Vertebral Artery Stump Syndrome Caused by Varicella-zoster Virus Vasculopathy in the Absence of a Skin Rash

Abstract

A 38-year-old man without skin rash was admitted to our hospital for recurrent cerebral infarctions. Cerebral angiography revealed vertebral artery stump syndrome (VASS), and a high varicella-zoster virus (VZV) antibody index suggested VZV vasculopathy. Treatment with aspirin and anticoagulants was initiated, along with intravenous acyclovir and methylprednisolone sodium succinate. No further cerebral infarction was observed. Clinicians should be aware that VZV vasculopathy may underlie ischemic stroke in young adults and VASS even in the absence of a rash. An early diagnosis and appropriate treatment have contributed to favorable clinical outcomes.

Introduction

Varicella-zoster virus (VZV) vasculopathy is a known cause of ischemic stroke in young adults; however, 37% of patients have no rash (1), complicating the diagnostic process. Therefore, it is essential to include VZV vasculopathy in the differential diagnosis from the initial evaluation. Vertebral artery stump syndrome (VASS) is also likely to recur with cerebral infarction and requires an early diagnosis and treatment to improve the outcomes.

We herein report a case of VZV vasculopathy without rash that led to VASS in a young adult patient. A prompt diagnosis and appropriate treatment resulted in a favorable clinical course. This case underscores the importance of considering VZV vasculopathy as a potential cause of ischemic stroke in young adults and VASS even in the absence of a rash.

Case Report

The patient was a 38-year-old man without a history of herpes zoster and an otherwise unremarkable medical history. In early April 2024, he suddenly experienced dizziness, nausea, and vomiting and was diagnosed with cerebellar infarction by his physician and treated with clopidogrel-aspirin in combination. In mid-April 2024, he experienced a decline in consciousness, and a new infarct was detected in the right occipital lobe on head computed tomography (CT). The patient was then transferred to our hospital.

Upon admission, his vital signs were stable, but his level of consciousness was E1V1M1 on the Glasgow Coma Scale. No notable skin rash was observed. Laboratory findings showed normal blood counts and no abnormalities in blood sugar, lipids, thyroid function, antinuclear antibody, rheumatoid factor, anti-SSA antibody, C-anti-neutrophil cytoplasmic antibody (ANCA) and P-ANCA, anticardiolipin immunoglobulin, anti-cardiolipin-beta2-glycoprotein I complex (CL-β2CPI) antibody, lupus anticoagulant, homocysteine, or vitamins. HIV antigen and antibody levels, quantified simultaneously by a chemiluminescence enzyme immunoassay (CLEIA), were negative. On a coagulation test, the D-dimer was 1.4 μg/mL, and protein C activity and protein S antigen showed no abnormalities. A standard electroencephalogram showed a theta wave of 4-5 Hz with no epileptiform discharge.

Brain magnetic resonance imaging (MRI) revealed infarcts in the bilateral thalamus, occipital lobes, and cerebellum (Fig. 1A), with some being associated with microhemorrhaging in the infarcted area. Three-dimensional-CT angiography showed an occluded left vertebral artery (Fig. 1B, C). Transcranial echo through the foramen magnum window showed that the left vertebral artery was anterograde. Cerebral angiography indicated occlusion at the origin of the left vertebral artery, collateral circulation inflow distal to the occlusion at the C5 vertebral body, and delayed anterograde perfusion (Fig. 1D, E). Transthoracic echocardiography, transcranial echocardiography, micro-bubble transcranial Doppler ultrasound, lower-extremity echo, and a Holter electrocardiogram showed no abnormalities. Contrast-enhanced MRI was performed because of a young-onset cerebral infarction without an identified cause. Circumferential contrast enhancement of the vessel wall of the left vertebral artery was observed from its origin to the C5 cervical level (Fig. 1F), raising the suspicion of vasculitis. No abnormal enhancement was observed in any of the other vessels. Additional tests were negative for serum VZV-IgM and positive for serum VZV-IgG. A cerebrospinal fluid (CSF) analysis revealed a cell count of 2/μL, protein level of 112 mg/dL, glucose level of 81 mg/dL (CSF/serum glucose ratio =0.69), negative oligoclonal bands, negative VZV DNA, negative VZV-IgM, positive VZV-IgG (EIA titer: 1.93), and a VZV antibody index of 8.5 (normal: ＜1.5 to 2.0), indicating intrathecal antibody production against VZV.

Figure 1.

Brain and cervical cord magnetic resonance imaging, computed tomography (CT) angiography and angiographic findings. Diffusion-weighted imaging (3.0 T; TR 5,010 ms, TE 66.2 ms, b-value 1,000 s/mm²) (A). Three-dimensional-CT angiography (B: Intracranial, C: extracranial). Left subclavian angiograms (D: anteroposterior view, E: lateral view); arrows: ascending cervical artery; arrowhead: deep cervical artery; yellow arrows: left vertebral artery. Gadolinium-enhanced T1-weighted images axial view (3.0T; TR 763 ms, TE 11 ms) (F: Pre-treatment, G: Post-treatment); yellow arrowhead: Left vertebral artery at the level of the seventh cervical vertebra.

Acute vertebral artery occlusion was considered unlikely because of well-developed collateral circulation. An atherothrombotic mechanism was ruled out, given the patient's young age and absence of atherosclerotic risk factors. Patients with cerebral artery dissection were excluded based on the absence of headaches and imaging findings. The patient had no rash but a high VZV antibody index; therefore, he was diagnosed with VZV vasculopathy.

