Acute ischaemic stroke and deep vein thrombosis following snakebite

Abstract

Snakebite envenomation remains a neglected tropical public health issue claiming thousands of lives every year. It is a common medical emergency and a threat to the impoverished populations of low-income and middle-income countries including India. A combination of ischaemic stroke and deep vein thrombosis is a devastating duo complication of snake bite, with no literature report to date. Here, the authors report an unusual case of a young woman developing ischaemic stroke and deep vein thrombosis following snakebite even after the use of antivenom. MRI brain showed right thalamic infarct with haemorrhagic transformation and, ultrasound Doppler revealed right lower limb deep vein thrombosis. The pathophysiology of deep vein thrombosis and ischaemic stroke is complex. It is believed that the activation of the coagulation cascade, complement system together with endothelial injury and immune activation leads to inflammation, thrombosis and occlusion of smaller and even larger vessels.

Background

Snakebite envenomation remains a neglected deadly disease, particularly common in the eastern part of India.¹ Snakebite deaths account for the major mortality in this part of the country with nearly 5.6 per 0.1 million population snakebite deaths/year.² Envenomation leads to several complications ranging from local cellulitis to systemic complications including neurological and haemorrhagic events.^{3 4} Haemorrhagic stroke has increasingly been reported following snake envenomation.⁵ However, ischaemic cerebrovascular accident is an uncommon event post snakebite envenomation, especially when compared with other serious complications including haemorrhagic stroke or bleeding. Ischaemic stroke following envenomation is thus sparingly reported, often poorly understood^{6 7} but subsequently found to be of multifactorial origin.⁸ Moreover, the complex mixture of compounds in snake venom causes a multitude of bodily effects.⁹ Additionally, the wide spectrum of neurological manifestations post snakebite typically includes paresthesias, paralysis, damage to local nerve structures and myokymia, which are commonly discussed. Despite these neurological complications, deep vein thrombosis occurring as a serious sequelae of snakebite envenomation is infrequently observed.¹⁰ So, here, we document the untying of the ‘gordian knot’ of ischaemic stroke and disseminated thrombosis causing multiple acute events following snakebite. The patient was managed diligently and thereby resulting in the improvement of the overall outcome.

Case presentation

A woman in her 30s was presented to our facility 10 days after an unknown snakebite on her left foot. She was initially treated at a nearby healthcare facility with antisnake venom, where she had also undergone two sessions of haemodialysis (second and fifth day following the snakebite) due to acute kidney injury. She was then referred to our facility with complaints of reduced sensation in the left half of her body and tingling sensation in her left upper and lower limbs for the last 6 days. She also had a history of four episodes of dark-coloured urine on fifth day after the snakebite incident. On admission, her vitals were found to be stable. The fang marks present on her left foot are shown in figure 1. Local swelling, tenderness and raised temperature were present in her left lower limb. Neurological examination revealed loss of fine touch, vibration, proprioception, pain and temperature on the left side of the body including her face. Higher mental function, cranial nerve examination and motor system examination had no abnormalities. She had a significant history of two abortions (12 weeks and 16 weeks of gestational age), but no history of any drug intake or use of oral contraceptive pills.

Figure 1.

Fang marks on left foot with left lower limb swelling.

Basic blood investigations revealed normal complete blood count, lipid profile, renal and liver function tests. C reactive protein (24.29 mg/L) and erythrocyte sedimentation rate (65 mm/hour) were found to be raised. In the coagulation profile, activated partial thromboplastin time (20.2 s) was found to be reduced while the prothrombin time/international normalised ratio was normal. Urine routine and microscopy were normal. Chest X-ray, ECG and echocardiogram were also normal. Non-contrast CT head revealed an irregular hypodense lesion in the right thalamic region (likely posterior cerebral artery territory acute infarct), as shown in figure 2. Ultrasound Doppler showed extensive thrombosis of the right external iliac vein to the popliteal vein and subcutaneous oedema of the left lower limb. These findings were suggestive of cellulitis. A bilateral adnexal haemorrhagic cyst was also noted in the ultrasound of the abdomen. Further evaluation for thrombophilia state was done (as mentioned in table 1 and the chronology of clinical events shown in table 2) and was found to be normal. MRI of the brain showed T2-weighted/fluid-attenuated inversion recovery hyperintensity in the right thalamus with foci of blooming likely due to right thalamic infarct with haemorrhagic transformation (figures 3–5).

Figure 2.

Acute ischaemic stroke in right thalamic region.

Table 1.

Workup for thrombophilia state

Serial number	Test name	Value
1.	Antithrombin III activity	105.3%
2.	Protein C activity	120.3%
3.	Protein S activity	104.1%
4.	Lupus anticoagulant(LAC)- LAC screen LAC confirm	36.2 s 31.4 s
5.	Beta-2 glycoprotein- IgM IgG	4.3 MPL/mL 5.7 SGU
6.	Cardiolipin antibody- IgM IgG	3.7 MPL/mL 4.8 GPL/mL
7.	ANA IFA and profile	Negative
8.	D-dimer assay	3.72 µg/L

ANA, Antinuclear antibody ; GPL, IgG phospholipid/mililitre; IFA, Immunofluorescence; MPL, IgM phospholipid/mililitre; SGU, standard IgG units.

