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Neurotoxicity and hypertension following European adder (Vipera berus berus) bites in Hungary: case report and review

T. Malina, L. Krecsak, D.A. Warrell
DOI: http://dx.doi.org/10.1093/qjmed/hcn079 801-806 First published online: 22 July 2008

Introduction

In Europe, the common adder (Vipera berus) is extensively distributed and causes more bites than any other species in the genus Vipera.1 In Hungary, there are two subspecies; the nominate form (V. b. berus) in the East and Northeast and the Bosnian adder (V. b. bosniensis) in the Southwest (Figures 1 and 2).2

Figure 1.

Common adders (Vipera berus) from Hungary: (a and b) V. b. berus, female specimens from the population where our patient was bitten (Vámosatya, Szabolcs–Szatmár–Bereg County, E Hungary) (Photographs Tamás Malina). (c) V. b. bosniensis female from Darvaspuszta, Somogy County, SW Hungary (Photographs Zoltán Korsós).

Envenomings by V. berus result in characteristic systemic symptoms including early ‘anaphylactic’ features such as tachycardia, dizziness, hypotension, shock and gastrointestinal symptoms, coagulopathy and neutrophil leucocytosis.1,3,4 These symptoms resemble those caused by V. aspis, reflecting the similarities in the composition of their venoms.5 Systemic neurotoxicity has been described in patients envenomed by certain populations of some subspecies of V. aspis and V. ammodytes in Europe.6 It has been attributed to pre-synaptic (ammodytoxins) or post-synaptic neurotoxic phospholipases A2 (PLA2) in their venoms.6 However, neurotoxicity is a most unusual and unexpected clinical feature of V. berus envenoming. We describe here a case from eastern Hungary with other interesting features and review the scanty and somewhat obscure literature on this phenomenon.

Case report

A previously healthy 27-year-old man was bitten by an adult female V. berus 70–72 cm in total length on 23 April 2007 in Szabolcs–Szatmár–Bereg County in eastern Hungary (Figure 2). The snake was captured alive and expertly identified. The victim reported no previous snakebites. Two fangs impaled the left thumb, causing burning pain that became throbbing in quality. The bitten finger swelled immediately and a small haematoma formed at the bite site. Swelling associated with erythema extended to the hand in 45 min. The patient applied a tourniquet around the proximal phalanx of the thumb and the wrist, which was released every 15–20 min. It was still in place when he was admitted. Within ∼90 min, he was transported to the nearest hospital.

Figure 2.

Distribution of Vipera berus populations are shown by grey shaded areas in eastern Hungary. The black square is the location of the present case described. Legend: Vipera berus berus populations are marked by grey shading, V. b. bosniensis by black shading.

On admission, the patient was fully conscious. He had two attacks of profuse diarrhoea and one episode of mild nausea. Examination revealed tense, tender swelling involving the whole hand and wrist. Erythema was mild and local haemorrhage was confined to the fang marks, which were clearly visible. He was unable to move his fingers or make a fist. He had been slightly nauseated and dizzy during the journey. On arrival at hospital he felt ‘drugged’ although he had taken no medications except two 500 mg calcium tablets. After 20–30 min, he suddenly noticed double vision; his gaze seemed to shift horizontally and there was a dim ghost image. He became increasingly dizzy and experienced true vertigo when he lay supine. On examination, there was no ptosis but diplopia was confirmed. There was definite strabismus and the second image disappeared when one eye was covered. His gait was found to be unsteady. There was no nystagmus and the pupils were moderately dilated, equal in size and reactive to light and accommodation. There was mild fever (37.6°C). When he was first examined, 1.5 h after the bite, the heart rate was increased (103/min) and the blood pressure was elevated to 180/120 mmHg. This hypertension was controlled with captopril 12.5 mg. The blood pressure decreased to 150/90 mmHg over the next few hours, but was still 139/82 mmHg the next morning. According to the patient, his blood pressure is usually about 118/79 mmHg with a heart rate of 65/min. At this stage, 2 h after the bite, he was given tramadol 50 mg i.v. ∼1–2 h later, he began to feel drowsy. On admission to hospital, his differential leucocyte count was mildly abnormal: absolute neutrophils count 9.59 × 109/l, 84.5% (normal: 42–74%), lymphocytes 9.9% (normal: 17–45%), eosinophils 0.5% (normal: 1–7%). Blood coagulation and urine were normal.

Although antivenom is indicated when neurological and/or other systemic symptoms evolve,1,3 it was not given in this case because the patient feared a reaction. The neurological signs were not considered life-threatening. Diplopia lasted for 11 h after the bite and then resolved spontaneously, while intense dizziness gradually wore off within 2 days. The dorsum of the hand was slightly bluish in colour until the third day. The moderate local swelling was receding by the fourth day. Tender arthralgia of metacarpal and interphalangeal joints of the bitten hand lasted for 8 days.

