Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 66

Venomous snake bites, scorpions, and spiders S.A.M. KULARATNE* AND NIMAL SENANAYAKE Department of Medicine, Faculty of Medicine, University of Peradeniya, Kandy, Sri Lanka

INTRODUCTION Historical background Of approximately 2700 described species of snakes in the world, 500 are venomous, mainly distributed in warm tropical regions (Chippaux, 2006). Species of scorpions and spiders number 600 and 30 000, respectively (Senanayake and Roman, 1992). Many other venomous creatures potentially dangerous to people exist in the environment, including insects (Hymenoptera), paralytic ticks, centipedes (Chilopoda), caterpillars, cone snails, shellfish, puffer fish, jellyfish, fish with ciguatoxins, and poisonous frogs. The destructive power of snakes caused serpents to be associated with the divine in most ancient cultures, and the neuroparalysis caused by the venom of the Egyptian cobra (Naja haje) was believed to have brought about the instantaneous death of queen Cleopatra (Chippaux, 2006). From the Middle Ages and Renaissance onwards, scientific thinking began to come to the fore, and Leoniceno Nicolo (1428–1524), a Greek scholar and Italian physician, studied herpetology and the toxicology of snake bites (Adler and Louis, 2007). At the end of the 19th century, Albert Calmette developed the concept of antivenom, which remains the treatment for envenomation by the bite or sting of venomous creatures (Calmette, 1907). Evolutionarily, snakes (the Squamata) can be traced to the middle of the Cretaceous period more than 100 million years ago. They originated in the ancient southern continent of Gondwana and their dispersal to the north could be explained by continental drift and ice ages that created land bridges (Holman, 2000; Ivanov et al., 2000; Pook et al., 2009).

Venom apparatus Snakes can be classified into more than 15 families, with venomous snakes belonging to the Viperidae, Elapidae,

Colubridae, and Atractaspididae families (Wuster and McCarthy, 1996; Chippaux, 2006). The venomous snakes posses a venom apparatus which is a complex device consisting of a specialized gland that synthesizes venom and a fang which injects the venom on bite. Depending on the position of the fang on the maxilla and the dentition, the snakes are further classified into four groups: aglyphous (fangless), opisthoglyphous (back-fanged), proteroglyphous (front-fanged), and solenoglyphous (mobile front-fanged) (De Silva, 1980; Chippaux, 2006). The terminal segment of a scorpion’s tail, called the telson, contains two venom glands connecting with a curved, needle-sharp sting, whilst spiders have a pair of horny fangs (chelicerae) among their mouth parts (Brownell and Polis, 2001; Sutherland and Tibballs, 2001; White, 2008). Among the insects, bees inject venom through a barbed sting which gets embedded and remains in the skin of the victim, but wasps and hornets carry modified ovipositors used for repeated stinging (Imms, 1939; Fitzgerald and Flood, 2006).

Venom Snake venom is a complex mixture of proteins that can be divided into two groups, the enzymes and the toxins. The enzymes are proteins which are generally high in molecular weight. These most often act on blood coagulation, compliment activation, and cause cytolysis and activation of metabolism. The venoms of the Viperidae are particularly rich in enzymes. Examples of enzymes that act on the nervous system are phospholipase A2 and acetylcholinesterase (AChE) (Ahmed et al., 2009; Robin et al., 2010). The toxins, on the other hand, have variable molecular weights, generally less than 30 kDa. These have the ability to bind to specific receptors on membranes of different anatomical sites including the nervous system, the cardiovascular system,

*Correspondence to: S.A.M. Kularatne, Professor, Department of Medicine, Faculty of Medicine, University of Peradeniya, Kandy, Sri Lanka. E-mail: [email protected]

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and muscle. The venoms of Elapidae are particularly rich in toxins (Chippaux, 2006; Mebs, 2008). Scorpion venom contains peptides capable of a variety of actions, whilst spider venoms are usually complex mixtures of substances, with the most potent neuroexcitatory toxins (White, 2008). The venom of the Hymenoptera contains mainly biogenic amines (histamine, 5-hydroxytryptamine, dopamine, noradrenaline, and acetylcholine (ACh)) and also some enzymes and toxins (Schmidt, 1995). The toxins in venom affecting the functions of the nervous system are referred to as neurotoxins (Table 66.1).

PATHOPHYSIOLOGY OF ENVENOMING Effects of venom on the nervous system From an evolutionary point of view, neurotoxins would be considered a hunting device, used in rapid immobilization of a prey. However, in clinical situations of envenoming, onset and progression of neurotoxicity is highly variable. A good knowledge of the structure and function of the nervous system is required to understand the mechanism of neurotoxic manifestations. The nervous signal is propagated along the nerve by means of

Table 66.1 Neurotoxins, their sources and mechanisms of action Source

Toxin

Action

Snake venom Elapidae Cobra Krait

a-toxin, cobrotoxin

Postsynaptic Presynaptic, except Bungarus multicinctus which has both a- and k-bungarotoxin *Presynaptic, increases ACh, {AChesterase, muscarine receptors Postsynaptic Presynaptic and postsynaptic

Mamba Coral snake Australian elapids Sea snakes Viperidae Daboia russelii Rattlesnake Scorpion venom All scorpions Tityus

b-bungarotoxin *Dendrotoxin, { fasciculins, muscarines a- neurotoxin Taipoxin, notexin, both a- and b-bungarotoxins Erabutoxins, phospholipase A2 Vipoxin, phospholipase A2 Crotoxin, crotamine More toxins and less enzymes Tityustoxin

Presynaptic, myotoxic Pre- and postsynaptic ? adrenergic receptor Postsynaptic, myotoxic Increase autonomic activity Pre-/postsynaptic, increases Naþ permeability Naþ/Kþ channels, autonomic storm Autonomic storm Presynaptic and axonal membrane

Mesobuthus tamulus Hemiscorpion lepturus Centruroides Spider venom All venomous spiders

a and b scorpion toxins, mixture

Latrodectus

a-latrotoxin

Australian funnel-web Hymenoptera venom Apidae Vespidae Tick venom Ixodidae Argasidae Ciguatera Barracuda, grouper, red snapper, amber jack

Atracotoxins

Increase autonomic/somatic transmission Presynaptic – increase neurotransmission Voltage-gated Naþþ channels

