Neurological and neuro-ophthalmological manifestations of snake bite: a systematic review

Objective: Snakebites, a major health concern in developing countries, affect rural farming communities. Venom, primarily neurotoxin, injected during a snake bite disrupts the nervous system, causing symptoms like muscle weakness, paralysis, altered sensation, and coordination issues. This review focuses on evaluating neurological and neuro-ophthalmological manifestations associated with snakebites. Methods: A database search was conducted in EMBASE and PubMed for studies published from 2000 to 2023. The investigation centered on examining neurological and neuro-ophthalmological symptoms and signs, treatment approaches, treatment outcomes, and long-term complications of snake bites. Results: Neurological and neuro-ophthalmological symptoms were common in both neurotoxic and hemotoxic snake bites, especially in neurotoxic cases. Ptosis was a prevalent manifestation across various snake bites, along with respiratory paralysis, limb weakness, dysphasia, and visual disturbances in some instances. However, most patients improved without residual neurological symptoms after treatment. Conclusions: Understanding patterns of neurological manifestations contributes valuable insights for the comprehensive management of snakebite.


Introduction
Snake bite is a major health concern, particularly in developing countries, affecting mainly rural farming communities [1] .It remains a neglected tropical disease that causes significant morbidity and mortality.Worldwide, an estimated 5.4 million snake bites occur annually, with half being envenoming, leading up to 138 000 preventable deaths and over 400 000 preventable amputations and other permanent disabilities [1] .In the United States (US), poison centres recorded over 7000-8000 snake envenomation in 2019, while in India, an average of 250 000 snake bites are recorded in a single year [2,3] .Snakes are found in deserts, forests, marshes, swamps, lakes, streams, and rivers of difficult terrains.The families of venomous snakes are Atractaspididae, Elapidae, Hydrophidae, and Viperidae [3] .Snake venom can be classified into hematotoxic, neurotoxic, necrotoxic, cardiotoxic, and nephrotoxic, depending on the predominant effects of the venom [4] .The venom consists of various components, including protein, enzymes, neurotoxins, coagulants, anti-coagulants, and substances with cytotoxic effects [5] .Venoms are a complex mixture of enzymatic and toxic proteins, which trigger different clinical manifestations depending on the pathophysiological changes of certain species.
Hemotoxins affects the cardiovascular system causing bleeding or coagulation disorder whereas neurotoxins affect the nervous system.When neurotoxin enters the body by a snake bite, it causes neurological symptoms like muscle weakness, paralysis, altered sensation, and coordination issues [4] .It can also impact the visual system, resulting in neuro-ophthalmological manifestations such as blurred vision, double vision, drooping eyelids, and vision loss.
This systematic review aims to outline the nature and severity of neurological and neuro-ophthalmological symptoms and signs, as well as their treatment approaches, outcomes, and longterm complications associated with snake bites.

Methodology
This review article has been reported in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-

HIGHLIGHTS
• Snake bites are major health concerns in developing countries, mainly rural farming communities.Analyses) guideline [6] and AMSTAR(Assessing the methodological quality of systematic reviews) guideline.

Study inclusion and exclusion criteria
The following requirements should have been met by the studies: (1) Included patients who had experienced a snake bite (2) Paediatric and adult patients (3) Information on one or more neurological manifestations.The exclusion criteria were as follows: (1) Animal or in vitro studies (2) Insufficient data and language other than english (3) Duplicate publications (4) Reviews or meta-analyses.

Search methods and study selection
PubMed and EMBASE databases were searched for studies published from 2000 to 2023.Boolean logic was used for conducting a database search, and Boolean search operators "AND" and "OR" were used to link search terms: "snake bite", "Neurological manifestation".

Search results and study selection
We found 184 studies through electronic database searches (83 from PubMed, 72 from EMBASE) and identified 29 additional studies through manual searches of reference lists and related systematic reviews.After removing duplicates, we screened 114 articles based on titles and abstracts.Subsequently, 33 full-text articles were retrieved and evaluated against predefined inclusion criteria.Ultimately, 18 articles met the criteria and were included in the review.The PRISMA diagram, illustrating the identification and selection process, is provided in Figure 1.