Dual antiplatelet therapy was de-escalated to aspirin monotherapy owing to the presence of hemorrhagic changes in the infarcted areas. Continuous intravenous infusion of heparin and treatment with edaravone were initiated. In addition, acyclovir (1 mg/kg, every 8 h for 14 days) and methylprednisolone sodium succinate (1,000 mg/day for 3 days) were administered intravenously. No further episodes of cerebral infarction were noted. Edaravone was subsequently discontinued, and the antithrombotic therapy was switched to a combination of aspirin and warfarin.

Follow-up MRI showed persistent occlusion of the left vertebral artery, but contrast-enhanced MRI on hospital day 19 demonstrated an improvement in vessel wall enhancement (Fig. 1G). The patient's level of consciousness recovered, although left upper quadrantanopia and generalized attentional deficits remained. He was transferred to a rehabilitation facility on hospital day 34 (Fig. 2).

Figure 2.

Clinical course. IVMP: Intravenous methylprednisolone

Discussion

VZV vasculopathy presents with neurological symptoms at a mean of 4.2 months after a rash; however, 37% of patients develop symptoms without any preceding skin manifestations. Vascular involvement is classified as small-artery (37%), large-artery (13%), or mixed type (50%) (1). Commonly affected sites include the A1 segment of the anterior cerebral artery, M1 segment of the middle cerebral artery, and the carotid siphon of the internal carotid artery (2). In recent years, involvement of the vertebrobasilar system, temporal artery, and aorta has been reported (3).

VZV reactivation occurs in the trigeminal and autonomic ganglia of the head and neck, where the virus spreads transaxonally to the cerebral arteries. Upon reaching the adventitia, it penetrates transmurally and infects all the layers of the vessel wall. This process leads to disruption of the internal elastic lamina, intimal thickening, and loss of smooth muscle cells in the media, ultimately resulting in granulomatous arteritis (4-6). Although intracranial vertebral artery involvement has been described, our case is unusual in that the lesion was located in an extracranial segment. Notably, sympathetic nerve fibers have been identified in the perivascular membrane at the vertebral artery origin (7), suggesting the possibility of viral spread along these fibers in the present case. The mechanisms underlying the diversity of the affected vascular territories remain unclear, underscoring the need for further case accumulation and pathological investigations.

Virological confirmation plays a critical role in the diagnosis. In patients with rash, CSF VZV DNA is detectable in 30% of cases and CSF VZV-IgG antibodies in 93% of cases (8). Among those without rash, 43% were positive for CSF VZV DNA, and 100% were positive for CSF VZV-IgG antibodies (9). Therefore, evaluating intrathecal antibody production, particularly using the VZV antibody index, is a valuable diagnostic tool.

The diagnostic criteria for VZV vasculopathy (10) include A) neurological symptoms of stroke, B) diagnostic imaging of cerebral ischemia or hemorrhaging, C) rash, D) angiopathy on angiography, and E) evidence of VZV infection (VZV level in CSF, production of specific IgM and IgG in CSF, and VZV antigen in brain tissue and cerebrovascular biopsy). A diagnosis was considered possible with criteria A+B±C, probable with A+B±C+D, and definitive with A+B±C+D+E. Although no standardized treatment exists, a combination of intravenous acyclovir (10 mg/kg, every 8 h for 14 days) and prednisone (1 mg/kg/day, every 5 days for inflammation; no taper is needed) has been reported to be effective (1,11). In our case, a definitive diagnosis of rash-negative young-onset VZV vasculopathy was made according to these criteria. If both CSF VZV DNA and antibody indices are negative, VZV vasculopathy can be reasonably excluded. Thus, early consideration of VZV vasculopathy is crucial for preventing treatment delays. Lumbar puncture should be actively performed in young patients without rash, particularly if they are immunocompromised, have suspected vasculitis, recurrent strokes, or no clear etiology, despite a thorough investigation.

VASS refers to embolic infarction that occurs after the documented occlusion of the vertebral artery in the posterior circulation. This mechanism is thought to involve embolization of stagnant clot fragments, a low-flow state, and the presence of a vascular stump (12). Two sets of diagnostic criteria for VASS have been proposed in literature (13,14). In our case, VASS was diagnosed after excluding alternative etiologies, such as intracranial vertebrobasilar artery lesions, cardioembolism, aortogenic embolism, paradoxical cerebral embolism, and bony stroke. Although no standard therapy has been established, anticoagulation has been reported to be effective (15). Recurrent ischemic events occur in one-third of patients during hospitalization, and one-quarter of patients have poor outcomes (modified Rankin Scale score 3-5 at discharge) (13). An early diagnosis and appropriate antithrombotic therapy are essential for improving the prognosis. In our case, timely initiation of anticoagulation therapy, along with accurate recognition of underlying VZV vasculopathy, successfully prevented VASS recurrence.

In conclusion, we herein report a rare case of VZV vasculopathy without a rash leading to VASS. This case highlights the importance of an early diagnosis and targeted treatment to improve the prognosis. Clinicians should consider VZV vasculopathy as a potential trigger for VASS even in the absence of cutaneous manifestations.

The authors state that they have no Conflict of Interest (COI).