Catastrophic Acute Ischemic Stroke After Crotalidae Polyvalent Immune Fab (Ovine)-Treated Rattlesnake Envenomation

Abstract

We report 2 cases of catastrophic ischemic stroke after Crotalidae polyvalent immune Fab (ovine)-treated rattlesnake envenomation, 1 fatal and the other resulting in significant permanent disability. It is possible these serious adverse events may have been related to venom factor(s), an interaction between venom and antivenom, occult patient blood dyscrasia, or to random unrelated events. We present the rationale for each possibility, and submit the experiences to elicit alternate postulation and communication of similar presentations.

Introduction

Ischemic stroke is extraordinarily rare after snakebite envenomation, particularly when compared with other serious yet uncommon complications, such as hemorrhagic stroke or other serious bleeding. Neurological complications after snakebite typically include paresthesias, paralysis, damage to local nerve structures, and myokymia. Many serious rattlesnake envenomings cause thrombocytopenia and hypofibrinogenemia that raise common concerns about easy bleeding, bruising, or even spontaneous bleeding. Ischemic stroke, although described for other snake envenomations (Bothrops lanceolatus, Daboia [Vipera] russelii, Echis carinatus [coloratus], Hypnale hypnale, and so forth), ^{1 –}6 has only been reported once after a rattlesnake envenomation in the United States and one other time after a South American rattlesnake bite. We describe 2 additional cases of catastrophic ischemic stroke after rattlesnake envenomation.

Case Presentations

CASE 1

A 50-year-old man was bitten on his left anterolateral calf on May 16, 2003, at approximately 12:15 pm to 12:30 pm after stepping on an unseen snake on the ground. The bite penetrated his jeans, and the patient presented to a local hospital approximately 30 minutes after the snakebite. The snake was not available for identification but was most likely a Southern Pacific rattlesnake (Crotalus oreganus helleri) based on a good description by the patient, geographical location of the incident, and clinical presentation. The patient’s pertinent medical history included coronary artery disease, for which he was taking daily aspirin as his only medication. The patient reported pain, swelling, and tenderness with palpation of approximately half of the left lower extremity. He also reported shortness of breath and paresthesias around the mouth and bilateral upper and lower extremities, with symptoms being worse in the left lower extremity. Vital signs included blood pressure, 155/96 mm Hg; heart rate, 101 beats/min; respiration, 18 breaths/min; temperature, 36.1°C; and oxygen saturation, 94% on room air. Treatment with 6 vials of Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV, Protherics, Brentwood, TN), was initiated at 2:37 pm, which was approximately 2 hours after the bite. Initial laboratory tests were significant for hemoglobin of 15 g/dL and platelet count of 269,000/mL³. Compartment pressures were obtained (anterior tibial compartment 26 mm Hg, lateral compartment 28 mm Hg, superficial posterior compartment 18 mm Hg, deep posterior compartment 20 mm Hg). Twelve additional vials of FabAV were given as illustrated in Figure 1.

Figure 1

Platelet counts, fibrinogen levels, and fab antivenom dosing over time. Stroke symptoms onset approximately 11 hours after the snakebite.

At 11:10 pm on May 16, 2003, the patient had the sudden onset of slurred speech, right-sided weakness, and right facial droop (Figure 2). Initial head computed tomography showed no signs of intracranial hemorrhage, mass effect, or sign of acute large-vessel infarct. The patient’s laboratory tests at about the same time showed no thrombocytopenia or hypofibrinogenemia. However, an additional 6 vials of FabAV were given because of the acute neurological symptoms. Stroke interventions were considered but decided against secondary to the risk of thrombolytic medication compounded by the patient’s underlying risk of hemorrhage from the rattlesnake envenoming. Brain magnetic resonance imaging showed acute infarctions involving the right frontal lobe and left parietal and occipital lobes (Figure 3). The patient continued care in the intensive care unit, and continued to deteriorate with progressive worsening of his neurological and mental status and progressive elevation in troponin I.

Figure 2

Neurological exam revealed right facial paresis sparing the forehead. Patient consented to picture for educational use.

Figure 3

Brain MRI showed infarctions.