Apitoxins, mellitin, apamin, etc. Mandaratoxins

Mild effect ?Pre- and postsynaptic

Salivary toxins

Presynaptic (terminal part of motor nerve fiber)

Ciguatoxin from Gambierdiscus toxicus

Presynaptic (Naþ channels of axonal membrane) and ?postsynaptic

Toxins on Naþ channels Neuroexcitotory toxins

VENOMOUS SNAKE BITES, SCORPIONS, AND SPIDERS

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Table 66.1 Continued Source

Toxin

Action

Shellfish

Saxitoxin Brevitoxin Tetrodotoxin

Presynaptic (Naþ channels of axonal membrane) Presynaptic (Naþ channels of axonal membrane)

Cone snail venom

Batrachotoxin, histrionicotoxin, pumiliotoxin B Conotoxin

Presynaptic (Naþ channels of axonal membrane), postsynaptic Postsynaptic, presynaptic (Naþ channels of axonal membrane)

Bacterial toxins Clostridium botulinum C. tetani

Botulinum toxin Tetanus toxin

Presynaptic Presynaptic

Pufferfish, porcupinefish, king crab, goby, newt, octopus, frog venom, etc. Frog venom

depolarization of the cell membrane. The depolarization travels from one nerve to another or from nerve to muscle across a synapse resulting in contraction of the muscle. The synapse in the neuromuscular junction (NMJ) is a complex structure in which a fine balance exists between the release of the chemical neuromediator ACh and its inactivating enzyme AChE (Estable, 1959). The neuron, at rest, has a difference in the electrical potential on the two sides of the cell membrane. A stimulus causes depolarization of the nerve by means of releasing potassium out of the cell and an inward flux of sodium through specific voltage-dependent ion channels. The resultant nervous signal propagates along the axon in the form of a wave called the action potential. The synapse presents itself as an interruption between two neurons or between a neuron and the muscle. Thus, synapse consists of presynaptic terminal/membrane, synaptic cleft/gap and postsynaptic terminal/membrane. On arrival of an impulse, ACh is released from the vesicles of presynaptic terminal to the synaptic cleft, establishing contact with the cholinergic receptors on the postsynaptic membrane. The receptor in turn activates the sodium and potassium ion channels allowing propagation of the action potential. Two types of cholinergic receptors have been identified by their response to transmitter substances. Of these, nicotinic receptors are found in the ganglia, the NMJ of skeletal muscles, medulla of the adrenal gland, and some areas of the brain and the spinal cord. Muscarinic receptors are widely distributed in the brain and in the ganglia of the parasympathetic nervous system. After activation of the cholinergic receptor, ACh is hydrolyzed by the enzyme AChE in the synaptic gap, making the receptor free for the next action. Certain other neurotransmitters, such as GABA, noradrenaline,

adrenaline, dopamine and g-aminobutyrate, also exist in the nervous system, but their involvement in neurotoxic snake envenoming is poorly understood. However, these neurotransmitters are thought to play an important role in scorpion, spider and mollusc envenomation (Ganong, 1999; Chippaux, 2006).

Neurotoxins Neurotoxins are classified into four groups according to their site and mode of action (Fig. 66.1).

POSTSYNAPTIC TOXINS (a-TOXINS AND k-TOXINS) Examples of postsynaptic neurotoxins are a-bungarotoxins in Chinese krait (Bungarus multicinctus), cobrotoxins in many cobra species such as Naja haja, N. kaouthia, N. naja, N. nigrecollis, and sea snake venom, for example, laticotoxin in L. laticaudata and hydrophitoxin in Hydrophis cyanocinctus. They comprise of 60–62 or 66–74 amino acids (Chippaux, 2006). a-Toxins are three-finger protein complexes and act in the same way as curare, an alkaloid extracted from strychnous, a Central and South American plant used as arrowpoisons by the native inhabitants (Senanayake and Roman, 1992; Chippaux, 2006; Del Brutto and Del Brutto, 2011). Nearly 150 years ago, Claude Bernard’s experiments showed that the crude extracts of curare were highly specific in interruption of electrical signals between nerve and muscle. Subsequent investigations have used curare as a ligand for binding studies on the nicotine ACh receptor (AChR) (Estable, 1959; Senanayake and Roman, 1992). The a-neurotoxins have a stronger affinity to the nicotinic ACh in the NMJ than others. Irditoxins are the best characterized a-neurotoxins (Del Brutto and Del Brutto, 2011).

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Fig. 66.1. Site of action of toxins in neuromuscular transmission.

In contrast, k- neurotoxins have a high affinity to the cells of the parasympathetic (ciliary ganglia) and sympathetic lumbar ganglia. They have less pronounced effects on the central nicotinic receptors such as cervical ganglia, retinal ganglia, cerebellum, and corpus striatum (Grant and Chiappinelli, 1985; Dewan et al., 1994). The venom of many banded kraits, particularly Chinese krait (Bungarus multicinctus), contains both a- and kbungarotoxins (Lee, 1972; Dewan et al., 1994). Other postsynaptic neurotoxins are adrenergic toxins and muscarinic toxins, the latter being found in African mamba venom. The first protein toxins that bind to muscarinic ACh receptors (mAChRs) were isolated from the venom of African green mamba (Dendroaspis angusticeps) (Adem et al., 1988). Some unclassifiable toxins, such as vipoxin from Daboia russelii, which do not act on either nicotinic or muscarinic receptors, but may be on adrenergic receptors, have also been isolated (Chippaux, 2006).

PRESYNAPTIC TOXINS (b-TOXIN) These toxins, present in the venom of many elapids and certain viperids, act by inhibiting the release of ACh from the presynaptic nerve terminal, e.g., bbungarotoxin, crotoxin, taipoxin, paradoxyn, trimucrotoxin, viperotoxin, pseudocerastes, and textilotoxin, which contains 120–140 amino acids and phospholipase A subunit. These toxins consist of one, two, or four subunits and have in common a phospholipase-like action that is necessary for their toxic activity (Chippaux, 2006; Robin et al., 2010; Del Brutto and Del Brutto, 2011). Of these, b-bungarotoxin (e.g., venom of kraits) acts on the voltage-dependent potassium channel, while crotoxin (venom of South American rattlesnakes, e.g.,

Crotalus durissus terrificus) binds to a not yet identified protein membrane (Chippaux, 2006; Doley et al., 2010). The progressive blockage of ACh release under the action of b-toxins occurs in three stages. The first stage is independent of phospholipase action, but in the third stage catalytic activity of phopholipase causes definitive arrest of ion exchange and damage to nerve terminal (Seu et al., 1976). The phospholipase activity is high in marine and Australian elapids that cause muscle necrosis and myoglobinuria (Doley et al., 2010). The venoms of Dendroaspis have calciseptin and calcicludin acting on calcium channels that can be included in this group (Chippaux, 2006; Hedge et al., 2009).

