Toxicon 54 (2009) 421–428 Contents lists available at ScienceDirect Toxicon journal homepage: www.elsevier.com/locate/toxicon Acute ischemic strokes due to bites by Daboia russelii in Sri Lanka – First authenticated case series I. Gawarammana a, *, S. Mendis b, K. Jeganathan b a b Department of Clinical Medicine and South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Sri Lanka Medical Unit, Teaching Hospital, Anuradhapura, Sri Lanka a r t i c l e i n f o a b s t r a c t Article history: Received 12 January 2009 Received in revised form 20 April 2009 Accepted 11 May 2009 Available online 20 May 2009 Bites due to Russell’s Viper (Daboia russelii) are common in Sri Lanka. Commonest haematological manifestation is consumptive coagulopathy and bleeding. Commonest neurological manifestations are ptosis, ophthalmoplegia and rarely respiratory failure which are due to presynaptic inhibition of neuromuscular transmission. There are no authenticated reports of acute ischemic strokes following bites by D. russelii. We report the first authenticated case series of ischemic strokes following bites by D. russelii in Sri Lanka. Keywords: Ischemic strokes Russell’s Viper Sri Lanka Methods: This was a prospective observational study of all atypical neurological manifestations following bites by D. russelii admitted to a hospital in Sri Lanka. We documented clinical features of all atypical neurological manifestations of D. russelii bites and recorded the findings of brain imaging. Results: During a period of 18 months, at one centre, 9 patients out of an estimated 500 victims of D. russelii bites were found to have Computerized Tomographic evidence of single or multiple ischemic (non-haemorrhagic) strokes of medium to large vessel territories of the brain. These patients had either low Glasgow coma scale or hemiparesis within minutes to 4 days following bites. One patient died and another had gross neurological deficit, while others had mild or no neurological deficit at three months. Discussion: This report confirms that ischemic strokes can occur following envenoming by D. russelii. Involvement of multiple medium to large vessel territories and absence of watershed infarctions points to prothrombotic properties of the venom as the putative mechanism. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Bites due to Russell’s viper (Daboia russelii) are common in Sri Lanka, particularly in the North central province of the Island (Kularatne 2003; Seneviratne and Dissanayake 2002; Thorpe et al. 2007). Typically, these bites produce a well characterized constellation of signs and symptoms with coagulopathy (77%), local swelling (92%), renal involvement (18%) and neurotoxicity (78%) (Kularatne * Corresponding author. Tel.: þ94 71 4225081; fax: þ94 81 4479822. E-mail address: indika@sactrc.org (I. Gawarammana). 0041-0101/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.toxicon.2009.05.006 2003). Typical neurotoxic complications include external ophthalmoplegia, ptosis and rarely respiratory failure (Kularatne 2003; Seneviratne and Dissanayake 2002). These complications are due to the presynaptic action of secretory phospholipase A2 (Prijatelj et al. 2008) present in the Russell’s viper venom (RVV). RVV also contains activators of factors V and X (Schiffman et al. 1969) and procoagulant metalloproteases (Mukherjee 2008) (Russell’s viper basic coagulant metalloprotease) that lead to consumptive coagulopathy and bleeding (Aung-Khin et al. 1977) which is diagnosed by inability of whole blood to clot within 20 min in a clean test tube (termed ‘positive WBCT20) (Warrell et al. 1977). 422 I. Gawarammana et al. / Toxicon 54 (2009) 421–428 Treatment of D. russelii bites in Sri Lanka includes administration of Indian anti snake venom (ASV) which is raised against Indian rather than Sri Lankan D. russelii viper venom. Severely envenomed patients with RVV have depleted fibrinogen, factors V, X and XIIIa, plasminogen and platelets leading to haemorrhages, the commonest haematological complication of RV bites (Phillips et al. 1988; Than-Than et al. 1988). Theoretically, victims of D. russelii bites can develop thrombotic complications during the early coagulative phase. Even though there are published reports of bleeding in to viscera including the brain due to defibrinogenimea (Kularatne 2003; Phillips et al. 1988; Seneviratne and Dissanayake 2002; Than-Than et al. 1989), there are no authenticated published reports of ischemic strokes following bites due to D. russelii nor have D. russelii bites been cited as a cause of ischemic strokes in widely read text. We present the first authenticated case series of acute ischemic strokes following bites due to D. russelii. 