The patient began to have hematuria and coffee grounds emesis. Laboratory testing revealed coagulopathy at this point. An echocardiogram was obtained without evidence of thrombus or significant cardiac abnormality. The patient was also tested for protein C and S activity, lupus anticoagulant, factor V Leiden, antithrombin III activity, homocysteine levels, factor II assay, and factor V assay, which were found to be normal. Subsequent head computed tomography scan showed extensive bilateral ischemic infarcts and cerebral edema, with concern for herniation. The patient continued to deteriorate until the decision between family and the medical team was made to terminate life-sustaining measures as the patient was found to have a poor prognosis and was unlikely to regain meaningful neurological function. The patient ultimately died on May 19, 2003, at 10:10 pm. Autopsy results showed significant multifocal infarction of the central nervous system and multiple emboli of small vessels involving the left ventricle and septum of the heart and right lung with associated areas of ischemia and congestion (ie, shower emboli).

CASE 2

A 17-year-old male was bitten on his right ring finger after attempting to pick up a snake on June 28, 2008, at approximately 6:40 pm. The patient was taken to a local hospital where he was found to have progressive pain, swelling, and paresthesia in the right upper extremity. He was treated with 6 vials of FabAV. The results of serial laboratory investigations are shown in Figure 4. Vital signs included blood pressure, 134/87 mm Hg; heart rate, 87 beats/min; respiration, 12 breaths/min; temperature 37°C; and oxygen saturation, 97% on room air. The snake was captured and brought with the patient to the emergency department and definitively identified as a Southern Pacific rattlesnake (C oreganus helleri) by the lead author and 2 professional herpetologists. The patient was observed in the emergency department, with additional FabAV given for progression of swelling and pain in the right upper extremity extending into the upper chest wall.

Figure 4

Platelet counts, fibrinogen levels, and fab antivenom dosing over time. Stroke symptoms onset approximately 3 days after the snakebite.

On July 1, 2008, at approximately 8:00 pm, 73 hours after the bite and after 26 vials of FabAV, the patient had acute onset of a left facial droop (CN VII paresis) (Figure 5) as well as left upper and lower extremity weakness (0/5). A head computed tomography scan was obtained, and no signs of intracranial hemorrhage, mass effect, or acute large-vessel infarct were noted initially. The patient was evaluated by our institution’s stroke team, and the decision was made to withhold thrombolytic medication owing to the risk of intracranial hemorrhage with concurrent use of thrombolytic medications with rattlesnake envenoming. The intensive care team made the decision to stop FabAV administration because of the possibility of the thrombotic event being related to the antivenom administration. Brain magnetic resonance imaging identified acute infarction in the right sylvian and parasylvian region along with scattered tiny foci of acute infarction seen in the bilateral frontal and occipital lobes as well as in the right cerebellar hemisphere (Figure 6). Echocardiogram showed no cardiac abnormality. Magnetic resonance angiogram of the head and neck found no aneurysm, malformation, or visible stenosis. The patient was also tested for protein C and S activity, lupus anticoagulant, antiphospholipid antibodies, antithrombin III activity, factor V Leiden, thrombin time, and homocysteine levels; and all were normal. He was observed for several days and was ultimately found to have normalization of all hematological abnormalities as well as some improvement in his gait with physical therapy but minimal improvement of control of his left upper extremity over the course of the next year.

Figure 5

On neurological exam, patient was found to have left facial paresis without forehead involvement.

Figure 6

Brain MRI showed infarction.

Discussion

These 2 cases have clinical and radiographic evidence that an acute ischemic stroke event occurred. Both events are also temporally associated with acute rattlesnake envenoming, with at least 1 case being definitively identified as C oreganus helleri. Neither patient was at high risk for stroke, but especially not the case involving the 17-year-old patient. Specific etiology of acute ischemic strokes after envenomation are not fully understood, although various mechanisms have been proposed, ^{7 –}11 and will be further discussed below as they relate to these cases.

It is possible that the venom from the snakes implicated in these 2 cases contained a procoagulant that is unique to this species or region, or even to these particular snakes, and is not found in other snakes. Snake venom is highly specialized, generally in a manner that optimizes the snake’s ability to capture the predominant prey in the area where the snake lives. This variability can be species distinct but there is considerable intraspecies variability. Individual snake venom composition may vary depending on the age of the snake, time of the year, and other things. Venoms of C oreganus helleri varied qualitatively and quantitatively in their activity (eg, hemorrhagic activity, amidolytic activity, coagulant activity, fibrinolytic activity, and so forth), even within a small geographical area in southern California. ¹² In a recent study, procoagulant activity was discovered for the first time in a single C oreganus helleri specimen’s venom from Wrightwood, California. ¹³ In the same study, procoagulant activity was not found in other C oreganus helleri venoms, and in contrast, other venoms, such as Crotalus atrox, had just the opposite, namely, anticoagulant activity. The C oreganus helleri venom is among the most varied venom ever described.^14,15 That may explain why thrombotic complications are so exceedingly rarely seen clinically. We believe that is the most likely explanation for these patients’ clinical presentations.