PRESYNAPTIC FACILITATING TOXINS AND FASCICULINS These facilitate the release of ACh from presynaptic terminal and are extremely potent, causing paralysis. Dendrotoxins that fall into this category have an elevated affinity to certain voltage-dependent potassium channels. The victim develops convulsions leading to respiratory paralysis (Chippaux, 2006). Fasciculins are small proteins found in the venoms of mambas (Dendroaspis; family Elapidae) which inhibit acetylcholinesterase and prevent destruction of ACh in the synaptic gap leading to repeated depolarization of the postsynaptic membrane. The victim develops muscle fasciculation and contraction. This effect is somewhat reversible with atropine (Chippaux, 2006; Harvey, 2010).

SNAKE ENVENOMING Epidemiology Snake envenoming is an important problem worldwide, mainly in Southeast Asia, sub-Saharan Africa, Central

VENOMOUS SNAKE BITES, SCORPIONS, AND SPIDERS 991 and South America, Australia and even in the US stimulation shows a decrement abolished by edrophonium (Kasturiratne et al., 2008). In 1998, an appraisal of the (Watt et al., 1998). The bite of the spectacled cobra global situation regarding snake bites estimated that (Naja naja), on the other hand, causes severe local worldwide there were 5 million snake bites with 125 000 reaction leading to spreading necrosis and gangrene; only deaths (Chippaux, 1998), and in 2008, a similar attempt 36% of victims developed neurotoxicity which had estimated that the global burden of snake envenoming rapid onset leading to respiratory failure in 2 hours was, at a minimum, 421 000 envenomings and 20 000 (Kularatne, 2009). Spitting cobras spit venom into eyes deaths (Kasturiratne et al., 2008). Being a neglected tropof victims causing venom ophthalmia manifested as ical problem, lack of accurate data from many regions has keratoconjuctivitis and occasional cranial nerve palsies made these estimates questionable. Australia records (Chu et al., 2010). approximately 1000–1500 snake bites, 150 envenomings, and two to four deaths annually (White, 2010). ConKRAITS versely, sub-Saharan Africa estimates that there are more than 1 million bites and 25,000 deaths per year (Chippaux, Kraits (Bungarus) are distributed through Asia and they 2010). The estimates from South Asia record the highest consist of 12 species of which the principal ones are B. candidus or Malayan krait, B. fasciatus or banded burden of snake envenoming, ranging from 121 333 to krait, B. caeruleus or common krait, B. multicinctus 463 550 annually (Kasturiratne et al., 2008). In Sri Lanka, hospital records show approximately 40 000 snake bites or Chinese krait, and B. niger or greater black krait and 100 deaths annually (Kularatne, 2001). (Chippaux, 2006; Warrell, 2010b). Of these, the common krait, B. caeruleus, is found in Sri Lanka, Bangladesh, Elapidae India, and Pakistan. It is reputed to be the deadliest in Sri Lanka (Kularatne, 2001). Krait venom contains Among the venomous snake families, the Elapidae famb-bungarotoxin, a presynaptic blocker which causes ily consists of cobras, kraits, mambas, coral snakes, and muscle paralysis as the sole clinical manifestation. The Australian elapids, whose venom is rich in neurotoxins. common krait is a nocturnal terrestrial snake living close They have unfoldable anterior fangs (proteroglyphous). to human dwellings and the bites happen mostly at night where people sleep on the floor in mud huts. Very often COBRAS the victims are unaware of the bite. Abdominal pain and In cobras, the genus Naja has 18 species spread over Africa progressive muscle paralysis occurs, causing respiratory and Asia. The principal African species are N. haje failure in about 50% of cases. The level of consciousness in deserts, N. nigricollis in savannas, N. melanoleuca in deteriorates and some patients develop a deep comatose forests, and N. mossambica (Chippaux, 2010). Over the state similar to brain death. They may still recover whole of Asia, 10 subspecies of Naja are recognized; of with the help of assisted ventilation (Kularatne, 2001; these, four are found in India (Wuster, 1998b). The Gawarammana, 2010). The observation of GABA relNaja naja or spectacled cobra is found in India, Pakistan, ease and production of deep coma in animal experiments Sri Lanka, and Bangladesh (Wuster, 1998b; Kularatne, with b-bungarotoxins (Wernicke, 1975), and binding of 2009). N. kaouthia or the monocellate cobra, is found a-bungarotoxins to hippocampal interneurons in experin northeastern India, Bangladesh, Malaysia, southern imental studies (Freedman, 1993) are some explanations Vietnam, and China. Other Indian Naja include N. oxiana to support the mechanism of changing sensorium in krait (northern India) and N. sagittifera (Andaman cobra) bite. Hypokalemia is yet another problem (Kularatne, (Wuster, 1998b). The spitting cobras include the Indo2001; Gawarammana, 2010). Even after recovery from Chinese spitting cobra (N. siamensis), the Sumatran the effects of acute envenoming, a few patients develop spitting cobra (N. sumatrana), N. sputatrix, and lasting neurologic deficits such as peripheral neuropathy N. mandalayensis (Warrell, 2010b). The king cobra with delayed nerve conduction, ulnar nerve palsies, sen(Ophiophagus hannah) is found in Myanmar, Thailand, sory deficits at the local site, and even cerebellar ataxia and India and the venom is strongly neurotoxic (Warrell, (Kularatne, 2001). The damaging effects of neurotoxins 2010b). Most cobras are generally diurnal and they live and their effects on nicotinic receptors in the brain and close to human dwellings, in agricultural fields and the involvement k-toxins and receptors should be considwater courses where prey is easy to find. Postsynaptic ered to explain these wide arrays of neurologic probtoxins are the main lethal principle in cobra venom. lems. In krait envenoming the mortality can be high The clinical manifestations vary with the species, Naja when intensive care facilities are limited and anticholinphilippinensis being an example causing severe neuroesterases showed no benefit in reversing the paralysis toxicty with mild local reactions. The muscle paralysis is (Sethi and Rastogi, 1981; Theakston et al., 1990). Similar typical of the myasthenic syndrome and repetitive nerve to common kraits, B. candidus also bites victims in their

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sleep and B. fasciatus frequents rice paddies at night and inflicts bites (Chippaux, 2006).

opthalmoplegia, and fixed dilated pupils, followed by paralysis of limbs (Jamieson and Pearn, 1989; White, 2010).