2. Materials and methods This was a prospective case series of all suspected D. russelii bites with atypical neurological complications admitted to General Hospital Anuradhapura (GHA), Sri Lanka from February 2007 to August 2008. All patients were examined for atypical neurological signs such as changes in Glasgow Coma Scale (Glasgow Coma Scale), hemiparesis and cranial nerve palsies. Patients with atypical neurological features were subjected to brain imaging by computed tomography (CT). All patients who presented with typical neurological presentations (external ophthalmoplegia, ptosis and respiratory failure) and normal GCS with no hemiparesis or cranial nerve palsies were excluded from further analysis. 3. Snake identification 7 patients presented with the killed snake specimens (cases 1–7) and were identified by KJ. Sri Lanka has 6 species of venomous snakes: Russell’s viper (D. russelii), Cobra (Naja naja), Kraits (Bangarus caeruleaus and Bangarus ceylonicus), Saw scaled viper (Echis carinatus) and Hump nosed viper (Hypnale spp.). These snakes give rise to characteristic constellation of clinical features which enables the clinicians to identify the offending snake with minimal error. D. russelii gives rise to local swelling, neurological features (ptosis and ophthalmoplegia), coagulopathy and renal failure (Kularatne 2003); cobra bites lead to severe local necrosis and neurological features (Theakston et al. 1990). Kraits give rise to neurological features (Kularatne 2002) (ptosis, ophthalmoplegia and respiratory failure) and no coagulopathy while the Hump Nosed Viper leads to local necrosis and blister formation with no neurological features (Ariaratnam et al. 2008). Pathmeswaran et al. (Pathmeswaran et al. 2006) developed a clinical scoring system using these features to identify D. russelii with 70% sensitivity and 99% specificity for epidemiological surveys. Cases 8 and 9 had coagulopathy, ptosis and ophthalmoplegia but no local necrosis or blister formation, the same clinical features used in the study by Pathmeswaran, which almost confirms that these two patients were bitten by D. russelii. 4. Results There were 10 patients with atypical neurological complications in addition to ptosis and opththalmoplegia following bites due to D. russelii. 9 patients (see below Table 1) had ischemic strokes while one patient had a haemorrhagic stroke and was excluded from the study. 4.1. Case 1 A 56-year-old man was bitten by a D. russelii on the left foot. He was admitted to GHA with a GCS of 15/15 and had no ptosis or ophthalmoplegia. His admission WBCT20 was negative. There was swelling of the site of the bite. Admission pulse was 72 beats per minute and the blood pressure was 120/76 mm Hg. Within 7 h of the bite, he developed bilateral ptosis and his GCS dropped to 13/15. At this point he had normal cardiovascular status and the ECG revealed a sinus rhythm. Table1 Summary of clinical features. Case Gender Age Typical signs Atypical signs on admission GCS Weakness No Left hemiparesis Left hemiparesis and cerebral oedema Onset time Infarction/s detected on brain CT Recovery 7h <1 h 4 days Cerebellum, B/L frontal and parietal R deep parietal/lentiform nucleus R frontal and R cerebellum Complete Complete Complete Dependent 1 2 3 M M F 56 37 45 P,O P,O P,O 13 14 14 4 F 45 P,O 10, convulsions Within minutes 5 M 28 P,O 6, convulsions Minutes 6 M 53 P,O 14 2h Left caudate B/L occipital and gross cerebral oedema Left and right middle cerebral artery territory and B/L occipital lobes Multiple B/L cortical and cerebellum 7 M 35 P,O 9 45 mins Left frontal lobe 8 9 M M 39 54 P,O P,O 13 15 Few minutes 1 h, 45 min Multiple, cerebellum and occipital R parietal-temporal Left hemiparesis M ¼ Male; F ¼ Female; P ¼ Ptosis; O ¼ Ophthalmoplegia; GCS ¼ Glasgow Coma Scale; B/L ¼ Bilateral. Died Residual motor weakness Expressive dysphasia Lost to follow up Complete I. Gawarammana et al. / Toxicon 54 (2009) 421–428 The WBCT20 turned positive and he was treated with 20 vials of ASV. The repeat WBCT20 6 h after was negative. CT scan of the brain was performed which revealed acute multiple bilateral cerebral (both frontal and parietal lobes) and cerebella infarctions (Fig. 1; case 1; images 1 and 2). His serum creatinine peaked (4 mmol/L) on day 6 and settled afterwards. He was noted to have a raised blood pressure (150/90) on 423 discharge. He made a good clinical recovery and his neurological examination was normal at the three months clinic follow up. 4.2. Case 2 A 37-year-old man was transferred to GHA following a bite by a D. russelii. He had presented with confusion, Fig. 1. CT images of brain. Infarctions are indicated by arrows. 