6. Narita K, Mebs D, Iwanaga S, et al. Primary structure of cx-bungarotoxin from Bungarus mu,lticinctus venom. J Formosan Med Assoc 1972;7 1:336-43 7. Changeaux JP, Kasai M, Lee CY. Use of a snake venom toxin to characterize the cholinergic receptor protein. Proc Natl Acad Sci USA 1970;67:1241-7 8. Low BW. T h e three-dimensional structure of postsynaptic snake neurotoxins: consideration of structure and function. In: Snake Venoms Lee CY, ed: Handbook of' Experimental Pharmacology, vol 52. Berlin: SpringerVerlag, 1979:213-57 9. Low BW, Corfield PWR. Acetylcholirie receptor a-toxin binding site-theoretical a n d model studies. Asia Pac J Pharmacol 1987;2:1 15-27 10. Endo T, Tamiya N. Current view on the structurefunction relationship of postsynaptic ncurotoxins from snake venoms. Pharmacol T h e r 1987;34:403-51 11. Chang CC. Ncurotoxins with phospholipase A, activity in snake venoms. Proceedings of the National Science Council (Taiwan) Part B. Lii'e Science, 1985;9: 126-42 2. Rosenbcrg P. T h e relationship between enzymatic activity and pharmacological properties of phospholipases in natural poisons. In: Harris JB, ed: Natural toxins: animal plant, and microbial. Oxford: Clarendon Press, 1986: 129-74 3. Johnson JK, Bieber AL. Mojave toxin: rapid purification. heterogenicity and resistance to denaturation by urea. Toxicon 1988;26:337-51 4. Weinstein SA, Minton SA, Wilde CE. T h e distribution among ophidian venoms of a toxin isolated from the venom of' the Mqjave rattlesnake (C~.otalusscutulatw scutulatus). Toxicon 1985;23:825-44 5. Moroz C, DeVries A, Sela M. Isolation and characterization of a neurotoxin from Vapera palacstinae venom. Biochim Biophys Acta 1966; 124: 136 6. Harris J B . Phospholipases in snake venoms and their effects o n nerve and muscle. Pharmacol T h e r 1985;31: 79-102.
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snakes, most sea snakes, and many cobras and kraits; however, antivenoms against Asian sawscaled vipers (Echis) are ineffective against African snakes of the genus and vice versa. There are no firm indications for initiating antivenom therapy. Ptosis, oculomotor palsy, slurred speech, and dysphagia are common early signs of neurotoxic envenoming and are indications for antivenom therapy. However, with coral snake and krait bites, antivenom should be started before signs of envenomation appear, because these venoms are difficult to neutralize after they have been bound at the myoneural junction. Antivenom is administered intravenously diluted with crystalloid or glucose solution. Antivenom is most effective if begun within 4 hours after a bite, however some venom effects such as coagulopathy may be reversed even after 24 hours. Total response of the patient rather than a single parameter should determine the quantity of antivenom given. Doses of 400 to 500 ml may be needed. Acute anaphylaxis is an ever present danger of antivenom therapy, and appropriate precautions should be taken. Some 70 to 80% of patients who receive antivenom develop serum sickness. Edrophonium hydrochloride counteracts the neuromuscular blocking action of cobra venom more rapidly than antivenom, although its action is temporary. Antivenom may be administered c o n c ~ m i t a n t l ~ . ~ ~ e o s t i g mmethyl i n e sulfate has been used in krait and cobra envenomation with variable r e ~ u l t s . ~ ~ ~respiratory ~ V h e paralysis caused by venom neurotoxins may be difficult to reverse with antivenom. Intermittent positive pressure ventilation with or without tracheostomy is often needed and may be lifesaving. It may be used alone or combined with antivenom and neostigmine-atropine.28~46~47 Artificial respiratory support often is needed for 14 to 48 hours in cases of krait and cobra bites and was required for more than 10 weeks in an Australian snakebite case; the patient eventually rec~vered."~ Of the other life-threatening complications of snakebite, hypovolemic shock usually responds to antivenom in adequate dosage plus intravenous fluids. Coagulopathy also usually responds favorably to antivenom. Supplemental fresh-frozen plasma, cryoprecipitate, and platelets may be helpful. Renal failure requires correction of electrolyte imbalance and often dialysis. Bacterial infections are uncommon. Culture and sensitivity tests should guide antibiotic therapy. Local tissue damage may result from impairment of circulation or the direct effect of the venom on tissues or both. If intracompartment pressure reaches 30 mmHg, fasciotomy should be
