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Postgrad MedJ 1998;74:596-599 C The Fellowship of Postgraduate Medicine, 1998 Postgrad Med J: first published as 10.1136/pgmj.74.876.596 on 1 October 1998. Downloaded from Myasthenic syndrome of envenomation: a clinical and neurophysiological study

P S Sanmuganathan

Summary out. The objective was to describe the natural In this prospective study, 65 consecutive history of this reversible muscle weakness. patients with neurological manifestations after snake envenomation, were examined Patients and methods in order to describe the natural history of the reversible nature of muscle weakness. PATIENTS Snake envenoming led to a completely Sixty-five patients with snake envenomation reversible muscle paralysis involving the were studied at the Teaching Hospital, Perad- external ocular muscles with sparing of eniya, in central Sri Lanka, where many snake- the pupils, muscles of mastication, facial bite victims from the main farming provinces muscles, palatal muscles, neck and proxi- are admitted. Over half (36) the patients iden- mal limb muscles. The deep tendon tified the snake when they were bitten and reflexes were preserved with no sensory another 19 patients had killed the offending abnormalities. The muscular weakness snake which was available for identification. usually set in within an hour ofenvenoma- Moreover, patients and relatives were shown tion and lasted up to 10 days, with photographs of venomous and non-venomous fatigability lasting for 12 days. Respiratory Sri Lankan and were carefully ques- muscle paralysis led to ventilatory failure tioned about the identity of the snake that had needing ventilation in severely envenomed bitten the patient. All patients had local and patients. Motor and sensory nerve con- systemic signs of envenomation. duction were normal with normal resting compound motor action potentials on METHODS electromyography. Repetitive nerve All patients were seen within an hour of admis- stimulation gave rise to a decremental sion to hospital. Complete neurological assess- response during high frequency stimula- ment was done on admission and thereafter 12 tion. The edrophonium test gave negative hourly in patients who came into hospital within 24 hours of the bite, followed by daily

results. These manifestations are due to http://pmj.bmj.com/ abnormalities of neuromuscular trans- assessment until all features had resolved. mission and are not typical of myasthenia These neurological assessments were inde- gravis. As the exact pathophysiology of pendently done on each occasion, without the -related is not known, bias of knowing the previous examination find- it is suggested that the neurological mani- ings. Nerve conduction study and repetitive festations of snake envenoming be desig- nerve stimulation (RNS) was carried out in 18 nated a (28%) patients. Edrophonium 10 mg was given myasthenic syndrome. Further on September 26, 2021 by guest. Protected copyright. studies to isolate the and its intravenously to all patients. Haematological mechanism and exact site of and biochemical measurements were made to blocking at monitor for coagulation and renal distur- the neuromuscular junction would pave bances. the way for the development of a novel long-acting neuromuscular blocking agent. Keywords: snake bites; neurotoxicity

Neurotoxic envenoming following snake bite Department of gives rise to a spectrum of clinical manifesta- Figur^e.. 1, Viper Vpea rusel. Medicine, University ofPeradeniya, tions ranging from respiratory failure needing Peradeniya, Sri Lanka assisted ventilation to mild ptosis with fatiga- P S Sanmuganathan bility. Neurological manifestations following snake envenomation have been described in Correspondence to several case histories, each involving motor Dr P S Sanmuganathan, '..:.e..~~~~~~~~~~~~~~~~~...... Department of Medicine and weakness of varying severity.' 2 This study Pharmacology, Floor L, describes, for the first time, results of a Fiur ' Vipe .Vpr russBelWo Royal Hallamshire Hospital, prospective study of 65 patients admitted to Sheffield S 10 2JF, UK hospital with systemic envenomation in whom Accepted 23 April 1998 serial neurological examinations were carried ~~~~~~~~~~~~~~ Snake envenomation 597

Figure 2 Table 1 Distribution and reversibility of muscle ( naja) weakness in 65 patients bitten by snakes