424 I. Gawarammana et al. / Toxicon 54 (2009) 421–428 Fig. 1. (Continued) hematuria and a positive WBCT20 when he was admitted to the referring hospital where he had been treated with 10 vials of ASV. On arrival to the GHA his GCS was 14/15 and was confused. He had by then developed bilateral ptosis and ophthalmoplegia. On further examination he had left hemiparesis (power 3/5 and an extensor plantar response on the left side). He had normal pulse and blood pressure and his ECG was normal. His WBCT20 was negative around 6 h after the first dose and further ASV was not administered. The CT brain (Fig. 1; case 2; image 1) performed 2 days after the bite revealed an acute right-sided deep parietal (lentiform nucleus) infarction. He had no neurological weakness at 3 months follow up. 4.3. Case 3 A 45-year-old woman was admitted within 2 h following a D. russelii bite. She had bi lateral ptosis, ophthalmoplegia and a positive WBCT20 on admission to GHA. Her pulse, blood pressure and the ECG were normal. She was treated with 20 vials of ASV. 6 h after the ASV infusion, the WBCT20 was negative. On day 4, she was noted to have mild confusion and weakness (4/5) of the left upper and I. Gawarammana et al. / Toxicon 54 (2009) 421–428 lower limbs. Her blood pressure was normal and the ECG revealed a sinus rhythm. The CT scan (Fig. 1; case 3; images 1 and 2) of the brain revealed an acute infarction in the right frontal lobe and the right cerebellum. She was discharged alive and noted to have no residual weakness at three months clinic follow. 4.4. Case 4 A 45-year-old previously healthy female was bitten by D. russelii on the right foot. She developed generalized tonic clonic seizures on her way to the local hospital and was noted to be drowsy. Her WBCT20 had been positive. She was then transferred to GHA within 3 h with a GCS of 10/15 and spontaneous bleeding from her gums. She had normal pulse, blood pressure and the ECG was normal. She had ptosis and ophthalmoplegia and was started on 20 vials of ASV. Her GCS further reduced to 8/15 upon which she was electively intubated and ventilated as she could not protect her airway. The repeat WBCT20 at 6 h after the first dose was negative. CT scan of the brain (Fig. 1; case 4; images 1 and 2) done 4 days after the bite revealed acute ischemic infarctions of the head of the left caudate nucleus and right occipital lobe along with cerebral oedema. Her GCS did not improve and a repeated CT demonstrated worsening cerebral oedema. She was discharged home and was severely handicapped (unable to walk, talk and attend to herself) at three months. 4.5. Case 5 A 28-year-old man was bitten by a D. russelii and was brought to the local hospital soon afterwards. He has been intubated on admission as his respiratory system was compromised. His WBCT20 was positive and was treated with 20 vials of ASV and transferred to GHA soon afterwards. He developed generalized tonic clonic seizures on the way to GHA. His GCS was 6/15 and had gum bleeding, conjunctival haemorrhages and hematuria and normal blood pressure. He deteriorated further and did not recover consciousness. CT scan of the brain (Fig. 1; case 5; image 1) performed within 24 h of the bite revealed infarctions of left parietal lobe and bilateral occipital lobes. His repeat WBCT20 was negative. He became hypotensive and died 5 days after the bite. 425 ischemic infarctions (Fig. 1; case 6; images 1 and 2). ECG (Fig. 1; case 6; image 3) done on the second day of the bite revealed T wave inversions of lead II, III and aVF and his troponin T was positive. He developed acute renal failure (serum creatinine peaked on day 4) and was treated with 3 days of peritoneal dialysis. He had residual motor weakness at discharge and was referred to the cardiology clinic and was lost to follow up. 4.7. Case 7 A 35-year-old farmer was bitten by a D. russelii in the paddy field. He was brought to the hospital within 45 min of the event. He had bilateral ptosis and a low GCS (9/15). His blood pressure was 110/70 mm Hg and admission ECG revealed sinus rhythm. There was bleeding from the canula sites and the WBCT20 was positive. He was treated with 20 vials of ASV soon after admission. Within 6 h, the WBCT20 became negative. Within 24 h his GCS became normal. However he was noted to have expressive dysphasia. CT scan of the