Discussion

Neurotoxic effects of V. berus envenoming are poorly documented in the literature. Subjective symptoms such as the respiratory distress and paraesthesiae cited by certain authors, are far too non-specific to be acceptable as evidence of neurotoxic envenoming.1 Patients severely envenomed by V. berus may become unconscious,4,7 but this is attributable to the early, profound, persistent or recurrent hypotension that is such a marked clinical feature of these envenomings. Coma certainly does not imply a central neurotoxic effect of the venom that would be inherently implausible since the molecular size of snake venom neurotoxins allows minimal penetration of the blood–brain barrier.8 ‘Lip paralysis’ is readily confused with angioedema, a characteristic feature of V. berus bite,1 and should not be considered a neurological sign.7

Only one case of cranial nerve disturbances following V. berus envenoming has been described in the literature. In Poland, bilateral ptosis and blurred vision developed in a case of V. b. berus bite.9 Ptosis is the classical early sign of snakebite neurotoxicity, while blurred vision resulting from impaired visual accommodation is also a familiar feature of neurotoxic envenoming.4 In these V. berus populations, the presence of venom neurotoxins is strongly suspected on the basis of these symptoms. Another report, of permanent partial left ptosis and persistent left facial nerve palsy following a bite in the left fronto-temporal area by V. b. berus in northern Germany,10 was explained by direct local effects of the venom and associated gross swelling of the face, orbit and eyelid rather than by systemic neurotoxicity.

We were able to find two further cases of cranial nerve disturbances after envenoming by V. berus in older Hungarian medical literature. In Bihar County (western Transylvania, Romania), where only V. b. berus occurs, a 43-year-old woman developed ophthalmoplegia11, and a 24-year-old man developed bilateral ptosis and blindness lasting for 2 days.12 Antivenom was given in neither case, but they recovered in 13 and 4 days, respectively.11,12 These cases are of particular relevance because Szabolcs–Szatmár–Bereg County, where our patient was bitten, is close to Bihar County (Figure 2).

Studies of V. b. berus venom have revealed antihaemostatic and myotoxic activity.13,14 There is, so far, no reliable report of neurotoxic activity in Vipera berus venom. Early laboratory studies suggested that venoms of certain German V. b. berus populations might be neurotoxic, but this has never been confirmed experimentally or clinically.15 Križaj et al.16 cited a personal communication by Alan Harvey that no neuromuscular blocking activity could be detected on chick biventer cervicis preparation in V. b. berus venom of Russian origin. Ramanazova et al.17 were unable to demonstrate neurotoxin in the venom of V. b. berus. Other authors have also concluded that the venom of this species lacks neurotoxic properties.6,7,18 However, in the venom of the Bosnian adder (V. b. bosniensis), neurotoxicity is more prominent than antihaemostatic effects.19 This is consistent with the clinical features, such as ptosis and ophthalmoplegia, exhibited by humans envenomed by V. b. bosniensis as documented by Reuss.20 Neurotoxin encoding genes (i.e. A and B chain of Vaspin) have been demonstrated in one population of V. b. berus in Central France,21,22 but these genes are either not expressed or expressed only very weakly, as neurotoxic proteins do not appear in the venom and, consequently, neurological symptoms do not evolve in bitten patients.21

After ptosis, diplopia resulting from paralysis of extra-ocular muscles is usually the next effect of the descending paralysis typical of snakebite neurotoxicity. Ours is the first clinical report of this feature after V. b. berus envenoming but it has been observed, together with other neurological signs such as ptosis, ophthalmoplegia and dysphagia, following bites by some populations of V. aspis and V. ammodytes, whose venoms are known to contain neurotoxins.7,22 (Table 1). Our patient's diplopia resolved rapidly, 11 h after the bite, suggesting that it was caused by a postsynaptic neurotoxin (i.e. Vaspin) in the venom of this V. b. berus population. Clinical effects of postsynaptic neurotoxins tend to resolve more rapidly than those caused by presynaptic neurotoxins which damage the nerve terminals. We presume that the neuromuscular junctions innervating the extraocular muscles (m. rectus, m. obliquus) were reversibly blocked by venom neurotoxin causing external ophthalmoplegia and hence double vision, which resolved when the neurotoxin dissociated from its receptor.