Alternatively, some venom components are not well neutralized by antivenom, likely because they are not immunogenic enough (too small, too rare) for antibodies to be formed. For example, myokymia is unfazed by megadoses of FabAV, probably because it is the result of small basic peptides similar to crotamine that do not generate much if any immune response. The procoagulant described above may be so rare that there are insufficient quantities or none in the venoms used to derive FabAV. FabAV has differential cross protectivity for C oreganus helleri venom.^15,16 That may, in part, be due to toxins such as Mohave toxin that are well-neutralized versus others that are not like components that cause myokymia. It is also possible that, under certain circumstances, antivenom better neutralizes anticoagulant properties versus procoagulant properties so that there can be a phase when hypercoagulation dominates over hypocoagulability. We believe it is a highly significant observation that the patients had both been treated with antivenom before the onset of stroke symptoms, and that this is the first time a temporal relationship of this nature has been clearly documented. We suggest that these be considered a “serious adverse event” and that the possibility of a relationship to this antivenom be considered. Specific data regarding Southern Pacific rattlesnake (C oreganus helleri) and ischemic stroke events are limited, and further investigation is needed to evaluate toxic vasculitis or endothelial injury as a cause of ischemic stroke after envenomation. Further investigation may aid in future treatment as no current guidelines or recommendations exist that illustrate appropriate actions to avoid, or treat, thrombotic events associated with rattlesnake envenomations.

Patient-specific risk factors for hypercoagulability were also considered; however, both patients had normal complete blood count, prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen, and tested negative for hypercoagulable risk factors (eg, factor V Leiden, protein C and S deficiency, lupus anticoagulant, antithrombin III activity, and homocysteine levels). True disseminated intravascular coagulation is generally not associated with rattlesnake envenomation but was a possibility we considered in these cases.

Hypotension due to hypovolemia, third spacing of intravascular fluid secondary to venom effect and systemic response, vasodilator effects of venom and systemic response, vomiting, sweating, and ultimately, hypotensive shock have been proposed as a possible etiology of acute ischemic stroke after envenomation.^8,11 In the cases presented, neither patient sustained significant or prolonged episodes of hypotension before the onset of their neurological symptoms. The ischemic strokes that occurred in these cases are also similar to those described in other case reports in the literature in that the infarcts did not appear in traditional watershed areas that are more indicative of hypotensive shock. Therefore, hypotension seems less likely as the etiology of acute ischemic stroke in the context of these cases.

Endothelial injury or toxic vasculitis from venom components resulting in increased susceptibility for thrombus formation has also been proposed as potential mechanisms. ^{8 –11,}17 In the case of Daboia russelli envenomations associated with ischemic stroke events, Gawarammana et al ¹⁸ report the vasculitis was a less likely mechanism, as many patients presented with neurological symptoms within minutes to hours of envenomation. In the cases presented in this article there was a delay in onset of neurological symptoms, providing increased time for potential vascular damage. However, each patient received timely administration of appropriate FabAV therapy before the onset of their ischemic stroke symptoms. Therefore, this mechanism seems less likely as well.

Finally, it is possible that these sequelae are multifactorial or that they are the result of a yet-to-be-described mechanism. It is for this reason that we have published these case reports—so that other experts may offer hypotheses.

Conclusions

Ischemic stroke after snakebite is a rare but devastating complication after rattlesnake envenomation. The exact cause of these events are unknown but may be related to venom components and their effect on vascular endothelial cells causing local damage and inflammation combined with venom-induced effects on coagulation, resulting in an increased susceptibility to thrombus formation. Currently, no guidelines exist regarding specific treatment of rattlesnake envenomings with complications of ischemic stroke. Further investigation is needed to better understand the exact pathophysiological mechanism and appropriate treatment as current treatments (ie, thrombolytic medications) may be contraindicated secondary to the risks of intracranial bleeding associated with these medications, particularly in the context of concomitant rattlesnake envenoming.