Study characterizations and patient's demography
The review encompassed a total of 1,424 patients across 18 studies, comprising 15 observational studies and three case series.The mean age of participants ranged from 6 months to 80 years.Among these studies, four exclusively involved pediatric patients, two exclusively involved adult patients, and 12 included both pediatric and adult participants.The research was conducted in various countries, with five studies from India, four from Sri Lanka, three from the United States, two from Italy, and one each from Thailand, South Africa, Croatia, and Brazil. .The remaining 305 cases did not identify the snake species.This data is illustrated in the Figure 2.

Neurological and neuro-ophthalmological manifestations
Marano et al. [16] examined 24 cases of paediatric viper bites and found neurological signs in 8.3% of cases, with ptosis being the most common manifestation.Tongpoo et al. [7] examined 78 cases of both paediatric and adult krait bites and found motor weakness to be present in 88.5% of cases.Lonati et al. [11] studied 24 cases of both paediatric and adult viper bites and observed that all patients had accommodation problems and diplopia, with ptosis being the most common neurological manifestation.Similarly, Silva et al. [17] studied 33 cases of krait bites and observed that ptosis was the most common manifestation.Anil et al. [19] examined 72 cases of krait bites and found that most of the cases had ptosis.Bawaskar et al. [12] studied 141 cases of krait bites and observed that 26% of cases had bulbar palsy and 11.34% had respiratory paralysis requiring mechanical ventilation.Additionally, this review included studies on Berg Adder bites, Copperheads bites, rattlesnake bites, and coral bites [13,14,18,23] .The detail can be found on Table 1.Incidence of various manifestations has been shown in Figure 3.

Treatment
Anti-snake venom (ASV) was administered in all the studies, and the patients were also provided with mechanical ventilation when necessary, except for a study conducted by Walt et al. [18] , who managed 14 cases of Berg Adder bite symptomatically.In the study conducted by Karabuva et al. [21] , along with anti-snake venom, antibiotics, corticosteroids, and antihistamines were administered to the patients.However, Anil et al. [19] 's study on the effect of neostigmine in krait snake bites showed that the treatment was ineffective.

Outcome
We found that ASV effectively improved the neurological and neuro-ophthalmological manifestations.However, there have been reports of anaphylaxis caused by ASV in studies conducted by Sharma et al. [20] , Kularatne et al. [10] , Roth et al. [23] , and Silva et al. [17] .The studies have reported mortality rates ranging from 2.48 to 13.7%.Seneviratne et al. [24] reported a case of mortality caused by intracranial haemorrhage.Nevertheless, the majority of patients improved without any residual neurological symptoms.