17. Chiappinelli VA. Actions of snake venom toxins on neuronal nicotinic receptors and other neuronal receptors. Pharmacol Ther 1985;3 1: 1-32 18. Harvey AL, Anderson AJ. Dendrotoxins: snake toxins that block potassium channels and facilitate neurotransmitter release. Pharmacol Ther 1985;3 1:33-55 19. Warrell DA. Tropical snake bite studies. In: Harris JB, ed: Natural toxins: animal, plant and microbial. Oxford: Clarendon Press, 1986:25-45 20. Reid HA, Theakston RDG: Changes in coagulation effects by venoms of Crotalus atrox as snakes age. Am J Trop Med Hyg 1978;27:1053-7 21. Watt G, Padre L, Tuazon ML, et al. Bites by the Philippine cobra (Naja naja philippinensis): prominent neurotoxicity with minimal local signs. Am J Trop Med Hyg 1988;39:306-ll 22. Trishnananda M, Oonsombat P, Dumavibhat B, et al. Clinical manifestations of cobra bite in the Thai farmer. Am J Trop Med Hyg 1979;28:165-6 23. Reid HA. Cobra-bites. Br Med J 1964;2:540-5 24. Karlsson E. Chemistry of protein toxins in snake venoms. In: Lee CY, ed: Snake Venoms, vol. 52. Handbook Experimental Pharmacology. Berlin: Springer-Verlag, 1979;159-212 25. Warrell DA, Greenwood BM, Davidson NM, Ormerod LD. Necrosis, hemorrhage, and complement depletion following bites by the spitting cobra (Naja nigricollis). Q J Med l976;45: 1-22 26. Tilbury CR. Observations on the bite of the Mozambique spitting cobra (Naja mossambica mossambica). S Afr Med J 1982;61:308-13 27. Visser J , Chapman DS. Snakes and snake-bite. Cape Town: Purnell & Sons, 1978 28. Karalliedde LD, Sanmuganthan PS. Respiratory failure following envenomation. Anaesthesia 1988;43:753-4 29. Looareesuwan S, Viravan C, Warrell DA. Factors contributing to fatal snake bite in the rural tropics: analysis of 46 cases in Thailand. Trans R Soc Trop Med Hyg 1988;82:930-4 30. Viravan C, Veeravat U, Warrell MJ, et al. ELISA confirmation of acute and past envenoming by the monocellate Thai cobra (Naja kaouthia). Am J Trop Med Hyg 1986;35: 173-81 31. Parrish HM, Khan M. Bites by coral snakes: reports of 11 representative cases. Am J Med Sci 1967;253:561-6 32. Kitchens CS, Van Mierop LHS. Envenomation by the Eastern coral snake (Micrurus fulvius fulvius). JAMA 1987;258: 1615-8 33. Azevedo-Marques MM, Hering SE, Cupo P. Evidence
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that Crotalus durissus ternficus (South American rattlesnake) envenomation in humans causes myolysis rather than hemolysis. Toxicon 1987;25:1163-8 Cupo P, Azevedo-Marques MM, Hering SE. Clinical and laboratory features of South American rattlesnake (Crotalus durissw temficus) envenomation in children. Trans R Soc Trop Med Hyg 1988;82:924-9 Rothan WB, Gennaro JF. Treatment of the bite of a Mojave rattlesnake. J Fla Med Assoc 1968;55:324-7 Hardy DL. Envenomation by the Mojave rattlesnake (Crotalus scutulatus scutulatw) in southern Arizona. Toxicon 1983;21:11 1-8 Ellis CG. The berg adder: a unique snake. Practitioner 1979;223:544-7 Sutherland SK. Australian animal toxins. Melbourne: Oxford University Press, 1983 White J. Elapid snakes: venom toxicity and actions; aspects of envenomation; management of bites. In: Covacevich J , Davie P, Pearn J, eds: Toxic plants & animals, a guide for Australia. Brisbane: Queensland Museum, 1987:369-457 Reid HA. Epidemiology and clinical aspects of sea snake bites. In: Dunson WA, ed: The biology of sea snakes. Baltimore: University Park Press, 1975:417-62 Mercer HP, McGill JJ, Ibrahim RA. Envenomation by sea snake in Queensland. Med J Aust 1981; 1: 130-2 Audley I. A case of sea snake envenomation. Med J Aust 1985;143:582 Watt G , Theakston RDG, Hayes CG, et al. Positive response to edrophonium in patients with neurotoxic envenoming by cobras (Naja naja philippinensis): a placebo-controlled study. N Engl J Med 1986;315: 1444-7 Warrell DA, Looareesuwan S, White NJ, et al. Severe neurotoxic envenoming by the Malayan krait, Bungarus candidus; response to antivenom and cholinesterase. Br Med J 1982;286:678-82 Mitrakul C, Dhamkrong-at A, Futrakul P, et al. Clinical features of neurotoxic snake bite and response to antivenom in 47 children. Am J Trop Med Hyg 1984; 33: 1258-66 Pawar DK, Singh H. Elapid snake bite. Br J Anaesth 1987;59:385-7 Casale FF, Patel SM. Elapid snake bite: a report of two cases. Br J Anaesth 1974;46: 162 Patten BR, Pearn JH, DeBuse P, et al. Prolonged intensive therapy after snake bite: a probable case of envenomation by the rough-scaled snake. Med J Aust 1985; 142:467-9
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