Reply to Jalink, M.B. Comment on "Senthilkumaran et al. Bilateral Simultaneous Optic Neuritis Following Envenomations by Indian Cobra and Common Krait. Toxins 2022, 14, 805".

We thank the author for showing interest in our article [...].

Partial segmental thrombosis of the corpus cavernosum following Russell's viper bite.

Snakebite envenoming (SBE) is common in rural communities living in tropical regions that often have fragile and/or overwhelmed healthcare systems. The complex scenarios around SBE lead to a high number of deaths, disabilities, and long-term consequences in patients. Russell's viper (Daboia russelii) is one of the most medically important snake species in India, which causes devastating pathological conditions characterised by a wide range of clinical manifestations. This broad spectrum of symptoms requires additional therapeutic interventions beyond the classical antivenom administration. Hence, positive outcomes for patients affected by SBE can be achieved with a better understanding of previous experiences describing clinical manifestations and various therapeutic interventions including for rare and underreported conditions. Here, we report an SBE victim who developed partial segmental thrombosis in the corpus cavernosum following Russell's viper envenomation and its diagnostic and treatment approaches. The patients received 180 ml of antivenom to resolve the abnormalities in their haematological parameters. Despite antivenom treatment, they developed severe pain in their genital region, and subsequent ultrasound and magnetic resonance imaging confirmed segmental thrombosis in the corpus cavernosum, which required supportive measures. The treatment using low molecular weight heparin, rivaroxaban and non-steroidal anti-inflammatory drugs resolved segmental thrombosis. In conclusion, this case report exemplifies the development of a rare segmental thrombosis in corpus cavernosum and how the medical, scientific, and general community can benefit from documenting clinical manifestations, medically relevant insights into patient care and the management of underreported complications.

Peripheral Arterial Thrombosis following Russell's Viper Bites.

Envenomings by Russell's viper ( Daboia russelii ), a species of high medical importance in India and other Asian countries, commonly result in hemorrhage, coagulopathies, necrosis, and acute kidney injury. Although bleeding complications are frequently reported following viper envenomings, thrombotic events occur rarely (reported only in coronary and carotid arteries) with serious consequences. For the first time, we report three serious cases of peripheral arterial thrombosis following Russell's viper bites and their diagnostic, clinical management, and mechanistic insights. These patients developed occlusive thrombi in their peripheral arteries and symptoms despite antivenom treatment. In addition to clinical features, computed tomography angiography was used to diagnose arterial thrombosis and ascertain its precise locations. They were treated using thrombectomy or amputation in one case that presented with gangrenous digits. Mechanistic insights into the pathology through investigations revealed the procoagulant actions of Russell's viper venom in standard clotting tests as well as in rotational thromboelastometry analysis. Notably, Russell's viper venom inhibited agonist-induced platelet activation. The procoagulant effects of Russell's viper venom were inhibited by a matrix metalloprotease inhibitor, marimastat, although a phospholipase A 2 inhibitor (varespladib) did not show any inhibitory effects. Russell's viper venom induced pulmonary thrombosis when injected intravenously in mice and thrombi in the microvasculature and affected skeletal muscle when administered locally. These data emphasize the significance of peripheral arterial thrombosis in snakebite victims and provide awareness, mechanisms, and robust strategies for clinicians to tackle this issue in patients.

Bilateral Simultaneous Optic Neuritis Following Envenomations by Indian Cobra and Common Krait.

In India, most snakebite envenomation (SBE) incidents are caused by the "Big Four" snakes which include Russell's viper, common krait, Indian cobra, and saw-scaled viper. Their common envenomation effects include neurotoxicity, myotoxicity, and coagulopathy. However, they also induce rare complications such as priapism, pseudoaneurysm, and sialolithiasis. Ocular manifestations such as optic neuritis develop rarely following envenomations by non-spitting snakes and they may cause temporary vision changes and blindness if untreated. While optic neuritis following Indian cobra envenomation has been reported previously, this was not encountered in victims of common kraits. Hence, for the first time, we report optic neuritis developed in a victim following envenomation by a common krait and compare its clinical features and diagnostic and therapeutic methods used with another case of optic neuritis in a victim of an Indian cobra bite. Both patients received antivenom treatment and made an initial recovery; however, optic neuritis developed several days later. The condition was diagnosed using ophthalmic examination together with computed tomography and/or magnetic resonance imaging methods. Due to very similar clinical features, both patients received intravenous corticosteroids which restored their vision and successfully treated optic neuritis. This case report suggests that the optic neuritis developed in a common krait envenomation is comparable to the one developed following a cobra bite, and therefore, the same diagnostic and therapeutic approaches can be used. This study also raises awareness of this rare complication and provides guidance for the diagnosis and treatment of SBE-induced optic neuritis.

