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Original Article
Comparative study of electrophysiological changes in snake bites Patwari Panduranga, S. A. Sangle, Abhay A. Mane, Suyog Doshi, D. B. Kadam Department of Medicine, BJ Medical College and Sassoon General Hospital, Pune, Maharashtra, India
ABSTRACT Aims: To study and compare the electrophysiological changes in neuroparalytic or vasculotoxic snakebites. Materials and Methods: 40 patients who had a definite history of snakebite, either vasculotoxic or neuroparalytic, were selected. They were grouped as Group A, 20 patients having a neuroparalytic snakebite with definite envenomation at the time of admission, and Group B, 20 patients having a vasculotoxic snakebite with definite envenomation at the time of admission. All patients underwent a detailed clinical examination, all relevant investigations and nerve conduction studies according to protocol. Results: In this study, we noticed that the motor nerve conduction amplitude, conduction velocity and distal latency were within normal limits in both the groups. On RNS (repetitive nerve stimulation study) of facial and median nerves, a decremental response was seen in 13 (65%) patients in facial nerve and in 7 (35%) patients in median nerve in Group A; while, the same response was seen in 8 (40%) patients in facial nerve and 3 (15%) patients in median nerve in Group B. A post exercise decremental response was seen in 13 (65%) patients in median nerve and 16 (80%) patients in facial nerve in Group A; and, in 3 (15%) patients in median nerve and 8 (40%) patients in facial nerve in Group B. Conclusions: In our study, we noticed that the decremental response on RNS was not only present in neuroparalytic snake bite (post-synaptic neuromuscular blockade) but also in vasculotoxic snakebite [pre-synaptic neuromuscular blockade] (seen in Russel’s viper). Key words: Facial nerve; median nerve; repetitive nerve stimulation study; snake bite
Introduction
adder (Vipera berus)[3,4] and the nose‑horned viper (Vipera ammodytes).[5]
Neurotoxicity is a well‑known feature of envenoming due to elapids (family Elapidae) such as kraits (Bungarus spp.) and cobras (Naja spp). Although considered relatively less common with true vipers (family Viperidae), neurotoxicity due to beta‑neurotoxins, mostly neurotoxic phospholipase A2 toxins[1] (PLA2s), is well recognized in envenoming with the Russell’s viper (Daboia russelii; found in Sri Lanka and South India), the asp viper (Vipera aspis),[2] the Access this article online Website: www.neurologyindia.com DOI: 10.4103/0028-3886.158214 PMID: xxxxx
Quick Response Code
Most of the electrophysiological studies have been performed on patients suffering from neuroparalytic snake bite (for example, krait and cobra), but the studies documenting electrophysiological abnormalities in patients with vasculotoxic snake bites (Viper) are few. Neurological manifestations (electrophysiological abnormalities) due to a viper bite are usually reported from South India and Sri Lanka but have not been reported from Western India. This study aims to document the neurological manifestations and electrophysiological abnormalities in cases of vasculotoxic snakebite from western India. The defective neuromuscular junction (NMJ) transmission can be pre‑synaptic or post‑synaptic. The pre‑synaptically active neurotoxins (beta‑neurotoxins, mainly neurotoxic phospholipase A2 toxins, bind to the motor nerve terminals, leading to the depletion of synaptic acetylcholine (Ach)
Address for correspondence: Dr. Patwari Panduranga, Room No. 506, Resident Quarters, BJGMC and SGH, Pune - 411 001, Maharashtra, India. E-mail: [email protected]
378
Neurology India / May 2015 / Volume 63 / Issue 3
[Downloaded free from http://www.neurologyindia.com on Tuesday, June 09, 2015, IP: 61.16.135.116]
Panduranga, et al.: Comparative study of electrophysiological changes in snake bites
vesicles, resulting in impaired release of ACh, and later, leading to degeneration of the motor nerve terminal.[6] The post‑synaptically active neurotoxins (alpha‑neurotoxins) bind to the post‑synaptic muscle nicotinic acetyl choline receptor (nAChRs). They resemble the action of d‑tubocurarine (dTC). dTC classically produces a reversible, non‑depolarising post‑synaptic block by competitive inhibition of ACh binding to the muscle nAChR.[6] In this type of toxicity, the antivenom may facilitate dissociation of the toxin from the ACh receptor and accelerate recovery[7] and a clinical response to acetycholineesterase inhibitors (AChEIs), similar to that seen in myasthenia gravis, is more likely. The recent insights into neuro-muscular junction (NMJ) transmission have enabled better and more comprehensive characterization of the more recently described toxins. Candoxin, a novel toxin isolated from the venom of the Malayan or blue krait (Bungarus candidus), is a non‑conventional three‑finger toxin (3FTX) with structural similarities to alpha‑bungarotoxin.[8,9] However, in contrast to the nearly irreversible blockade produced by alpha‑bungarotoxin, candoxin produces a readily reversible block of the post‑synaptic nAChR. In addition, candoxin also inhibits the pre‑synaptic neuronal AChRs and produces tetany and tetanic fade on rapid repetitive stimulation.[8,9]
Subjects and Methods This study was conducted in the Department of Medicine, from September 2011 to August 2013. A synopsis of the study protocol was submitted to the Institutional Ethical Committee and approval was obtained. Patients were selected from the ward and medical ICU of the hospital. In the study, patients having a definite history of snake bite, either vasculotoxic or neuroparalytic, were included. Patients with unknown bites and snake bites without definite envenomation were excluded from the study. The total sample size of 40 was divided into two groups of 20 each (Group A: Neuroparalytic snake bite patients, Group B: Vasculotoxic snake bite patients). The study protocol was explained in detail to all the subjects. Informed written consent was taken from the subjects willing to participate in the study. A questionnaire was designed to obtain their basic clinical information. A nerve conduction study was conducted at a fixed room temperature of 300C within 6 to 10hrs after the patient’s hospitalization.