brain (Fig. 1; case 7; image 1) performed revealed an ischemic infarction of the left frontal lobe. Patient had no motor weakness of the limbs and was found to have expressive dysphasia at three months follow up. 4.8. Case 8 A 39-year-old man was admitted following a bite by suspected D. russelii on the left foot. He became drowsy soon afterwards and was brought to the emergency department by his relatives. On admission his GCS was 13/15 and the bitten site was swollen. He was later noted to have bi lateral ptosis and ophthalmoplegia. His blood pressure and the ECG were normal. His WBCT20 was positive and had no blistering or necrosis of the site of the bite. He was treated with ASV 20 vials. Within 6 h the WBCT20 became negative. CT brain (Fig. 1; case 8; images 1, 2 and 3) was performed which revealed multiple infarctions involving the cerebellum and occipital regions with peripheral oedema. He had residual motor weakness at discharge and was lost to follow up. 4.9. Case 9 4.6. Case 6 A 53-year-old male presented within 2 h after a bite by a D. russelii on the left foot. There was swelling around the site of the bite along with bilateral ptosis and ophthalmoplegia. His GCS was 14/15 and blood pressure 90/ 60 mm Hg. His WBCT20 was positive and was started on 20 vials of ASV. Admission ECG was normal. His GCS dropped to 12 within 10 h after the bite while maintaining normal cardiovascular functions. His WBCT20 was still positive at this point and a further 20 vials of the ASV was administered. WBCT20 became negative 6 h after the second dose of ASV. After 24 h, his GCS dropped further to 10/15 and the CT brain revealed multiple bilateral cortical and cerebella A 54-year-old man was admitted to General Hospital Anuradhapura (GHA) following a suspected D. russelii bite on the right foot which was swollen. On admission his cardiovascular status and the ECG were normal. His GCS was 15/15 and had no neurological weakness. His admission WBCT20 was negative. 1 h and 45 min after the bite, he developed sudden weakness of the left side of the body. At this time his WBCT20 was positive and was also noted to have ptosis and ophthalmoplegia. There was no blistering or necrosis of the site of the bite. He was treated with ASV 20 vials and his WBCT20 became negative 11 h after the bite. The CT brain (no images available) revealed an acute parieto-temporal infarction. He had complete recovery at three months follow up. 426 I. Gawarammana et al. / Toxicon 54 (2009) 421–428 5. Incidence Accurate incidence of these events could not be calculated as the total number of Daboia russelii bite victims admitted during the study could not be counted reliably. During this period, 35% of snake bite admissions to the emergency treatment unit, where an ASV dose finding study was underway were due to D. russelii. From 2002 onwards, GHA has received around 1000 cases of snake bites accounting for an estimate of 350 of D. russelii bites each year. This gives an estimate of 500 viper bites during the 18 month period and hence the incidence could be conservatively estimated to be 1.8%. 6. Management All patients with ischemic strokes were started on aspirin 75 mg daily after the clotting abnormality was resolved. All patients were referred for physiotherapy. All were subjected to 2 D echocardiograms and carotid duplex studies which were normal. Patient in case 1 was started on captopril and atorvastatin. Patient in case 6 was started on nitrates and was referred to the cardiology department for follow up. All patients were treated with polyvalent anti snake venom (VINS Bioproduct, Andra Pradesh, India) when one or more of the three indications (neurological manifestations, coagulopathy (20WBCT) or local swelling) was present as per guidelines given by Ministry of Healthcare and Nutrition of Sri Lanka (Anonymous 2007). However, ASV administration has deviated somewhat, and physicians increasingly use 20 vials instead of the 10 vials recommended in the national guidelines due to perceived lack of benefit. 