Hirata's disease (insulin autoimmune syndrome) following envenomation by a common krait.

Snakebite envenomation is known to cause local as well as systemic haematological, myotoxic and neurological effects. Adverse effects on the endocrine system following envenomation are rarely reported. Hirata's disease, also known as insulin autoimmune syndrome (IAS) is a rare disorder that causes hypoglycaemia due to excessive production of insulin autoantibodies. This report describes a rare case of IAS which developed in a snakebite victim following envenomation by a common krait and antivenom treatment. The patient was initially treated with dextrose and corticosteroids, although plasmapheresis was required to reduce the concentration of insulin antibodies and normalise the patient's glucose level. The patient then made an uneventful recovery without permanent sequelae. This report demonstrates the impacts of envenomation by a common krait on developing Hirata's disease and creates awareness among clinicians who treat snakebite envenomation.

Development of Wunderlich syndrome following a Russell's viper bite.

Snakebite envenomation is a high priority neglected tropical disease that predominantly affects rural communities living in developing countries. Due to myriad of complications including coagulopathies, neurotoxicity, nephrotoxicity and local tissue destruction, treating snakebite victims is a major challenge for clinicians. Russell's viper (Daboia russelii) is one of the 'Big Four' venomous snakes in India, and it is responsible for the most snakebite-induced deaths and disabilities. Acute kidney injury occurs frequently following Russell's viper bites and it is a critical factor contributing to disabilities, deaths and excessive treatment costs. In addition to commonly observed envenomation effects, Russell's viper bites induce some rare complications such as priapism, sialolithiasis and splenic rupture. Here, we report a case of Wunderlich syndrome that developed in a 22-year-old male following a Russell's viper bite. The patient displayed severe coagulopathies, abdominal tenderness, and hypotension. Notably, a peri-nephric haematoma was identified through ultrasound and computerised tomographic imaging. The haemorrhage was successfully treated using angioembolisation, and the patient recovered without any difficulties. Although a clinical condition such as this is rare, it is important to create awareness among treating clinicians about its occurrence, diagnosis and clinical management.

Ultrasound-Guided Compression Method Effectively Counteracts Russell's Viper Bite-Induced Pseudoaneurysm.

Russell's viper (Daboia russelii), one of the 'Big Four' venomous snakes in India, is responsible for the majority of snakebite-induced deaths and permanent disabilities. Russell's viper bites are known to induce bleeding/clotting abnormalities, as well as myotoxic, nephrotoxic, cytotoxic and neurotoxic envenomation effects. In addition, they have been reported to induce rare envenomation effects such as priapism, sialolithiasis and splenic rupture. However, Russell's viper bite-induced pseudoaneurysm (PA) has not been previously reported. PA or false aneurysm is a rare phenomenon that occurs in arteries following traumatic injuries including some animal bites, and it can become a life-threatening condition if not treated promptly. Here, we document two clinical cases of Russell's viper bites where PA has developed, despite antivenom treatment. Notably, a non-surgical procedure, ultrasound-guided compression (USGC), either alone, or in combination with thrombin was effectively used in both the cases to treat the PA. Following this procedure and additional measures, the patients made complete recoveries without the recurrence of PA which were confirmed by subsequent examination and ultrasound scans. These data demonstrate the development of PA as a rare complication following Russell's viper bites and the effective use of a simple, non-surgical procedure, USGC for the successful treatment of PA. These results will create awareness among healthcare professionals on the development of PA and the use of USGC in snakebite victims following bites from Russell's vipers, as well as other viper bites.

Exotic Snakebites Reported to Pennsylvania Poison Control Centers: Lessons Learned on the Demographics, Clinical Effects, and Treatment of These Cases.

Exotic snakebites (i.e. from non-native species) are a rare occurrence, but they present a unique challenge to clinicians treating these patients. Poison control centers are often contacted to assist in the management and care of these medical emergencies. In this study, we analyzed case records of the two Pennsylvania poison control centers from 2004 to 2018 to describe clinical features reported as a result of exotic snakebite envenomation. For the 15-year period reviewed, 18 exotic snakebites were reported with effects ranging from mild local tissue injury to patients who were treated with mechanical ventilation due to respiratory failure. The mean age of the patients was 35 years and males accounted for 83% of the cases. Antivenom, the only specific treatment, was administered in seven of 18 patients within an average of four h of envenomation. The procurement of antivenom against these exotic species may require substantial logistical efforts due to limited stocking of this rarely used treatment. Newer, targeted, small molecule treatments that are being currently investigated may aid in the treatment of snakebites in general. However, people should be cautious when handling these exotic species, and clinicians should be aware of these bites and relevant clinical effects in order to manage these when reported.