Assessment of Patient Clinical evaluation The patients were asked questions regarding symptoms of the snake bite at the time of admission; patients with a neuroparalytic snakebite, presenting with ptosis, respiratory distress, neck muscle weakness and respiratory paralysis were
included in Group A. Patients with vasculotoxic snakebite presenting with bleeding manifestations (haematuria), extensive cellulitis at the site of bite, prolonged bleeding time (BT), clotting time (CT) and 20 min whole blood clotting time (WBCT) were included in Group B. A detailed history, general examination and neurological examination were carried out in all the patients selected for the study. The offending snake was identified by examination of the dead snake brought by the patients at the time of admission, or by the photograph of the snake. The patients with a definite history of snakebite, with either neuroparalytic or vasculotoxic manifestations, who were not able to identify the snake, or did not bring the dead snake along with them, were classified as patients having an unidentified snakebite. Patients were inducted into the study regardless of whether or not the antisnake venom (ASV) had already been administered. Patients who had already received neostigmine were also included in the study. The relevant laboratory investigations were done on the day of admission. Electrophysiological evaluation of peripheral nerve function The methodology adopted for measurement of nerve conduction parameters was as follows: The patients underwent nerve conduction studies. Nerve conduction parameters were measured by using the standard RMS ALERON 401 machine (Recorders and Medicare systems, India) in the Department of Medicine. Recordings were done using the standard procedure such as temperature control (32‑34 oC), careful distance measurements and recording of well‑defined and artefact‑free responses. M o t o r n e r v e c o n d u c t i o n a n d re p e t i t i v e n e r v e stimulation (RNS) were performed on median and facial nerves of either side. The procedure was carried out by using surface electrodes. The amplitude and latency of the motor action potential and velocity of conduction in the concerned nerve were recorded. After this motor nerve conduction, a repetitive nerve stimulation (RNS) study was performed. The nerves selected for RNS were the facial and median nerves. In this study, the nerve was stimulated repeatedly at either 3 cycles per second [slow RNS] (5 such stimulations were given); or, at 30 cycles per second [rapid RNS] (5‑100 stimuli were given). The action potentials resulting as a consequence of this repeated stimulation were sequentially recorded and a comparison was made between the amplitude of the first (s1) and the fourth (s4) action potentials to find out if decrement was present. If the results of this test were borderline, the test was repeated after voluntary muscle activity for 30 seconds, or if this was not possible (in comatose patients), the muscle was stimulated repeatedly to stimulate voluntary
Neurology India / May 2015 / Volume 63 / Issue 3
379
[Downloaded free from http://www.neurologyindia.com on Tuesday, June 09, 2015, IP: 61.16.135.116]
Panduranga, et al.: Comparative study of electrophysiological changes in snake bites
muscle contraction and the repetitive stimulation test was performed again. This record constituted the post-tetanic action potential study. As per the standard protocol, a decrement was considered significant if s4/s1 (i.e., the difference in the amplitude between the fourth and first stimuli during repetitive stimulation study) was more than 10% (i.e., a decrement of 10%). On testing at 30 cycles per second, a decrement of more than 20% was considered significant. Statistical analysis The data was managed in a Microsoft excel spreadsheet. General informative tables were prepared with mean and standard deviation. Scatter plot was used to observe correlation between the parameters. Demographics and general information like the count, average and percentage figures for various parameters, with all permutations and combinations, were calculated on Microsoft Excel sheets. A P
Original Article
Comparative study of electrophysiological changes in snake bites Patwari Panduranga, S. A. Sangle, Abhay A. Mane, Suyog Doshi, D. B. Kadam Department of Medicine, BJ Medical College and Sassoon General Hospital, Pune, Maharashtra, India
ABSTRACT Aims: To study and compare the electrophysiological changes in neuroparalytic or vasculotoxic snakebites. Materials and Methods: 40 patients who had a definite history of snakebite, either vasculotoxic or neuroparalytic, were selected. They were grouped as Group A, 20 patients having a neuroparalytic snakebite with definite envenomation at the time of admission, and Group B, 20 patients having a vasculotoxic snakebite with definite envenomation at the time of admission. All patients underwent a detailed clinical examination, all relevant investigations and nerve conduction studies according to protocol. Results: In this study, we noticed that the motor nerve conduction amplitude, conduction velocity and distal latency were within normal limits in both the groups. On RNS (repetitive