Duration Postgrad Med J: first published as 10.1136/pgmj.74.876.596 on 1 October 1998. Downloaded from n (%) (days) Ptosis 65 (100) 6.5 ± 2.3 Fatigability 65 (100) 9.8 ± 1.9 External ophthalmoplegia 44 (68) 5.7 ± 1.8 Masticatory muscle weakness 31 (48) 3.9 ± 1.0 Bilateral facial muscle weakness 18 (28) 1.6 ± 0.9 ~~~~~~~~~~~~~~~~~~~~~.::..m:...:6; Palatal weakness 12 (18) 1.3 ± 1.1 Weakness of neck flexion 65 (100) 8.2 ± 4.7 Proximal limb muscle weakness 38 (58) 6.5 ± 2.1

patients were nauseated with giddiness and 46 had headache lasting for less than 12 hours; 52 patients complained of diplopia, 22 of whom had difficulty in swallowing; 54 patients TREATMIENT vomited. All patients were treated with a single dose of Abdominal pain was noted by 46 10 ampoule H-affkeine Institute polyspecific patients. No patient lost consciousness. (Vzipera russeli, Naja naja, carinatus, SIGNS caeruleus) , reconstituted Local swelling was observed in 58 (89%) with 100 ml of diluent and further diluted in patients, eight of whom (12%) had necrotic 500 ml of normal saline, infused intravenously wounds at the bite site. Systemic manifesta- over 30 minutes. Patients who passed less than tions were present in all 65 patients. Haemo- 400 ml of urine over 24 hours despite rehydra- static failure, as evidenced by spontaneous sys- tion, and where blood urea was rising were temic bleeding, occurred in 14 (22%) patients managed with fluid restriction, and a salt-free (bleeding gums in 10 patients and bleeding low- diet. Peritoneal dialysis was insti- into the in the other four). tuted when conservative measures were inad- Incoagulable blood was the only clinical sign of equate Patients with ventillatory failure due to coagulopathy in 32 (49%) patients. Oliguria respiratory muscle weakness had intermittent with persistent elevation of blood urea devel- positive pressure ventilation. oped in 24 (37%) patients, eight of whom needed peritoneal dialysis. Results NEUROLOGICAL MANIFESTATIONS Among the 65 patients with neurotoxic enven- The neurological manifestations of snake oming, 49 (75%) were male. The mean age was envenomation are shown in table 1. Deep 31.5 + 14.3 years (range 14-66). Most (78%) reflexes were preserved with no sensory distur- patients were bitten on the feet with another bances. Motor and sensory nerve conduction 184 being bitten on the lower leg. The interval studies were normal with no specific abnormal- http://pmj.bmj.com/ between bite and admission ranged from 25 ity in electromyography. Low-frequency RNS min to 92 h (median 18 h 35 mi). The viper (20 Hz) gave variable muscle action potentials (figure 1) was the offending snake in 36 (55%) with a decremental response in two of the more patients, cobra (figure 2) in 14 (22%), and krait severely envenomed patients. Higher frequency (figure 3) in five (8%); 10 patients were unable RNS (50 Hz) produced a decremental re- to definitely identify the offending snake. sponse, most marked around 6 days after the

bite, which normalised in 10 days. The on September 26, 2021 by guest. Protected copyright. edrophonium test did not give rise to any con- SYMPTOMSbetween bite and admission All patients had marks atrangedthe25~~~~~~~~~...... sitefromof vincing improvement in weakness. min 92.....1fang 3 in.Te iethe bite. Local pain, the commonest symptom, usually started within minutes of the bite. Dur- Discussion ing the (figure~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-next few hours the pain spread-n31)upwardswas---nin5% to involve the whole limb. Thereafter, 62 The snake's venom is stored in glands and injected to kill its natural prey. Snake venom is not a single but a complex mixture of several components, including enzymes, Figure 3 Krait polypeptide , non-toxic , carbo- (Bungarus caeruleus) hydrates, metals, lipids, free amino acids, nucleotides and bionic amines.3 of these components with their various actions leads to the immediate of small . However, when a snake bites a human, the dose of venom in relation to body size is too small to produce this dramatic effect. Snake envenom- ing of humans gives rise to an assortment of clinical manifestations which occur insidiously. Although the procoagulants which activate the clotting cascade do not cause massive fatal intravascular coagulation in human victims, 598 Sanmuganathan

