Acute Cryptogenic Stroke During West Nile Virus Infection: Case Report

Abstract

West Nile virus is an emerging infection in North America but has not traditionally been associated with acute vascular events. We report a 57-year-old healthy male who developed pharyngitis and a corporeal rash, followed 1 week later by an acute cryptogenic stroke. Following successful endovascular thrombectomy, cerebrospinal fluid analysis revealed acute West Nile virus infection. While severe cases of vasculopathy have been described with flavivirus infection, stroke associated with relatively mild symptoms has not been. Given increasing evidence that viral and bacterial infections of many varieties may be stroke triggers, West Nile virus and other flaviviruses may represent an uncommon but underappreciated trigger of cryptogenic stroke. We review indirect evidence that viral endothelial tropism or a nonspecific peri-infectious inflammatory state may be causative mechanisms.

Introduction

West Nile virus (WNV) is an emerging infection in North America but has not traditionally been associated with acute vascular events. Infection is presumed to be minimally symptomatic in the majority of cases. We report a 57-year-old healthy male who presented with fever and rash, retrospectively diagnosed as typical of WNV, who subsequently presented with an acute stroke. We raise the possibility that acute WNV infection may be a trigger for stroke, even with relatively mild symptoms, and review indirect evidence that viral endothelial tropism or a nonspecific peri-infectious inflammatory state may be causative mechanisms.

Case Presentation

A healthy 57-year-old male working in rural southern Alberta, Canada, in August developed pharyngitis and a descending maculopapular rash on the torso, arms, legs, and feet including the palms, but sparing his soles, head, and neck. He presented to his primary physician and received amoxicillin-clavulanic acid for a presumptive diagnosis of Streptococcal pharyngitis. When symptoms did not improve, this was followed by doxycycline for empiric coverage of Rocky Mountain spotted fever due to possible occupational tick exposure. His symptoms were relatively mild and he continued to work in a physical outdoor role.

Eight days from symptom onset, he had acute onset of right hemiplegia and aphasia. He was airlifted to a stroke center where a “T” occlusion of the distal left internal carotid artery was treated with intravenous thrombolysis and endovascular thrombectomy with TICI 2c flow. Following successful first-pass recanalization, noted middle cerebral artery vessel irregularities were presumed due to vasospasm and were treated with intra-arterial verapamil (Figure 1). Due to the emergent nature of the procedure, a 4 vessel angiogram was not performed.

Figure 1.

Acute “T” occlusion of left middle cerebral artery during thrombectomy (A). Postrecanalization images show marked vasospasm in the middle cerebral artery (B). C and D, Final infarction seen on fluid attenuated inversion recovery and diffusion weighted images.

Following recanalization, hemiplegia improved but aphasia persisted on day 2 and the National Institutes of Health Stroke Scale (NIHSS) improved from 13 to 5 at 24 hours. He was mildly encephalopathic, though his rash completely resolved during hospitalization. Magnetic resonance imaging showed patchy infarction in the left insula, basal ganglia, and operculum that did not fully explain his mental status (Figure 1C and D). Echocardiogram and 24-hour cardiac monitoring were unremarkable and no diffuse vasculopathy was noted on angiography. Blood counts, coagulation parameters, and C-reactive protein were normal. Cerebrospinal fluid (CSF) cell count was normal, with a mild increase in protein (0.58 g/L). West Nile virus was detected via polymerase chain reaction in CSF and serum immunoglobulin (Ig)M was positive with negative serum IgG. Lyme and Rickettsial serologies were ultimately negative.

His clinical state improved markedly on day 5 and he was discharged with an NIHSS of 0. At 1-month follow-up, he had returned to work with no residual neurologic deficits. Two years later, he had no recurrence on low dose acetylsalicylic acid and had not developed any vascular risk factors.

Discussion

Although WNV neuroinvasive disease is reported to occur in 0.7% of infections,¹ few cases of stroke have been reported,^2-5 and there has been no evidence of increased cardiac or acute vascular events during WNV infection.⁶ A single case of intracranial hemorrhage and intracranial vasculitis coincident with typical WNV encephalitis has been published.⁷ Despite the paucity of reported large vessel involvement, WNV associated chorioretinitis with retinal vasculitis is described in multiple cases, often occurring 2 weeks after infectious symptoms.^8,9

Related flaviviruses have equally not been strongly associated with cardiovascular events, although Dengue virus has been associated with infrequent cases of myocardial dysfunction,¹⁰ lacunar stroke,^11,12 and coagulopathy. However, the endothelial dysfunction and vasculopathy of Dengue viruses typically manifest as increased vessel permeability and hemorrhagic complications rather than vasospasm or thrombosis.¹³ Such endothelial viral tropism has been studied in experimental settings for many flaviruses.¹⁴ The viral NS-1 protein, highly conserved throughout the flavivirus family, has been shown to disseminate widely in the blood stream, where it acts to disrupt blood–brain barrier tight junctions, increase vascular permeability in multiple vascular beds, and disrupt many key endothelial cell proteins.¹⁴ Whether such mechanisms also predispose to arterial, venous, or cardiac atrial thrombosis is unclear, although the observations of WNV associated chorioretinitis suggest that various vascular beds may respond differently.

Alternatively, infection has nonspecifically been associated with a short-term increase in stroke risk.^15-17 This has been the case for both bacterial infections as well as viral illnesses: preceding influenza-like illness has been associated with increased risk of stroke in otherwise young, healthy patients.¹⁸ The contemporary Coronavirus disease-19 epidemic has provided similar suggestions of an increased stroke risk during the acute infection period.^19,20 As with our present case, knowledge of whether this increased risk is driven by specific viral mechanisms or more general physiologic factors could help improve our understanding of stroke pathophysiology and provide opportunities for primary prevention.

Although our case does not exhaustively exclude uncommon causes of stroke, the co-occurrence of clinically and laboratory-proven acute WNV infection and acute stroke is by itself novel, regardless of the underlying mechanism. The lack of stroke recurrence or emergence of vascular risk factors 2 years later is also supportive.

West Nile virus is a notifiable disease in Alberta and is known to seasonally circulate in the south-eastern region of the province. In 2018, there were 49 reported cases including 14% with neurological involvement for a total rate of 1.17 cases per 100 000 people that year.²¹ Given the low incidence of WNV infection in many regions for much of the year, there is currently insufficient evidence to suggest indiscriminate WNV screening in stroke patients. However, history taking that emphasizes explicit questions about recent infectious symptoms may produce a higher yield population in which to consider testing. However, a counterpoint to testing only those who are symptomatic is found in reports that even asymptomatic herpesvirus infection is a risk factor for pediatric stroke.²² Consideration could be given for testing for WNV in young patients with cryptogenic stroke in areas and seasons with known WNV circulation.

We hypothesize that WNV infection directly causes cerebrovascular endothelial dysfunction. As 80% of patients are asymptomatic,¹ WNV infection and other flaviviruses may be an overlooked stroke trigger in the appropriate season, although this hypothesis remains untested. Recent or mild viral illness of any cause should be considered as a potential stroke trigger in cryptogenic cases. The possibility that cryptogenic stroke may be triggered by mild infections with other endemic flaviviruses in affected jurisdictions also warrants further study.