Table 2.

Day of onset of symptoms from snakebite

Symptoms/events	Day on onset/detection
Snakebite	Day 0
Acute kidney injury	Day 2
Left-sided loss of sensation	Day 4
Dark-coloured urine	Day 5
Detection of right lower limb deep venous thrombosis	Day 10

Figure 3.

T2-weighted/fluid-attenuated inversion recovery hyperintensity in the right thalamus with foci of blooming likely right thalamic infarct with haemorrhagic transformation.

Figure 4.

T2-weighted/FLAIR hyperintensity in the right thalamus with foci of blooming. FLAIR, fluid-attenuated inversion recovery.

Figure 5.

T2-weighted/FLAIR hyperintensity in the right thalamus with foci of blooming. FLAIR, fluid-attenuated inversion recovery.

Relevant investigations are mentioned in table 3.

Table 3.

Relevant investigations

Test	Patient value	Reference values
ESR	65 mm at the end of first hour	20 mm/hour
CRP	24.29 mg/L	Less than 1 mg/L
aPTT	20.2	26–38 s

aPTT, activated partial thromboplastin time; CRP, C reactive protein; ESR, erythrocyte sedimentation rate.

Differential diagnosis

The diagnosis of procoagulant state of snake envenomation with right-sided acute ischaemic thalamic stroke, deep vein thrombosis of the right lower limb and cellulitis of the left lower limb was reached.

Treatment

Intravenous antibiotics (ceftriaxone 1 g 12 hourly and clindamycin 900 mg 6 hourly), anticoagulants (rivaroxaban 15 mg two times per day), statins, pregabalin and methylcobalamin (75 mg+1500 µg once a day) and analgesics were administered. Gradually, the cellulitis and the tingling sensation of her left upper and lower limbs was subsided. The follow-up ultrasound Doppler post 2 weeks showed right superficial femoral vein thrombosis with recanalisation of the right popliteal vein. She was then discharged from the hospital after 3 weeks of admission.

Outcome and follow-up

The patient came for follow-up to the OPD after about 1 month. Her limb swelling had subsided (as shown in figure 6). Follow-up Doppler scan of lower limb vessels was found to be normal. There was no evidence of thrombosis post 1 month of her discharge and the same anticoagulant was advised to be continued.

Figure 6.

Bilateral foot with decrease in swelling on follow-up.

Discussion

Snakebite envenomation and cerebrovascular events are widely reported in medical literature.¹¹ Viper venom causes anticoagulant and procoagulant action.¹² A few of its actions are detailed below:

• Hypnale hypnale (hump-nosed pit viper)—cerebral infarction.¹³

• Vipera russelli (Russell’s viper)—cerebral infarction¹⁴

• Bothrops spp (pit vipers)—cerebrovascular complications (intracranial haemorrhages are more frequent than cerebral infarcts).¹¹

The eastern India is abode to many venomous snakes, with majority of envenomation with Vipera russelli (around 60%), followed by common krait and Naja kaouthia.¹⁵ Towards this end, Feola et al reported 2.6% of patients with cerebrovascular complications among 309 snakebite victims.⁹ Ischaemic stroke has also been reported in various snake envenomation.^16–21 Gawarammana et al found 1.8% ischaemic stroke cases in 500 viper bite patients.²² Deep vein thrombosis following snake envenomation has rarely been reported in India, with a few documented cases worldwide.^{10 23 24} In this vein, the authors take the pride to report the duo complication of ischaemic stroke and deep vein thrombosis post snakebite for the first time. However, the aetiopathogenesis of ischaemic stroke and deep vein thrombosis following snake envenomation still needs further elucidation.^{25 26} It is believed that the activation of coagulation cascade in the initial phase might have led to the event.²³ Thromboinflammation which may be activated by different forms of toxins of the venom may lead to endothelial injury, immune activation and hypercoagulable state.^{3 4} Some species of snake also activates the complement system leading to inflammation and thrombosis.²⁷ It is worth mentioning that the deep vein thrombosis, in the present study, was detected 10 days after the snakebite, which is also a rare event. In this context, our study has highlighted such catastrophic complications, which may have otherwise led to morbidity in the patient, a few days post snake envenomation. It is, therefore, imperative to consider such diverse events in snakebite envenomation, several days post snakebite, presented in this part of the world. Thus, these findings call for a rethinking of the duration of hospitalisation postinjecting of antisnake venom.

Learning points.

• The combination of Ischaemic stroke and deep vein thrombosis is rarely encountered following snakebite envenomation.

• A high index of suspicion and rapid vigilant workup is of utmost importance in snakebite envenomation.

• Timely detection of deep vein thrombosis is crucial to start anticoagulation despite coagulopathy to improve patient outcome.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).