7. Discussion Cases 1–9 demonstrate that bites due to D. russelii can produce ischemic infarctions of the brain. Confusion, mild reduction in GCS or hemiparesis was present in all the patients. These features are not seen in typical cases of D. russelii bites and the occurrence of which should initiate further investigation with brain imaging. The onset of the event may be as early as soon after the bite, within a few hours or may occur as late as 4 days after the bite. The incidence was based on the estimated number of total admissions to the 2 medical units of the hospital. Our estimate of number of annual admissions is comparable to the 336 cases received over 2 years to a single unit during the mid nineties by Kularatne (Kularatne 2003). Ischemic strokes attributable to both D. russelii and Daboia siamensis have been reported in the past. Ameratunga reported the first arterial occlusion (middle cerebral artery; (MCA)) following a suspected D. russelii bite in SriLanka (Ameratunga 1972). Even though the snake was not identified by the author, the clinical features were consistent with a bite by a D. russelii. Panicker et al reported of a ischemic stroke of the left frontal lobe 2 h after a bite by a D. russelii in India (Panicker and Madhusudanan 2000). Small and medium sized multiple arterial thrombosis were detected in 2 of the 18 patients with D. siamensis bites in a retrospective survey in Taiwan by Hung et al in 2002(Hung et al. 2002a). These events occurred within 2–4 h and included multiple cerebral infarctions and myocardial infarction. Ischemic strokes have also been reported following bites by other viper species. Lee et al reported a brainstem stroke following a Korean viper bite (Lee et al. 2001). Bashir reported an ischemic stroke in a 13-year-old girl 10 h after a suspected Echis carinatus bite in Saudi Arabia. Digital subtraction angiography performed 2 weeks later revealed changes compatible with thrombosis of supraclenoid internal carotid artery (Bashir and Jinkins 1985). Aravanis reported a case of ST segment elevation myocardial infarction soon after a suspected bite by either of Vipera barus, Vipera ammodytes or Vipera lepetine in Greece (Aravanis et al. 1982). This 17-year-old girl also had clinical evidence of a stroke 4 days afterwards. Even though, ischemic strokes are rare following bites by snakes of the Russell’s viper complex, acute thrombotic strokes are common following bites by the crotalid, Bothrops lanceolatus in Martinique (Merle et al. 2005; Thomas et al. 2006; Thomas et al. 1998). In their report, Thomas et al reported a high incidence (42%) of thrombotic events (myocardial infarction, cerebral infarctions and pulmonary infarctions) in patients who were untreated or treated later than 8 h post bite (Thomas et al. 1998). The mean time to develop these events was 36 h (range 7 h to 4 days). Further, a case of multiple cerebral infarctions has been reported following a bite by Bothrops caribbaeus in Saint Lucia (Numeric et al. 2002). Most of the ischemic strokes reported in literature involve medium to large vessels. This phenomenon is in favour of RVV induced thrombosis rather than any other possibility such as hypotension or vasculitis as the putative mechanism. The 18-year-old girl reported by Ameratunge had arteriographic evidence of middle cerebral artery occlusion while the 21 year old reported by Panicker developed a large frontal lobe infarction (Ameratunga 1972; Panicker and Madhusudanan 2000). Even though the latter patient had a brief period of hypotension (80 mm Hg), the description of the CT (images not presented) is of a large frontal lobe infarction, a large vessel occlusion, rather than a watershed infarction as a consequence of hypotension. Further, the thrombotic events such as myocardial, pulmonary and occipital infarctions following B. lanceolatus and B. caribbaeus are due to thrombosis of medium to large arteries. If these events are due to a predisposing vascular anomaly of the individual patient, the infarctions would most probably involve a single territory. In the arteriographic demonstration by Ameratunge, in addition to the complete occlusion of MCA, there was partial occlusion of angular and temporal branches. Bites due to Formosan Russell’s viper (D. siamensis; formerly D. russelii formosensis) have also been reported to lead to multiple large vessel infarctions (Hung et al. 2002b). B. lanceolatus and B. caribbaeus too have been reported to cause multiple thrombotic occlusions involving different arterial territories (cerebral vascular, coronary and pulmonary). In the present study, 7 of the 9 patients developed multiple strokes, indicating a generalized prothrombotic tendency. I. Gawarammana et al. / Toxicon 54 (2009) 421–428 Further, thrombotic events occurring in up to 42% of bites by B. lanceolatus indicate that the phenomenon is most likely due to generalized prothrombotic action of the venom rather than the existence of a common prothrombotic tendency in these patients. None of the authors cited in the present discussion looked further for a cause of inherent hypercoagulable state in