nerve stimulation study) of facial and median nerves, a decremental response was seen in 13 (65%) patients in facial nerve and in 7 (35%) patients in median nerve in Group A; while, the same response was seen in 8 (40%) patients in facial nerve and 3 (15%) patients in median nerve in Group B. A post exercise decremental response was seen in 13 (65%) patients in median nerve and 16 (80%) patients in facial nerve in Group A; and, in 3 (15%) patients in median nerve and 8 (40%) patients in facial nerve in Group B. Conclusions: In our study, we noticed that the decremental response on RNS was not only present in neuroparalytic snake bite (post-synaptic neuromuscular blockade) but also in vasculotoxic snakebite [pre-synaptic neuromuscular blockade] (seen in Russel’s viper). Key words: Facial nerve; median nerve; repetitive nerve stimulation study; snake bite
Introduction
adder (Vipera berus)[3,4] and the nose‑horned viper (Vipera ammodytes).[5]
Neurotoxicity is a well‑known feature of envenoming due to elapids (family Elapidae) such as kraits (Bungarus spp.) and cobras (Naja spp). Although considered relatively less common with true vipers (family Viperidae), neurotoxicity due to beta‑neurotoxins, mostly neurotoxic phospholipase A2 toxins[1] (PLA2s), is well recognized in envenoming with the Russell’s viper (Daboia russelii; found in Sri Lanka and South India), the asp viper (Vipera aspis),[2] the Access this article online Website: www.neurologyindia.com DOI: 10.4103/0028-3886.158214 PMID: xxxxx
Quick Response Code
Most of the electrophysiological studies have been performed on patients suffering from neuroparalytic snake bite (for example, krait and cobra), but the studies documenting electrophysiological abnormalities in patients with vasculotoxic snake bites (Viper) are few. Neurological manifestations (electrophysiological abnormalities) due to a viper bite are usually reported from South India and Sri Lanka but have not been reported from Western India. This study aims to document the neurological manifestations and electrophysiological abnormalities in cases of vasculotoxic snakebite from western India. The defective neuromuscular junction (NMJ) transmission can be pre‑synaptic or post‑synaptic. The pre‑synaptically active neurotoxins (beta‑neurotoxins, mainly neurotoxic phospholipase A2 toxins, bind to the motor nerve terminals, leading to the depletion of synaptic acetylcholine (Ach)
Address for correspondence: Dr. Patwari Panduranga, Room No. 506, Resident Quarters, BJGMC and SGH, Pune - 411 001, Maharashtra, India. E-mail: [email protected]
378
Neurology India / May 2015 / Volume 63 / Issue 3
[Downloaded free from http://www.neurologyindia.com on Tuesday, June 09, 2015, IP: 61.16.135.116]
Panduranga, et al.: Comparative study of electrophysiological changes in snake bites
vesicles, resulting in impaired release of ACh, and later, leading to degeneration of the motor nerve terminal.[6] The post‑synaptically active neurotoxins (alpha‑neurotoxins) bind to the post‑synaptic muscle nicotinic acetyl choline receptor (nAChRs). They resemble the action of d‑tubocurarine (dTC). dTC classically produces a reversible, non‑depolarising post‑synaptic block by competitive inhibition of ACh binding to the muscle nAChR.[6] In this type of toxicity, the antivenom may facilitate dissociation of the toxin from the ACh receptor and accelerate recovery[7] and a clinical response to acetycholineesterase inhibitors (AChEIs), similar to that seen in myasthenia gravis, is more likely. The recent insights into neuro-muscular junction (NMJ) transmission have enabled better and more comprehensive characterization of the more recently described toxins. Candoxin, a novel toxin isolated from the venom of the Malayan or blue krait (Bungarus candidus), is a non‑conventional three‑finger toxin (3FTX) with structural similarities to alpha‑bungarotoxin.[8,9] However, in contrast to the nearly irreversible blockade produced by alpha‑bungarotoxin, candoxin produces a readily reversible block of the post‑synaptic nAChR. In addition, candoxin also inhibits the pre‑synaptic neuronal AChRs and produces tetany and tetanic fade on rapid repetitive stimulation.[8,9]
Subjects and Methods This study was conducted in the Department of Medicine, from September 2011 to August 2013. A synopsis of the study protocol was submitted to the Institutional Ethical Committee and approval was obtained. Patients were selected from the ward and medical ICU of the hospital. In the study, patients having a definite history of snake bite, either vasculotoxic or neuroparalytic, were included. Patients with unknown bites and snake bites without definite envenomation were excluded from the study. The total sample size of 40 was divided into two groups of 20 each (Group A: Neuroparalytic snake bite patients, Group B: Vasculotoxic snake bite patients). The study protocol was explained in detail to all the subjects. Informed written consent was taken from the subjects willing to participate in the study. A questionnaire was designed to obtain their basic clinical information. A nerve conduction study was conducted at a fixed room temperature of 300C within 6 to 10hrs after the patient’s hospitalization.