Table 2 Comparison of myasthenia gravis and Lambert-Eaton myasthenic syndrome with snake envenomation Myasthenia gravis Snake envenomation Lambert-Eaton myasthenic syndrome Postgrad Med J: first published as 10.1136/pgmj.74.876.596 on 1 October 1998. Downloaded from Ptosis common common uncommon External ophthalmoplegia common common uncommon Weakness of neck flexion and proximal limb muscles common common common Reflexes preserved preserved absent or decreased Edrophonium test positive negative negative RNS decrement at low frequency decrement at high frequency decrement at low, facilitation at high frequency

they do cause the deposition of microthrombi Myasthenia gravis, Lambert-Eaton and activation of the fibrinolytic system.4 The myasthenic syndrome, and snake envenoma- clinical result of procoagulant activity is a con- tion share similar features, such as ptosis with sumption coagulopathy, resulting in incoagula- fatigability, external ophthalmoplegia, and ble blood in 49% ofpatients. Once the patient's weakness of masticatory, facial and palatal blood is defibrinated, the further action of muscles, but there are also some interesting haemorrhagins, which damage vascular differences, shown in table 2. endothelium5 and cause platelet Snake venom that bind to abnormalities,6 leads to spontaneous systemic receptor sites on the motor haemorrhage in 22% of patients. Micro- endplate produce effects similar to those of thrombi deposition and vasoconstriction of curare and myasthenia gravis.'2 Another group renal vessels with hypotension contribute to of neurotoxins with A2 bind acute tubular .7 Activation of the fibri- presynaptically, thereby depressing transmitter nolytic system which gives rise to intravascular release, and are completely resistant to haemolysis, and disseminated intravascular anticholinesterases.'3 In our patients, high coagulation,8 together with the direct nephro- frequency RNS gave rise to a decremental toxic action9 of venom, lead to acute renal fail- response which was not apparent with low ure in 37% of patients. Proteolytic enzymes frequency RNS. Clinical trials testing anti- present in snake venom are responsible for the drugs have demonstrated both local necrosis which occurs in 12% of patients, favourable'146 and unfavourable7 18 results. while increased vascular permeability causes Venom are immediate local and observed in components species-specific and swelling pain, therefore, there is a variance in the response to 89% of patients in our series. anticholinesterase This study shows the diversity of clinical drugs. Patients in our series manifestations after snake envenomation, with are postulated to have had predominantly special emphasis on neurotoxic manifestations. presynaptic blocking venom components, as Identification of the snakes in this study was they showed no improvement with edropho- done using photographs and verbal descrip- nium. However, the decremental response on tions and we do not therefore intend to corre- high frequency RNS needs further explanation. late any clinical findings with the snake species. http://pmj.bmj.com/ This study describes the waning nature of the Conclusions muscle weakness which suggests the reversible action of snake neurotoxin. However, the onset Clinical observations on these patients point to of weakness was not observed in this study, as a characteristic myasthenic distribution of many patients came to hospital while they were muscle weakness involving external ocular, developing the paralysis. All 65 patients had masticatory, facial, palatal, neck flexor and ptosis with fatigability and weakness of neck proximal limb muscles. As RNS at high on September 26, 2021 by guest. Protected copyright. flexion, starting with ocular and oropharyngeal frequency led to a decremental response and weakness that progressed to involve proximal the outcome of edrophonium testing was nega- limb muscles in 58% of patients. This syn- tive, the features can best be described as a drome ofspared pupillary response, no sensory myasthenic syndrome, at least until the patho- or cerebral abnormalities and preserved deep physiological mechanisms of the neurological reflexes, is probably due to abnormal neuro- manifestations are worked out. muscular transmission. The motor weakness Further laboratory studies are necessary to was completely reversible and lasted for a mean isolate and characterise the neurotoxic compo- period of 5 days. Two patients envenomed by nents of snake venom, which will allow us to the common krait (Bungarus caeruleus) had elucidate the molecular basis of the reversible reversible respiratory muscle paralysis needing proximal muscle weakness. This will pave the assisted ventilation for 18 and 48 hours, way for the development of a novel long-acting respectively. We have previously described the neuromuscular blocking drug. In this context it need for ventilation in a patient envenomed by is worth noting that the five patients enven- the Ceylon krait (Bungarus ceylonicus).'1 Snake omed by B caerulerus, two of whom needed venom neurotoxin causing muscle weakness assisted ventilation, had only neurotoxic fea- due to rhabdomyolysis has been described." tures. Therefore, it would be prudent to isolate Rhabdomyolysis was excluded by the absence the neurotoxic components from krait venom of generalised muscle pain, myoglobinuria and first, as this seems to lack the components of normal serum creatinine phosphokinase and other snake which cause haemostatic, aspartate transaminase activity. renal and vasoactive dysfunction. Snake envenomation 599

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