MAMBAS

SEA SNAKES

The mamba (Dendroaspis) is an arboreal snake in Africa and the genus consists of four species: the green mambas (D. angusticeps, D. jamesoni, D. viridis) and the black mamba (D. polylepis). The venom contains phospholipases, dendrotoxins, fasciculins, and a-neurotoxins commonly enhancing nervous transmission (Chippaux, 2006, 2010). The mamba bite causes painful local inflammation. Neurologic manifestations include muscarinelike features such as sweating, lacrimation, disturbed vision, abdominal pain, diarrhea and vomiting. Rapid onset of respiratory paralysis can kill the victim (Harvey and Anderson, 1985; Chippaux, 2006).

Sea snakes represent a diverse lineage of elapid snakes that have adopted a marine lifestyle. They are distributed in the Australasian region, across the Indian Ocean, and in the Western Pacific region. The Hydrophiinae or true sea snakes comprise 16 genera and as many as 53 species whilst the partially terrestrial Laticauda or sea kraits comprise five species (Lukoschek and Keogh, 2006). The important species include beaked sea snake (Enhydrina schistose), blue spotted sea snake (Hydrophis cyanocinctus), banded sea snake (Hydrophis fasciatus atriceps), Hardwick’s sea snake (Lapemis curtus), yellow-bellied sea snake (Pelamis platurus), and sea krait (Laticauda colubrine) (Warrell, 2010b). The erabutoxins a and b are the major neurotoxins in the venom of Laticauda semifasciatus (Guinea et al., 1983; Tamiya and Arai., 1966). The venoms of E. schistose, H. cyanocinctus and Microcephalophis gracifis gracilis are rich in 50 -nucleotidase and phospholipase A2 activity (Alam et al., 1996; Tamiya et al., 1983). The myotoxic activity causes myalgia and passage of dark urine indicating myoglobinuria. The myasthenic manifestations become superimposed on the myotoxic syndrome and produce ptosis, external opthalmoplegia, dysphagia, and even respiratory paralysis. Recovery occurs within 1 week, but respiratory failure may cause death (Reid, 1975a, b).

CORAL SNAKES The genus Micrurus (coral snake) consists of 64 species distributed in Central and South America. The species responsible for the majority of coral snake bites is M. nigrocinctus which often bites fingers of the victim during handling (Gutierrez, 1995; Chippaux, 2010). The bites are not frequent and the venom contains postsynaptic a-neurotoxins which have a high affinity to the cholinergic receptors at the motor endplate (Chippaux, 2010; Gutierrez, 2010). Muscle paralysis sets in within several hours and it can last up to 2 weeks. This postsynaptic defect is not corrected by edrophonium (Pettigrew and Glass, 1985; Gutierrez, 2010).

AUSTRALIAN ELAPIDS Australia contains a diverse array of snakes, with a predominance of elapids, and their bite causes neurotoxic paralysis, myolysis, coagulopathy, renal failure, and microangiopathic hemolytic anemia. These snakes are classified under five major groups: brown snake (Pseudonaja spp.), tiger snake (Notechis spp.), black snake (Pseudechis spp.), death adder (Acanthophis spp.), and taipan (Oxyuranus spp.) consisting 29 species of snakes (White, 2010).). Of these, brown snake bite is the commonest in both the rural and the urban environment, and the inland taipan is the deadliest. Neurotoxicity of the venom of many Australian elapids is responsible for deaths. The venom contains both presynaptic and postsynaptic neurotoxins belonging to high molecular weight b-bungarotoxin types and smaller molecular weight a-bungarotoxin types. The first sign of flaccid paralysis may appear from 1 hour after envenoming to as late as 24 hours, leading to progressive respiratory paralysis requiring ventilatory support. The first signs to appear are cranial nerve palsies with ptosis, external

Viperidae The family Viperidae has relatively long upper jaw fangs which are kept folded but erected upon strike (solenoglyph). Viperidae consists of two subfamiles: Viperinae or “old world vipers” (Atheris, African bush vipers; Bitis, African vipers; Cerastes, horned vipers; Daboia russelii, Russell’s viper; Echis, saw-scaled or carpet vipers) and Crotalinae or “pit vipers” (Cerrophidion, Central American mountain pit vipers, Bothrops, lanceheads; Crotalus, rattlesnakes; Calloselasma rhodostoma, Malayan pit viper; Trimeresurus complex, Asiatic arboreal pit vipers; Agkistrodon, Deinagkistrodon, Hypnale). Viperidae are relatively short, thick-bodied snakes, having a triangular head and characteristic patterns of colored markings on the dorsal surface of the body. The subfamily Crotalinae has a sense organ, the loreal pit organ, situated between the nostril and the eye, which is heat-sensitive to detect warm-blooded prey. A few species of Viperidae, notably Palla’s pit viper (Agkistrodon halys), Sri Lankan and South Indian Daboia russelii; South American rattlesnake Crotalus durissus terrificus, Mamushi or Fu-she Gloydius from China, cause neurotoxic manifestations in man (Mascarenas