View this table:
Table 1

Clinical symptoms suggesting activity of snake venom neurotoxins that have been observed so far in patients envenomed by different taxa

TaxaNeurotoxins found in the venomPtosisOphthalmoplegia ± diplopiaBlurred visionDysphagiaDysphonia
Genus: Vipera
    V. ammodytes ammodytes+++++
    V. a. meridionalis++++
    V. aspis aspis
    V. a. aspis (in SE France)++++
    V. a. zinnikeri++++
    V. a. francisciredi+++
    V. berus berus−/?#Pw#
    V. b. bosniensis±++
Genus: Daboia
    D.siamensis (Taiwan)+++
  • +: detected/observed; –: not detected/not observed; ±: most probably present;

  • ?: questionable in certain populations; Pw: recorded in the present work; #: observed but cannot be attributed to neurotoxicity per se (Weinelt et al.,10; Ciszowski and Modla9).

Drowsiness is a puzzling and unexplained feature of neurotoxic and other snakebites,7 but in our patient this may have been attributable to the analgesic he had been given. Neurotoxicity and the resulting diplopia, dizziness or high blood pressure may have contributed to our patient's dizziness, positional vertigo and unsteady gait.

Our patient showed another extraordinary sign, pronounced and protracted high blood pressure as opposed to hypotension, which is the most dangerous effect of V. berus envenoming.1,3,4 In a case of V. b. bosniensis bite in south-western Hungary in 1979, an abnormally high blood pressure was recorded (200/120 mmHg), which peaked 32 h after the bite. This patient also developed bilateral ptosis (Dr Miklós Lőke, personal communication). However, apart from that case, we could find no records of hypertension and tachycardia following European Vipera bites, except in a 6-year-old boy in Denmark who developed high blood pressure secondary to renal damage.23 Anxiety can raise the blood pressure, but our patient denies that he was anxious on admission. His high blood pressure fluctuated, responded promptly to the angiotensin-converting enzyme vasodilator captopril, but later recurred. It has been suggested that the venom of certain V. berus population might contain cardiotoxins,1 capable of acting at autonomic synapses to affect blood pressure.

Hypertension without neurotoxic symptoms was observed in patients envenomed by Western Russell's vipers (D. siamensis) in Taiwan.24 Neuro-myotoxic signs caused by bites of Eastern Russell's vipers (D. russelii) and attributable to PLA2 neurotoxins in Sri Lanka and India are not associated with hypertension (Table 1).4 It seems likely, therefore, that distinct toxins are responsible for these neurological and cardiovascular symptoms. Scorpion ion channel toxins release noradrenaline, dopamine and other catecholamines causing hypertension with tachycardia as seen in human victims of envenoming by Androdoctonus spp., Leiurus quinquestriatus and other taxa.25 Perhaps a venom constituent of this V. b. berus population releases catecholamines from adrenergic nerve endings to cause similar effects on blood pressure.

Some authors suppose that Vaspin genes may occur in all the species of Palaearctic vipers.22 Ammodytoxin genes have been demonstrated in different viperid species from south-eastern France to Slovenia.22 It seems likely that Vaspin genes are expressed in the populations of V. b. berus in eastern Hungary, while the venom of V. b. bosniensis in south-western Hungary may contain Ammodytoxins, as well. The presence of Ammodytoxins would support the hypothesis of some Hungarian authors’ that Slovenia is a possible origin of this population.2 Alternatively, the neurotoxic activity of the venom of eastern Hungarian V. b. berus populations may have evolved in parallel with V. b. bosniensis populations in the Balkans, or have been retained after the recolonisation from the Balkans, since the Balkan Peninsula was a possible refugia.22 This could explain the occurrence of neurotoxicity after bites by V. b. berus in Bihar County, which is close to the area where our patient was bitten. Fortunately, there is so far no suggestion that neurotoxic envenoming by V. berus populations or by any other European Vipera is in itself life-threatening.

In conclusion: (i) Venom composition is probably highly variable among the different populations throughout the area of distribution of V. berus. (ii) Neurotoxins such as Vaspin are presumably present in certain V. b. berus populations in Hungary. (iii) We hypothesize that these toxins are atavistic constituents of the berus-toxin, which disappeared from the venom of the other V. b. berus population during venom evolution.

Acknowledgements

We thank the András Jósa Hospital of Nyíregyháza (E Hungary), which permitted the publication of this case. We are grateful to Dr Andrea Czvikli (Neurology and Psychiatry, Municipal Hospital of Komló, Hungary) and Dr Christine Karlson-Stiber (Karolinska Hospital, Stockholm, Sweden) for their valuable comments on the manuscript. The authors also thank Dr Miklós Lőke (Municipal Hospital of Nagyatád, SW Hungary) for his personal communication of a case of a V. b. bosniensis bite and Dr Zoltán Korsós (Hungarian Natural History Museum) for the V. b. bosniensis photograph.

Conflict of interest: None declared.

References

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