these patients and the cause of thrombosis was temporally attributed to the procoagulant properties of the venom. The timing of the stroke in relation to the bite too would add further insight to the cause of the phenomenon. In patients reported by both Ameratunga and Panicker, stroke occurred soon after the bite. 3 of the 9 cases in the present study, the stroke occurred within minutes of the bite while 7 out of the 9 cases in the present study, the stroke occurred in less than two hours of the bite. This feature, together with absence of watershed infarctions favours acute thrombosis over hypotension, vasculitis or vaso constriction as the putative mechanism. However, strokes due to B. lanceolatus, occur at a later stage (mean time 36 h) after the bites, a phenomenon that needs further investigations. Further evidence for the thrombotic theory could be seen in a few experimental models. An in vitro model of haemostasis using fibrinopeptide and platelet factor 4 as markers of thrombosis demonstrated dose dependent clot formation (Lorenz et al. 1992) following incubation of whole blood with RVV. Injection of RVV venom has shown massive coagulation of blood within hearts and great vessels of small animals(Aung-Khin et al. 1977). Human autopsy studies have revealed deposition of fibrin microthrombi in many organs including the brain following bites due to Burmese viper (Than-Than et al. 1989). Whether, these microthrombi occur in all cases of D. russelii and remain clinically silent and if the large occlusions are part of a spectrum of the same disorder is unknown. Non bacterial thrombotic endocarditis was reported in an autopsy study following a suspected D. russelii bite in India (Singh et al. 1998). This patient arrived in hospital 3 days after the bite in acute renal failure. The autopsy revealed large friable vegetations (0.5–0.8 cm) attached to the aortic valve and the brain, spleen and kidneys revealed small multiple embolic infarcts, pointing to an embolic phenomenon from the vegetations, rather than in situ thrombosis. It is not clear if the vegetations were due to an effect of the venom or the altered hemodynamics of this patient due to renal failure and gangrene. None of the patients in the present series had echo-cardiographic evidence of vegetations. Acute hypotension may cause these strokes in susceptible patients. Isoforms of phospholipase A2, may potentially lead to vaso dilatation and shock (Warrell 1989). Cases of hypotension and shock have been reported following bites due to D. siamensis (Myint-Lwin et al. 1985; Swe- et al. 1997; Tun-Pe et al. 1987). Further, a canine model demonstrated hypotension following intravenous administration of RVV (Thamaree et al. 2000). None of the 9 patients in the current series had hypotension during the hospital stay. Hypotension generally gives rise to watershed infarctions. None of the patients had watershed infarctions visible on CT scans, thus excluding hypotension as the major cause of this phenomenon. 427 Vasculitis, a theory that has been entertained by some authors (Panicker and Madhusudanan 2000), induced by the venom is an unlikely event as some patients developed these events within minutes after the bite. There are two important questions that need to be addressed with the emergence of this new phenomenon. First, the lack of reports of this phenomenon despite numerous publications on viper bites in Sri Lanka needs investigation. CT scans became available in 2006–07 at Anuradhapura and most cases of hemiparesis would have been attributed to haemorrhages. Personnel communication with some physicians further confirmed this theory. As these events occur soon after the bite, it may also be argued that the ensuing coagulopathy causes lysis of the young thrombi and remain clinically undetectable. A further explanation may be occurrence of thrombosis of silent areas of the brain that may not manifest clinically. Second, why only a smaller number of victims seem to develop this phenomenon is another interesting question. There may be differences of venom composition of the snakes due to geographical variations of the vipers, even though this has not been proven in Sri Lanka. Tun-Pe et al. reported an association of snake length and severity of systemic envenoming amongst patients bitten by D. siamensis in Myanmar (Tun-Pe et al. 1991) even though a previous study failed to show a similar association (Myint-Lwin et al. 1985). However, the former paper did not report of thrombotic strokes in these patients. 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