VENOMOUS SNAKE BITES, SCORPIONS, AND SPIDERS 993 and Wuster, 2010; Warell, 2010b). Recent clinical, laboRATTLESNAKES (CROTALUS) ratory and neurophysiologic evidence supports neuroThe rattlesnake venom contains mainly enzymes that toxic envenoming in the Sri Lankan hump-nosed pit cause severe local inflammation, necrosis, and severe viper (Hypnale) bite (Kularatne and Ratnatunga, 1999). hemorrhagic syndromes. Several North American species, namely C. atros, C. horridu, C. scutulatus, cause neurologic manifestations. The South American species RUSSELL’S VIPER (DABOIA RUSSELII) C. durissus durissus and C. d. terrificus also have myotoxic and neurotoxic venoms (Chippaux, 2010). The neuThe genus Daboia has two species, the Eastern Russell’s rotoxins are crotamine and crotoxin that block the NMT viper (D. siamensis) distributed in far eastern countries by competitively, antagonised by edrophonium and sucsuch as Thailand, Indonesia, and Myanmar, and the cinylcholine (Vital-Brazil et al., 1979). Reduced release Western Russell’s viper (D. russelii), mainly found in of ACh due to interference with calcium entry or other Sri Lanka and southern India (Wuster, 1998a; Warrell, mechanisms has also been suggested (Howard and 2010b). Envenoming by D. russelii produces frequent Gundersen, 1980). The envenoming manifests as cranial neurotoxic manifestations similar to elapid bites. Studies nerve palsies, myalgia, and muscle weakness. Myokymia in Sri Lanka showed an incidence of neuroparalytic responding to antivenin and calcium has been observed manifestations exceeding 70%, predominantly involving following envenoming by the timber rattlesnake (Brick cranial nerves, manifesting as ptosis and external et al., 1987). ophthalmoplegia and lasting up to 5 days. Weakness of limb muscles and respiratory muscles, however, is extremely rare (Phillips, 1988; Kularatne, 2003). Only SCORPIONS the comorbidities such as bronchial asthma, allergies, anaphylactic reactions to antivenom, or intracranial Scorpion envenoming is a serious public health problem in some regions in the world. In Tunisia, 30 000–45 000 problems demand artificial ventilatory support in mancases are reported per year with 10–100 fatalities (Krifi aging these patients. In Sri Lanka, D. russelii is responsible for frequent bites causing high morbidity and et al., 2005). A similar situation prevails in Mexico, mortality among rural paddy farmers. It is a nocturnal Iran, Algeria, and even in India. Hottentotta tamulus snake, but day biting is frequent during harvest time (Scorpiones: Buthidae), the Indian red scorpion (accordas the snake prefers to rest in the paddy fields during ing to the most recent taxonomic revision) has recently daytime. Envenoming causes severe coagulopathy, been found in Sri Lanka too (Ranawana et al., 2013). Scoracute renal failure, and multiorgan dysfunction. The pions belong to the group Scorpionida and the most dangerous species to man are Centruroides (southern United procoagulant and anticoagulant components of the States, Central America), Tityus (South America), venom cause acute cerebrovascular accidents such as intracerebral hemorrhages and acute ischemic strokes, Androctonus (Africa), Leiurus (Africa and the Middle and in rare situations, ischemia to the pituitary East), and Buthus (Asia). Scorpion venom is a complex gland causing chronic pituitary insufficiency similar to mixture consisting of low molecular weight basic proSheehan’s syndrome (Ameratunga, 1972; Kularatne, teins, neurotoxins, mucus oligopeptidases, nucleotides, 2003; Gawarammana et al., 2009; Antonypillai et al., and amino acids. Unlike most spider or snake venoms, 2011). D. siamensis envenoming, on the other hand, is many scorpion venoms generally lack enzymes or possess low levels of enzymes with the exception of Heterometrus free of neurotoxic manifestations, but there are many scaber. 5-Hydroxytryptanine, proteases, angiotensinase, reports of pituitary insufficiency following its bites (Tun pe et al., 1987; Antonypillai et al., 2011). The mechand succinate-dehydrogenase are found in the venoms anism of neurotoxicity in D. russelii is less clear, but of Mesobuthus tamulus, Centruroides exilicauda, and may be attributed to phospholipase A2 acting presyHeterometrus fulvipes (Gwee et al., 2002). naptically and also postsynaptic toxins (Shelke et al., The main molecular targets of scorpion neuro2002; Gopalan et al., 2007). A study on the molecular toxins are the voltage-gated sodium channels and diversity in venom protein of D. russelii has shown the voltage-gated potassium channels. There are aand b-scorpion toxins acting at different receptor sites. that its phospholipase A2 is of “S” type in contrast to Venom from the Israeli scorpion (Leiurus quinquesD. siamensis which has phospholipase A2 of “N” type to support the differences in clinical manifestations triatus quinquestriatus) has the most lethal of scorpion in these two species (Suzuki et al., 2010). The venom venoms. Other scorpions, including the Indian red scorof D. palaestinae is also known to contain a phosphopion (Mesobuthus tamulus) and the Chinese scorpion lipase A2 that can provoke neurotoxic manifestations (Buthus matensi Karsch), can cause lethal envenoming (Chippaux, 2010). to humans (Gwee et al., 2002). Tityus toxins (TsTx) of

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the Brazilian scorpion Tityus serrulatus have pre- and postsynaptic actions at the NMJ by increasing sodium permeability (Meves et al., 1982). The Asian black scorpions Heterometrus longimanus and Heterometrus spinifer of the family Scorpionidae are the largest in the Southeast Asian region. However, there has been no documentation of the black scorpion causing lethal envenoming in humans.

Clinical manifestations As a result of venom action on the voltage-gated channels, massive release of autonomic neurotransmitters leading to an autonomic storm is a major contributor to the pathophysiology of scorpion envenoming. The clinical manifestations of envenoming by the Buthidae family include sympathetic excitatory effects such as tachycardia, hypertension, arrhythmia, and mydriasis. Parasympathetic effects manifest as excessive salivation, lacrimation, bradycardia, and hypotension. Death is related to cardiac failure and pulmonary edema as a result of massive release of catecholamines from the adrenals and noradrenergic nerve terminals (Bawaskar and Bawaskar, 1982, 2011; Gwee et al., 2002). Envenoming by Hemiscorpion lepturus, the Iranian scorpion, produces dry mouth, thirst, dizziness, vomiting, fever, confusion, convulsions, hypoglycemia, leukocytosis, thrombocytopenia, ST depression in ECG, and severe local envenoming. Centruroides stings produce fasciculations and spasms; Tityus sting may cause acute pancreatitis.

