Varicella-related Multifocal Vasculopathy: Under-recognized Cause of Young Stroke
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.266233
Source of Support: None, Conflict of Interest: None
Varicella zoster virus (VZV) vasculopathy is an infection of intracranial arteries often manifesting as stroke, mostly ischemic and less often hemorrhagic. It may occur either after primary infection with VZV or after viral reactivation. It has been presented with various nomenclatures, namely, granulomatous angitis, VZV vasculitis, or post-varicella arteriopathy. Being an under-reported entity, the exact incidence of VZV-associated stroke in adults is difficult to estimate, but in children it accounts for ~31% of all arterial ischemic strokes. Common clinical features seen associated with VZV vasculopathy include headache, changes in mental status, aphasia, ataxia, hemianaesthesia/paresis, and visual loss.
A 32-year-old self-employed gentleman, with no prior comorbidities, presented with vesiculo-papular eruptions all over the body [Figure 1]c with sudden onset weakness of the right side of the body and difficulty in speaking before presentation. Five members of his family including his wife, children, and brothers had similar eruptions. Detailed evaluation showed right hemiparesis with global aphasia. There were no other neurologic abnormalities including nuchal rigidity. Magnetic resonance imaging (MRI) brain showed multiple patchy T2/FLAIR hyperintensities in the grey and white matter in left frontal, parietal, and temporal lobes [Figure 1]a. MR angiography showed normal M1 and M2 segments with attenuated M3 and M4 segment of the left middle cerebral artery (MCA) [Figure 2]a and [Figure 2]b.
Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis (10 cells) with high proteins (78 mg/dL) and normal sugars (114 g/dL, against random blood sugar of 166 g/dL). India ink preparation for Cryptococcus spp. and adenosine deaminase (ADA), ZN staining, and polymerase chain reaction (PCR) for Mycobacterium tuberculosis were all negative. CSF IgM/IgG antibodies against VZV were negative. Serum PCR for varicella zoster was positive. CSF and serum herpes simplex virus (HSV) PCR and IgM/IgG antibodies were negative. The results of laboratory blood tests, including glycemia, coagulation panel, and thrombophilia screening, were normal. Immune diseases' markers were negative. Human immunodeficiency virus, hepatitis B virus surface antigen, and anti-hepatitis C virus antibody tests were negative. Echocardiography and electrocardiography were normal ruling out the possibility of cardioembolic origin of stroke.
Clinical history with MRI findings and positive VZV PCR in serum added up to the diagnosis of VZV vasculopathy-related acute ischemic stroke. He was managed conservatively with intravenous acyclovir (30 mg/kg/day in three divided doses) for 14 days along with intravenous methyl prednisolone for 5 days. Over the next 2 weeks, his aphasia improved with improved comprehension and word output with occasional literal paraphasias. At 3 months follow-up, his weakness has improved completely, but continues to have naming difficulty.
VZV is the only virus in human beings that has been demonstrated to replicate in arteries and produce vasculopathy. Contrary to the common presentation, it per se is not primarily encephalitis, but a vasculopathy due to secondary to VZV infection within cerebral arteries. The clinical diagnosis is based on a continuum of recent zoster infection followed by focal neurological signs with radiologic abnormalities proving cerebral ischemia/hemorrhage. Narrowing or beading in cerebral arteries, as demonstrated in cerebral angiography, with CSF pleocytosis aids clinical possibility.
VZV vasculopathy may be unifocal or multifocal. The most common location unifocal vasculopathy affects is the ophthalmic distribution zoster in elderly adults or childhood varicella infection. Multifocal vasculopathy usually affects branches of large cerebral arteries or small cerebral arteries, mostly in immunocompromised individuals. Most often, both large and small arteries are involved, followed by small arteries alone, and, least often, by large arteries alone. Various animal studies have put forth the hypothesis of direct spread of VZV to cerebral arterial walls, with replication and damage of the cerebral vessels. Both intracranial and extracranial blood vessels receive the afferent fibers from trigeminal and other ganglia, thus providing an anatomical pathway for the transaxonal spread of virus.
Common radiological abnormalities in VZV vasculopathy include cortical and deep grey and white matter involvement, especially at the grey–white matter junction. Segmental constriction, often with poststenotic dilatation, is a common angiographic finding. A detailed description of 30 subjects with virologically verified VZV vasculopathy, brain imaging, and vascular studies indicated involvement of both large and small arteries in 50%, pure small-artery involvement in 37%, and pure large-artery disease in four (13%) patients. VZV vasculopathy resulting in intracranial hemorrhages has been reported in literature.,
CSF analysis usually shows pleocytosis (usually <100 cells, predominantly mononuclear), in two-thirds of patients. CSF VZV PCR and anti-VZV IgG antibody tests are the cornerstone in confirming the diagnosis of VZV vasculopathy. The detection of VZV antibody is more sensitive than VZV DNA for diagnosis and the former generally lasts for weeks to months.
VZV vasculopathy is often underdiagnosed because (1) symptoms and signs may occur months after zoster; (2) around 30% of patients do not have a preceding zoster rash; (3) up to one-third of patients do not have CSF pleocytosis; and (4) sensitivity of PCR analysis of CSF for VZV DNA is only 30% and that of IgM VZV antibodies 96%.
In our patient, prima facie clinical features of eruptions all over the body with similar features in his family members and MRI features of prominent grey and white matter involvement along with angiography showing attenuation of distal left MCA narrowed in on the diagnosis of VZV vasculopathy-related stroke. Positive VZV PCR in serum was contributory to the diagnosis. This article aims to sensitize the readers toward VZV vasculopathy and its features, which would help in early identification and management, decreasing the morbidity and mortality caused by the disease.
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[Figure 1], [Figure 2]