Assessment of Patient Clinical evaluation The patients were asked questions regarding symptoms of the snake bite at the time of admission; patients with a neuroparalytic snakebite, presenting with ptosis, respiratory distress, neck muscle weakness and respiratory paralysis were
included in Group A. Patients with vasculotoxic snakebite presenting with bleeding manifestations (haematuria), extensive cellulitis at the site of bite, prolonged bleeding time (BT), clotting time (CT) and 20 min whole blood clotting time (WBCT) were included in Group B. A detailed history, general examination and neurological examination were carried out in all the patients selected for the study. The offending snake was identified by examination of the dead snake brought by the patients at the time of admission, or by the photograph of the snake. The patients with a definite history of snakebite, with either neuroparalytic or vasculotoxic manifestations, who were not able to identify the snake, or did not bring the dead snake along with them, were classified as patients having an unidentified snakebite. Patients were inducted into the study regardless of whether or not the antisnake venom (ASV) had already been administered. Patients who had already received neostigmine were also included in the study. The relevant laboratory investigations were done on the day of admission. Electrophysiological evaluation of peripheral nerve function The methodology adopted for measurement of nerve conduction parameters was as follows: The patients underwent nerve conduction studies. Nerve conduction parameters were measured by using the standard RMS ALERON 401 machine (Recorders and Medicare systems, India) in the Department of Medicine. Recordings were done using the standard procedure such as temperature control (32‑34 oC), careful distance measurements and recording of well‑defined and artefact‑free responses. M o t o r n e r v e c o n d u c t i o n a n d re p e t i t i v e n e r v e stimulation (RNS) were performed on median and facial nerves of either side. The procedure was carried out by using surface electrodes. The amplitude and latency of the motor action potential and velocity of conduction in the concerned nerve were recorded. After this motor nerve conduction, a repetitive nerve stimulation (RNS) study was performed. The nerves selected for RNS were the facial and median nerves. In this study, the nerve was stimulated repeatedly at either 3 cycles per second [slow RNS] (5 such stimulations were given); or, at 30 cycles per second [rapid RNS] (5‑100 stimuli were given). The action potentials resulting as a consequence of this repeated stimulation were sequentially recorded and a comparison was made between the amplitude of the first (s1) and the fourth (s4) action potentials to find out if decrement was present. If the results of this test were borderline, the test was repeated after voluntary muscle activity for 30 seconds, or if this was not possible (in comatose patients), the muscle was stimulated repeatedly to stimulate voluntary
Neurology India / May 2015 / Volume 63 / Issue 3
379
[Downloaded free from http://www.neurologyindia.com on Tuesday, June 09, 2015, IP: 61.16.135.116]
Panduranga, et al.: Comparative study of electrophysiological changes in snake bites
muscle contraction and the repetitive stimulation test was performed again. This record constituted the post-tetanic action potential study. As per the standard protocol, a decrement was considered significant if s4/s1 (i.e., the difference in the amplitude between the fourth and first stimuli during repetitive stimulation study) was more than 10% (i.e., a decrement of 10%). On testing at 30 cycles per second, a decrement of more than 20% was considered significant. Statistical analysis The data was managed in a Microsoft excel spreadsheet. General informative tables were prepared with mean and standard deviation. Scatter plot was used to observe correlation between the parameters. Demographics and general information like the count, average and percentage figures for various parameters, with all permutations and combinations, were calculated on Microsoft Excel sheets. A P