Management of scorpion envenoming The local pain could be alleviated by local infiltration or digital block with 1% lidocaine or peripheral nerve block with 0.25% bupivacaine. Opiates may relieve the symptoms. Severe envenoming may need intensive care. Scorpion antivenoms are available for specific species. a1-Adrenergic receptor blockers, e.g., prazosin, are effective in controlling the autonomic storm. An Indian study used oral prazosin 250 mg for children and 500 mg for adults in repeated doses 3 hourly until the peripheries were cold. The same study found that a combination of prazosin and antivenom was superior to prazosin alone in treating Mesobuthus tamulus envenoming (Bawaskar and Bawaskar, 2011). Management of complications such as arrhythmias, pulmonary edema, and convulsions is also required.

SPIDERS Spiders (Araneae) are an enormous group, comprising ubiquitous arthropod predators found in many environments. They act as biological controls for pests and insects to maintain natural balance. The Order Aranea,

suborder Mygalomorphae and Arneamorphae contain the vast majority of spiders, and about 12 species of spiders stand out as clinically important. These include widow spiders, recluse spiders, banana spiders, and Australian funnel web spiders. The most dangerous are the female widow spiders of the genus Latrodectus, e.g., black widow (L. mactans), grey widow (L. geometricus), American Loxosceles causing cytotoxin-mediated local cutaneous damage, and world’s most toxic, Australian funnel web spiders. In Brazil, three groups of spiders are found: banana spiders (genus Phoneutria; phoneutrism), recluse or violin spiders (genus Loxosceles; loxoscelism), and widow spiders (genus Latrodectus; lactrodectism). Widow spiders are widely distributed in all continents including Australia (Senanayake and Roman, 1992; White, 2008). The subfamilies Ornithoctoninae, Poecilotheriinae, and Selenocosmiinae are found in India and Sri Lanka, but their envenoming does not cause fatalities despite high morbidity due to muscle spasms (Ahmed et al., 2009). Spider venoms are usually a complex mixture of substances containing peptides falling within neuroexcitatory toxins and necrotoxins in recluse spider venom.

Clinical effects of spider bites The dry bite rate could exceed 80% and both neuroexcitatory envenoming and necrotic envenoming do not coexist in the same spider. Most species cause local effects such as pain, mild swelling, and erythema. Systemic symptoms include headache, malaise, nausea, abdominal pain lasting a few days. The toxins responsible for such symptoms are not characterized. Fang marks, if present, lie close together depending on the size of the spider. A few species will cause notable local effects such as distinct lumps or even blistering. The recluse spider venom contains a number of toxins that cause tissue necrosis, directly or indirectly. The necrosis sets in gradually taking days to become established. The widow spiders, banana spiders, and Australian funnel web spiders are known to cause neuroexcitatory effects of envenoming. A subset of recluse spiders can induce hemolysis, DIC, renal failure, shock, liver failure, and multiple organ dysfunction. The widow spider bite causes progressive severe local pain, often with swelling. The pain and swelling migrate proximally associated with sweating, nausea, and hypertension. The clinical picture could mimic acute abdomen or myocardial ischemia. On many occasions, the bites are nonlethal. In contrast, the Australian funnel web spider bite causes immediate pain and rapid onset of systemic manifestations. In 2–5 minutes, the victim develops tingling around the lips and tongue followed by catecholamine storm with piloerection, hypersalivation, lacrimation, hypertension, abdominal pain, nausea, pulmonary

VENOMOUS SNAKE BITES, SCORPIONS, AND SPIDERS 995 edema, and impaired conscious state. Without adequate Clinical manifestations and treatments antivenom therapy, death is likely (White, 2008). The The commonest manifestations of envenoming follow“facies lactrodectismica” is characterized by the flushed, ing bee stings are allergy and anaphylaxis; rarely, myosweating face with painful grimace present in Lactrodcardial infarction and ischemia to visceral organs (bowel ectus envenoming. The patient may develop opisthotonus, infarction) can occur. Wasp stings rarely cause myasthecogwheel neck movements, and “pavor mortis”(fear of nia gravis, allergic encephalomyelopolyradiculoneuritis, death). In the untreated patient, the duration of illness mastocytosis and reversible optic neuropathy (Kularatne varies from 1 to 21 days. The management may demand et al., 2003; Budagoda., 2010). Bee venom can induce a assisted ventilation (Maretic, 1983). In recent literature, weak muscle contracture followed by abolition of inditwo clinical syndromes are described, “latrodectism and rect excitability. The block is irreversible and not antagloxoscelism,” caused by widow spiders (Latrodectus onized by neostigmine. The respiratory paralysis is spp.) and Loxosceles spp., respectively, where latrodectprobably peripheral in origin (Vital-Brazil, 1972). Hornet ism causes pain and autonomic effects while loxoscelism venom probably has both pre- and postsynaptic actions is characterized by formation of necrotic ulcer (Isbister causing NMJ blockage (Kawai and Hori, 1975). and Fan, 2011). Management includes immobilization of the patient and, if retained, stings should be removed carefully to prevent continuous delivery of venom. Attention should Treatment of spider bite be given to all vital signs as anaphylaxis may cause bronReassurance is important. Where available, antivenom is chospasm and hypotension. the most effective treatment for systemic envenoming, particularly in Australian funnel web spider bite, to preTICK PARALYSIS vent deaths. The antivenoms are available in Australia and Brazil (White, 2008). However, the effectiveness In human and veterinary medicine, ticks are important of antivenom against recluse spiders in Brazil in preventreservoirs and vectors of numerous viruses, bacteria, ing tissue necrosis is contestable (White, 2008). and protozoa. Certain tick species cause pathologic and pathophysiologic changes in their hosts after inoculating noninfectious noxious substances, which are genANT, BEE, HORNET, ANDWASP (INSECTA, erally considered to be toxins which could cause HYMENOPTERA) STINGS neuromuscular paralysis. Some 43 tick species in 10 genAnts, bees and wasps constitute a stinging hazard to era including both hard ticks (Ixodidae) and soft ticks humans. The commonest and most severe Hymenoptera (Argasidae) have been incriminated as causing tick stings are caused by members of the family Apidae paralysis (Gothe et al., 1979). A tick embeds itself in (Giant Asian honeybee or Apis dorsata, Africanized the victim’s skin with its barbed hypostome introducing honey bees or killer bee or Apis mellifera scutellata), the salivary toxins to the host. The toxins appear to be Vespidae (e.g., wasp, Vespula vulgaris), American rapidly excreted or metabolized once the tick is removed. yellow jackets (genus Dolichovespula) and hornets The early experiments suggested action of the toxins at (genus Vespa). Only females of Hymenoptera are able the NMJ causing a presynaptic failure to liberate acetylto sting, the sting being a modified ovipositor found at choline (Rose and Gregson, 1956). Subsequent studies the posterior tip of the body. Associated with the sting showed reduction of both amplitude and conduction is the venom gland. Venom glands of bees produce a velocities of mixed motor and sensory nerves mixture of various enzymes, peptides, and amines, (Emmons and McLennan, 1960). The Dermacentor sometime labeled apitoxin; and those of wasps contain and Argas paralysis are generally defined essentially a mixture of histamine-releasing factors, enzymes, as motor polyneuropathies with only limited participahemolysins, neurotoxins, vasodilators, and vasospastic tion of the afferent pathways. However, Ixodes holocyamines. Stings are used for both offense and defense. clus paralysis is of a different mechanism and has been Of practical significance is the fact that the stings of implicated in intra-aural infestation and facial nerve bees are barbed and therefore left embedded at the sting palsy (Gothe et al., 1979; Indudharan et al., 1996). sites together with their associated structures. The sting Weakness usually begins about 5 days after attachapparatus has its own musculature and ganglion which ment of the tick. A prodromal phase is often present, keeps delivering venom even after detachment. Wasps consisting of fatigue, irritability, distal paresthesias, have barbless stings, leaving behind only a puncture and ataxia. An ascending flaccid paralysis develops wound (Franca et al., 1994; Fitzgerald and Flood, 2006; over a period of hours to a day, involving bulbar and Ciszowski and Mietka-Ciszowska, 2007). respiratory muscles. Muscle stretch reflexes are either

