Complex regional pain syndrome following viper-bite

1 Introduction

Complex regional pain syndrome (CRPS) is a serious and disabling chronic pain condition, usually occurring in a limb. The clinical picture is dominated by pain and symptoms of autonomic dysfunction, but may also involve motor disability. Complex regional pain syndrome (CRPS) has a reported incidence up to 26 per 100,000 person years [1]. CRPS may develop as a consequence of an injury, most frequently following fractures [1,2], but may also occur without any known eliciting event [3]. Despite the high number of snake-bites worldwide, CRPS are described only in three case-reports (from Turkey, Nepal and Korea) [4,5,6]. CRPS after snake bites in Western Europe has to our knowledge not previously been reported.

2 Case story

The patient is a 22 year old woman, previously healthy and with no family history of chronic pain syndromes. She was prior to the incident working full time as a cook. On October the 7th 2014, she discovered a discolouring of the skin in the right arm, above the elbow up to the shoulder. Simultaneously, she developed a deep aching pain in the same area, rapidly expanding to involve the whole right arm. She consulted her private doctor (Dr. Skulberg) who noticed two bites of viper in the elbow region. She recalled having thrown a bag of garbage in a bin, situated on the edge of a wood two days prior to the appearance of her symptoms. The red discolouring of the skin gradually disappeared within a week while the pain continued. She was treated with cortisone. In addition to the spontaneously ongoing aching pain, she also suffered from paroxysmal pain in the whole right arm, of short duration (seconds) and with a stinging character. She had no allodynia to light touch or hyperalgesia to pin-prick/blunt pressure in this early stage.

She was during the two following months on 100% sick-leave and the pain gradually diminished but did not disappear. The pain worsened as she returned to work, first 50% in 1½ month and 100% from January 2015.

From December 2014 she developed an intermittent oedema in the fingers and the radial part of the lower right arm, appearing with duration of one day each 1-3 weeks, from January 2015 with a simultaneous blue discolouring of the skin, from the back of the hand and lower arm up to the level of the elbow. She also noticed that her hand often was cold, and if not cold it was moist with an excessive abnormal sweating, the sweat drops dripping from her hand. She had neither noticed additional autonomic dysfunctions nor any motor problems. Prior to the investigation at OUS-Rikshospitalet, EMG/neurography had proven normal. The patient consents to the publication of her experience (Fig. 1).

Fig. 1

Picture of discolouring of skin a few days after viper bite.

3 Methods

We performed a clinical investigation, quantitative sensory testing (QST; measurement of thermal detection thresholds), measurement of spontaneous sweating (resting sweat output (RSO)) and quantitative sudomotor axon reflex (QSART).

4 Quantitative sensory testing (thermal detection thresholds)

Threshold temperatures for the sensation of warmth, cold, heat pain and cold pain were determined using a computerized Thermotest (SENSElab, Somedic A/B, Hörby, Sweden) with a ther-mode size of 5 cm × 2.5 cm. Warmth detection threshold (WD), cold detection threshold (CD), heat pain detection threshold (HP) and cold pain detection threshold (CP) were determined from a baseline temperature of 32° C with a 1 °C/s rate of change. The patient was instructed to push a signal-button when the relevant sensation was perceived. When this happened or if cut-off temperature (50° C and 10° C) was obtained, the temperature returned to baseline. WD, CD, HP, CP were determined from the thenar eminence, the region of the elbow and the upper arm. For calculations of thresholds, an average of five recordings for WD and CD and the average of three recordings for HP and CP were used. The values were compared with the healthy left arm.

5 QSART

Evoked sweat response at rest was measured by the Quantitative sudomotor axon reflex tester (WR Medical Electronics Co., Stillwater, USA). It turned impossible to perform the investigation from the palm of the hand as intended, and we therefore had to investigate the dorsum of the hand.

To evoke axon reflex sweating, iontophoresis (2 mA for 5 min) of 10% acetylcholine (ACh) was started after a stable baseline sweating level had been obtained. A commercially available device (Ion-tophor ll, Life-Tech Inc, Stafford, TX, USA) was used for this purpose. Axon reflex sweat output during the 5 min of iontophoresis and additional 10 min was recorded via a sweat capsule with an area of 0.767 cm² attached to the skin of the back of both hands.

6 Results

7 Discussion

The patient fulfilled the Budapest criteria [7] of CRPS with a lasting pain six months following a bite, with symptoms of hyperalgesia and autonomic dysfunction and findings of hyperalgesia and abnormal sweating. Sweating abnormality was demonstrated by measuring increased resting sweat output [8] at the thenar aspect of the affected side, but was not apparent by a mere clinical inspection of the arm. We also found signs compatible with a small fibre affection in the right arm, both as reduced sensation of cold and warmth (mediated via afferent small A-delta/C-fibres) as well as an asymmetric QSART with decreased response on the affected side (function of distal postganglionic sympathetic sudomotor C-fibres).