Discussion
Our review showed that snake bites are prevalent in both children and adults.Most of the cases studied were of Krait bite.The majority of cases were reported from India, followed by Sri Lanka and the United States.In India alone, an average of 250 000 snake bites are reported each year [3] , while Sri Lankan hospitals admit around 37 000 snake bite cases annually [25] .This has been shown in Figure 4.
Neurotoxins present in snake venom bind to neuromuscular junctions both pre-synaptically and post-synaptically, resulting in muscle weakness.For instance, alpha-bungarotoxin found in krait venom binds to acetylcholine receptors, leading to a reduction in acetylcholine receptor sites in the postsynaptic membrane [26] .On the other hand, alpha-cobra toxin produces features of myasthenia gravis in experimental animals due to its similar action [27] .Neurotoxicity is caused by the pre-synaptic actions of phospholipase A2 enzyme and Beta-bungarotoxin [22,28] .
Hematotoxic venoms, on the other hand, can cause neurological symptoms like ptosis, ophthalmoplegia, and weakness due to three mechanisms: presynaptic inhibition of neurotransmission by phospholipase A2 in Russell's viper venom, intracranial haemorrhage, or acute brain infarction [29,30] .
Most patients in this review report ptosis followed by neurological weakness of limbs and ophthalmoplegia, while nystagmus, delayed neuropathy, and dysarthria were reported in fewer patients.A moderate number of patients reported decrease in the visual acuity with snake bites.In neurotoxic snake bites, ptosis followed by neuroparalysis are the most common ocular signs and symptoms [19,31] , while hematotoxin snake bites can cause symptoms ranging from accommodation deficiency and ptosis to ophtalmoplegia, neck muscle weakness, and dysphagia [10,20] .According to Silva et al. [17] , patients who do not develop bulbar weakness or respiratory paralysis within 12 hours of the bite are unlikely to experience severe paralysis.
Several authors have reported muscle weakness after snake bites, which clinical and electrophysiological studies have attributed to defective neuromuscular transmission [32,33] .However, there have also been cases where muscular weakness was caused by rhabdomyolysis [34] .Snake bites can lead to potentially fatal respiratory muscle weakness, with krait bites being particularly notorious for rapidly causing respiratory failure [24] .However, in a series of ten patients with respiratory failure, all were successfully managed with mechanical ventilation, underscoring the importance of timely intervention [24] .Snake bites can also lead to Guillain-Barre syndrome and delayed neuropathy [31] .Neurotoxin snake bites commonly cause high blood pressure and tachycardia, which may be due to decreased parasympathetic activity [35] .Electrolyte imbalances, including hyponatremia, are also recognized clinical manifestations [36] .
ASV was administered to patients with systemic features, and our review revealed that it had a positive effect.Nevertheless, instances of anaphylaxis to ASV were also noted and were handled appropriately.The use of anti-venom has a high incidence of anaphylaxis [37,38] , as demonstrated in this review, which may limit its efficacy when widely used for snake bites and envenomation.The administration of anti-venom must be done in a high-care environment with constant monitoring and should be preceded by the administration of intramuscular adrenaline [39] .
The syndromic approach to managing snake bites, as popularized by Blaylock in 2005, divides management into three clinical syndromes that correspond to the three venom types [40,41] .The therapeutic triad, which includes elevation, intravenous fluids, and analgesia, is the mainstay of conservative management when the type of snake involved is unknown [40] .In severe cases of progressive painful swelling or bleeding, anti-venom administration and fasciotomy may be necessary [42] .Low dose anti-venom has been found to be as effective as high dose anti-venom for both neurotoxic and hematotoxic snake bites [43] .Early, empirical anti-venom is lifesaving, but good supportive care with mechanical ventilation is equally important and can lead to a good outcome [44] .The use of anti-coagulants in viper bites is controversial, with some reports suggesting it may increase the risk of haematoma and functional impairment [9,45] .The role of anticholinesterases in reversing neuroparalysis is also debated, with some studies showing ineffectiveness [8,31] .
Most cases in the reviewed studies recovered without neurological deficits.However, mortality rates were higher with neurotoxic snake bites compared to hemotoxic ones.Factors like younger age, ptosis, cardiac arrest, and lack of PICU beds were associated with higher mortality rates in children with EMNS, but prompt recognition, respiratory support, and PICU care can decrease mortality [15] .
To effectively prevent and treat snake bites, it is important to establish a proper documentation system such as a Snake Bite Registry that includes information on snake species, patient history, clinical signs, treatment, and final outcome.The North American Snakebite Registry (NASBR) is an example of such a registry [46] .

Conclusion
Ptosis is a prevalent neurological symptom in various snakebites, often accompanied by respiratory paralysis, limb weakness, dysphasia, and visual disturbances in certain cases.Notably, improvements are observed after ASV treatment, with almost no residual manifestations.

Figure 1 .
Figure 1.The PRISMA diagram detailing the identification and selection process.

Figure 2 .
Figure 2. showing number various snake species discussed in this review.

Figure 3 .
Figure 3. showing incidence of various neurological and neuro-ophthalmological manifestations.

Figure
Figure showing the rate of snake bite year.

Table 1
Key methodological characteristics of studies included in this systematic review. ) Two independent authors (K.P. and H.M.S.M.) rigorously reviewed selected studies for systematic review which met our inclusion criteria and extracted the precise information on different headings under one table depicting Author/Published year, study site, study design, sample size, participants (adults, paediatric), age (in years), sex, snake and venom type, neurological and neuro-ophthalmological manifestation, treatment, outcome and late complications were recorded in Microsoft Excel 2013 (Microsoft Corp).