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diminished or absent. Although diplopia is common, extraocular palsy is not a usual finding. The clinical features may be mistaken for Guillain–Barre´ syndrome. However, finding a tick, usually hidden by hair in the neck or scalp, provides the clue to the diagnosis. Removal of the tick leads to recovery within 24 hours (Senanayake and Roman, 1992).

OTHER NATURAL TOXINS Ciguatoxin is the commonest form of fish poisoning in the tropics. It is produced by a dinoflagellate, Gambierdiscus toxicus, loosely attached to algae on coral reefs. Ingestion of the flagellate by small fish and maintaining it in the food chain has resulted in more than 400 species of fish harboring the toxins. Clinical features include gastrointestinal and neurologic manifestations, sometimes even causing paralysis of respiratory muscles (Craig, 1980). The view is that ciguatoxin enhances quantal transmitter release at the NMJ due to an abnormally prolonged sodium channel opening in nerve membranes (Molgo et al., 1990). Paralytic shellfish poisoning (PSP) may cause similar manifestations due to saxitoxins produced by dinoflagellates belonging to the Porotogonyaulax species causing high mortality (Rodrigue et al., 1990). The consumption of bivalve molluscs such as mussels, clams, scallops, and oysters that have ingested the dinoflagellate cause acute paralytic illness worldwide. PSP is one of the most severe forms of food poisoning with a high mortality rate, as high as 50% in children (Rodrigue et al., 1990). Within minutes of ingestion of the contaminated shellfish intraoral and circumoral paresthesias occur, which soon spread to the trunk and distal parts of the limbs. Pupils may remain dilated and nonreactive. Respiratory paralysis may cause death. Some crab species, particularly king crab in Southeast Asia, also contain saxitoxins and tetrodotoxins, and their flesh causes poisoning resembling that caused by PSP (Yasumura et al., 1986). Puffer fish and porcupine fish also contain tetrodotoxins which act as sodium channel blockers. Poisoning occurs when the highly toxic liver is used in the preparation of fugu which is consumed to achieve a state of exhilaration. In severe poisoning, the patient develops descending paralysis and respiratory failure; risk of fatality is high. Tetrodotoxin has also been discovered in some species of goby, newt, skin, and eggs of frogs, octopus, shellfish, and starfish (Mosher and Fuhrman, 1984). Ingestion of the flesh of the hawksbill turtle had caused poisoning in India and Sri Lanka. Toxic algae ingested by the turtle is supposed to make its flesh poisonous, and the poisoning causes flaccid paralysis of muscles (Senanayake and Roman, 1992). Conotoxins

are a group of neurotoxic peptides found in the venom of fish-hunting marine snails of the genus Conus. Careless handling of the cone shell has resulted in human fatalities (Cruz et al., 1985). The sting causes numbness at the site which spreads to the rest of the body followed by blurred vision, impaired speech and paralysis of respiratory muscles. The skin secretion of certain frogs which live in the humid rain forests of South America and southern Central America belonging to the family Dendrobatidae are used as dart poisons by Amerindians. It has alkaloids such as batrachotoxin and histrionicotoxin which act on ion channels at the NMJ causing paralysis (Myers and Dally, 1983). The venom of centipedes (Chilopoda) contain neurotoxins which are potent enough to paralyze its prey, but insignificant clinically. These nerotoxins involve G-protein-coupled receptors (Undheim and King, 2011). Bacterial exotoxins such as botulinum toxins and tetanus toxins are known neurotoxins of importance. Botulism commonly results from consumption of canned foods contaminated with Clostridium botulinum which produces toxins that block the release of Ach from cholinergic nerve terminals (Brown, 1981).

MANAGEMENT OF SNAKE BITE Immediate management First aid is important to retard venom absorption. Reassurance of the victim and the immobilization of the bitten limb by using a splint or sling are the important first steps until arrangements are made to take the patient to the nearest medical facility. Tampering with the bite wound or applying a constriction band above it should be avoided (Warrell, 1990; Cheng and Currie, 2004). Pressure immobilization using a crepe bandage has proved effective in animal experiments, but it has not been subjected to formal clinical trials (Sutherland et al., 1979). Distressing and life-threatening manifestations of envenoming may appear before the patient reaches hospital. For severe local pain, oral paracetamol is preferable to aspirin or nonsteroidal anti-inflammatory drugs, which carry a risk of bleeding. Avoiding anything orally is prudent as the patient has a risk of vomiting, and of aspiration and choking due to neuromuscular paralysis. The patient should be laid in the left lateral position with head down to avoid aspiration. The venom could induce anaphylaxis, which should be treated with adrenaline by intramuscular injection followed by antihistamine and hydrocortisone. If cyanosed, or if the respiratory movements are weak, oxygen should be given. If respiratory effort is significantly compromised and the tidal volume

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is falling, a cuffed endotracheal tube should be introduced using a laryngoscope (Warrell, 2010a, b).