There are only three case reports describing development of CRPS following snake bites world-wide, from Korea [6], Nepal [5] and Turkey [4].There has, to our knowledge, been no report of CRPS following bite of a Vipera Berus, the most widely distributed viper in Europe [9]. At least 30% of bites from Vipera Berus are “dry” [10], i.e. without poison and local/systemic reactions. In addition, patients may be unaware of being bit, possibly also because a bite from a viper is not necessarily painful [11], although typically immediate pain is described [11,12]. Normally one would be able to see the bite as two pin-prick areas with a distance of 3-9 mm apart [13], It is, however, not uncommon to find only bite from one tooth, due to possible oblique hit, the patient wearing sandals or other reasons (Dr. Skulberg’s experience).

In our patient, despite a short time lag before the debut of symptoms, the clear symptoms would indicate a venomous bite. The poison of Vipera Berus is a mixture of enzymes and polypep-tides with both local and systemic actions 13], predominantly being cytotoxic and haemorrhagic [9]. In addition, endogenous substances such as histamine, bradykinin, prostaglandin and serotonin are released [13], substances which are, amongst other, linked to modulation of nociceptors [14] and a potential development of hyperalgesia and pain. However, the complete effect of the venom on aspects involved in nociception and pain may not have been fully elucidated. In this respect, although of unknown relevance for Vipera Berus, it was demonstrated both how a snake venom (from Texas coral snake) may evoke pain [15], but also, somehow more surprisingly, how pain may be abolished by a snake venom (from black mamba) [16], adding to the list of possible new pharmacological targets derived from venomous animals [17].

The local reactions will normally appear within a few hours and may further develop over 2-3 days and may include pain, skin discolouring, oedema, blisters, thrombophlebitis, and rarely rhabdomyolysis and compartment-syndrome [13]. Although most patients will recover within relatively short time, some will have prolonged complaints. One study described that recovery in a quarter of patients took between 1 and 9 months, often with disabling aching pain and intermittent swelling [11]. Some of these cases may possibly reflect undiagnosed CRPS.

It is not surprising that a viper-bite may result in CRPS, since CRPS may result from many kinds of eliciting events. However, there are millions of snake bites world-wide annually [18] and although long lasting pain are reported (e.g. [11]), CRPS after snake bites has only been reported in a very few patients in the research literature [4,5,6]. In our opinion, it is not unlikely that CRPS after snake bite is underdiagnosed and/or underreported. We therefore think it is important to report this case to increase the awareness of also bites from a common viper as a possible reason for development of CRPS. CRPS-conditions need special attention and care, and, despite some scarcity of evidence-based data, there is a consensus that CRPS should be diagnosed and treated early to avoid a long-lasting chronic pain situation [19]. In the report from Nepal, the patient was successfully treated with sympathetic blocks [5]. Our patient had received cortison-treatment and used pregabalin (Lyrica) and an antiflogisticum (Ibux) with some effect. She was admitted to a pain clinic for sympathetic blocks, but has not yet been treated. It may also be a problem that patients are unaware of being bit (personal reference Dr. Skulberg, six patients in 2014). This implies also that in a sudden development of skin discolouring, swelling and pain during summer-season, one should consider the possibility of a viper-bite, in particular in areas where vipers are common.

In the present case report, we have employed neurophysio-logical evaluations like QST (measurement of thermal detection thresholds) as well as sudomotor testing (RSO and QSART) to elaborate on small nerve function. We emphasize that these methods are not necessary investigations in order to diagnose a complex regional pain syndrome. CRPS is a clinical diagnosis, according to the criteria of Harden et al. [7]. It is very important that doctors are aware of this. As neurophysiologists, we receive many admittances to QST (testing of thermal detection thresholds) with the question of CRPS, but it is a misunderstanding that determination of thermal tresholds is necessary to set a diagnosis, as affection of afferent small nerve fibres are not part of the diagnostic criteria of CRPS. We may, however, in some cases find an allodynia to cold or warmth, which could be helpful in the sensory evaluation of the patients.

Likewise, it is not necessary to use neurophysiological methods to prove autonomic dysfunction. However, sudomotor abnormalities might exist in isolation from vasomotor abnormalities and may be difficult to expose. As pointed out by Low [8], methods assessing sudomotor asymmetries may be helpful in the diagnosis of CRPS. This is illustrated by the finding of sudomotor side differences (QSART and RSO) in our patient, despite normal findings at clinical inspection. It should be noted that there was an inverse relationship between (reduced) QSART and (increased) RSO in the affected side. A lack of positive correlation between RSO and QSART has previously been described in patients with chronic limb pain with/without reflex sympathetic dystrophy [20], probably reflecting that these methods measure different aspects of sweating. It would be impossible to describe the pathophysiological mechanisms involved in the development of CRPS in our patient, other to guess that they would be related to the venom.

Highlights

• CRPS-1 is a complex regional pain syndrome without obvious damage to a peripheral nerve.

• CRPS-1 developed after a viper-bite in the right elbow of a young woman, recognized only by her GP.

• Viper-bites are frequent in the Nordic countries and are often not recognized by the bitten person.

• Thus, we propose that unrecognized viper-bites are among the 10% of CRPS-1 with no obvious inciting event.

• This patient became pregnant shortly after the CRPS-1 started, limiting treatment options.

• Lidocaine 5% patch (Versatis®) relieved her intense allodynic upper arm.