The dose regimen and repeated administration should depend on the local guidelines.

Treatment in the hospital

Supportive treatment in neurotoxic envenoming

Any snake bite needs immediate attention. The history, symptoms, and signs must be assessed rapidly to decide appropriate management. The airway, breathing and circulation should be monitored, and if compromised, resuscitation should begin immediately. In the case of neuromuscular paralysis, the patient builds up hypoxemia gradually, but it remains undetected as the patient remains still due to weakness of muscles. Thus, careful monitoring of breathing, paradoxical abdominal breathing, and measurement of tidal volume is essential. The earliest symptoms and signs of neurotoxicity after elapid bites are often blurring of vision, a feeling of heaviness in the eyelids, drowsiness and contraction of the frontalis muscle to keep eyes open. Subsequently, ptosis and double vision can be demonstrated. Patients with generalized rhabdomyolysis may have trismus, stiff tender muscles resistant to passive stretching (Warrell, 2010a, b). The level of consciousness may decline for many reasons. In common krait bite, some patients develop a progressive deep comatose state lasing days that may mimic brain death. However, gradual improvement can be anticipated with sustained life support (Kularatne, 2001). Antivenom is the only specific treatment available that has proved effective against snake envenoming. Antivenom neutralizes the venom antigens in the blood and significantly reverses the coagulopathy. However, its ability to penetrate and neutralize the bound toxins in the NMJ is limited. Thus, reversal of established neurotoxicity is unlikely to happen with antivenom. Ativenom is a refined g immunoglobulin or a fragment of it raised in horses or sheep. The antivenom could be either monovalent or polyvalent, depending on the spectrum of species of snakes. Monovalent antivenom is raised against the venom of a single species and is effective for treating envenoming by that species of snake only. Polyvalent antivenom is raised against the venom of more than one species of snake in a particular geographical region. As antivenom contains foreign proteins, severe allergic reactions can develop. Thus, it should be used only for specific indications. These include hemostatic abnormalities such as incoagulable blood, spontaneous bleeding, thrombocytopenia; cardiovascular abnormalities such as hypotension, arrhythmias; neurotoxic paralysis, rhabdomyolysis, and severe local envenoming. However, depending on the species of snake and type of anivenom available, the indications for therapy may differ from region to region. Antivenom is given as an infusion over 30–60 minutes.

Assisted ventilation is the most important life-saving management measure. With the onset of bulbar and respiratory muscle paralysis, the patient needs assisted ventilation in an intensive care unit. Neurotoxic effects are fully reversible with time, and the duration of ventilation depends on the species of snake. Neurotoxic paralysis is faster in onset lasting about 24 hours in cobra bite, but in common krait bite the onset could be slow and the duration extend a few days (Kularatne, 2001; Kularatne et al., 2009). The anticholinesterase drugs may produce a rapid improvement in neuromuscular transmission in patients envenomed by some species of Asian and African cobras, mambas, death adders, and Malayan krait (Warrell et al., 1983; Watt et al., 1986). The edrophonium test will be useful to detect response, and in positive cases, anticholinesterase drugs can be used to treat the patient. However, there is a risk of acute cholinergic crisis in overdosing. Snake venom ophthalmia should be managed initially by irrigation of the eyes with a large volume of water followed by specific ophthalmologic management.

CONCLUSION Natural neurotoxins continue to be an important health hazard to man, particularly in tropical countries. In the limited space in the globe, with rapid expansion of the human population, a conflict exists between humans and other creatures in nature. This has resulted in an imbalance in ecology and even the extinction of some species from the earth. On the other hand, the identification of neurotoxins from these biological sources has helped in the study of neurophysiology. The use of purified toxins from Elapidae snakes constituted a crucial event in the understanding of the pathophysiology of myasthenia gravis and the myasthenic syndrome. The use of purified AChRs from the electric organ of the electric ray Torpedo californica and the electric eel provided the first quantifiable laboratory diagnostic test for myasthenia gravis. Neurotoxins have already led to the development of several groups of pharmacologic and therapeutic agents, and there is vast potential in the future in this sphere. A testimony to this is provided by the results obtained by the use of botulinum toxin in the treatment of dystonic disorders (Kraft and Lang, 1988; Cohen et al., 1989). Similarly, m-conotoxins have been used to develop new analgesics (Nortan, 2010) and a toxin called “ancrod,” a serine protease derived from the venom of the Malayan pit viper,

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has been used to treat acute ischemic strokes (Del Brutto and Del Brutto, 2011). However, many unanswered questions remain. Observations made in good clinical studies need neurophysiologic and biochemical explanations. For example, the deep comatose state with EEG changes and retrograde memory loss in common krait envenoming has so far remained unexplained. Bridging these gaps in knowledge is necessary. For most of the toxins there are no antidotes. This has hampered the management. Toxinology is a neglected field, and there is lack of enthusiasm in manufacturing good quality antivenoms. Even the available antivenoms seriously lack efficacy and cause severe anaphylaxis upon administration (Warrell, 2008). Neurotoxic paralysis results in death within minutes or hours. Shortage of ventilators and intensive care beds in affected regions in the globe hamper its effective management. Making Ambu bags available in the field, training of volunteers in resuscitation, and transportation of victims are important. In Nepal, an attempt has been made to introduce motor bikes to transport victims of snake bite (Sharma et al., 2004). Finally, a concerted effort should be made to enhance research interests in toxinology and to develop good quality antivenoms to salvage the lives which otherwise would be lost from fatal envenoming.

ACKNOWLEDGMENTS The authors are grateful to Dr. Kalana Maduwage for his assistance in preparation of references and the figure.

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Venomous snake bites, scorpions, and spiders.

Neurologic dysfunction due to natural neurotoxins is an important, but neglected, public health hazard in many parts of the world, particularly in the...
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