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Objective: Varicella zoster virus (VZV) is an under-recognized yet treatable cause of stroke. No animal model exists for stroke caused by VZV infection of cerebral arteries. Thus, we analyzed cerebral and temporal arteries from 3 patients with VZV vasculopathy to identify features that will help in diagnosis and lead to a better understanding of VZV-induced vascular remodeling. Methods: Normal and VZV-infected cerebral and temporal arteries were examined histologically and by immunohistochemistry using antibodies directed against VZV, endothelium, and smooth muscle actin and myosin. Results: All VZV-infected arteries contained 1) a disrupted internal elastic lamina; 2) a hyperplastic intima composed of cells expressing α-smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SM-myosin) but not endothelial cells expressing CD31; and 3) decreased medial smooth muscle cells. The location of VZV antigen, degree of neointimal thickening, and disruption of the media were related to the duration of disease. Conclusions: The presence of VZV primarily in the adventitia early in infection and in the media and intima later supports the notion that after reactivation from ganglia, VZV spreads transaxonally to the arterial adventitia followed by transmural spread of virus. Disruption of the internal elastic lamina, progressive intimal thickening with cells expressing α-SMA and SM-MHC, and decreased smooth muscle cells in the media are characteristic features of VZV vasculopathy. Stroke in VZV vasculopathy may result from changes in arterial caliber and contractility produced in part by abnormal accumulation of smooth muscle cells and myofibroblasts in thickened neointima and disruption of the media.

A patient with zoster in multiple dermatomes, severe headache, and normal magnetic resonance angiography (MRA) and 4-vessel digital subtraction angiogram (DSA) developed 9 anterior circulation aneurysms 2 months later. Antiviral treatment resulted in clinical improvement, size reduction of most aneurysms, and complete resolution of the 2 largest aneurysms.

Background: Varicella zoster virus (VZV) vasculopathy produces stroke secondary to viral infection of cerebral arteries. Not all patients have rash before cerebral ischemia or stroke. Furthermore, other vasculitides produce similar clinical features and comparable imaging, angiographic, and CSF abnormalities. Methods: We review our 23 published cases and 7 unpublished cases of VZV vasculopathy. All CSFs were tested for VZV DNA by PCR and anti-VZV IgG antibody and were positive for either or both. Results: Among 30 patients, rash occurred in 19 (63%), CSF pleocytosis in 20 (67%), and imaging abnormalities in 29 (97%). Angiography in 23 patients revealed abnormalities in 16 (70%). Large and small arteries were involved in 15 (50%), small arteries in 11 (37%), and large arteries in only 4 (13%) of 30 patients. Average time from rash to neurologic symptoms and signs was 4.1 months, and from neurologic symptoms and signs to CSF virologic analysis was 4.2 months. CSF of 9 (30%) patients contained VZV DNA while 28 (93%) had anti-VZV IgG antibody in CSF; in each of these patients, reduced serum/CSF ratio of VZV IgG confirmed intrathecal synthesis. Conclusions: Rash or CSF pleocytosis is not required to diagnose varicella zoster virus (VZV) vasculopathy, whereas MRI/CT abnormalities are seen in almost all patients. Most patients had mixed large and small artery involvement. Detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA ( p GLOSSARY: EIA = enzyme immunoabsorbent assay; VZV = varicella zoster virus.

A 75-year-old woman developed periorbital pain and blurred vision OS. Visual acuity (VA) was 20/40 OD, 20/400 OS with mild left relative afferent pupillary defect (APD). Left optic nerve was swollen and hyperemic with peripapillary flame hemorrhages (figure, A). Erythrocyte sedimentation rate (ESR) was 124 mm/h. She was treated with IV methylprednisolone, 250 mg every 6 h. On day 3, headache and vision improved. ESR was 98 mm/h and C-reactive protein was 1.40 mg/L. Rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies titers were negative. On day 4, left temporal artery biopsy revealed thickened intima and intact internal elastic lamina (figure, B) but no medial necrosis characteristic of giant cell arteritis (GCA). Sections of the temporal artery were deparaffinized and incubated with 10% normal sheep serum (NSS) in phosphate-buffered saline (PBS) for 1 hour at room temperature, rinsed 3 times in PBS, and incubated overnight at 4°C with polyclonal antibodies raised against the varicella-zoster virus (VZV) open reading frame 63 protein (1:1,000 dilution) or with normal rabbit serum (1:1,000 dilution). The next day, sections were washed 3 times in PBS, incubated with a 1:300 dilution of biotinylated goat antirabbit immunoglobulin G (IgG) in PBS containing 5% NSS, washed 3 times in PBS, incubated for 1 hour at room temperature with alkaline phosphatase–conjugated streptavidin (1:100 dilution), and washed 3 times with PBS. The color reaction was developed for 5–30 minutes with fresh fuchsin substrate system. Levamisole was added to the color reaction to block endogenous phosphatase. Uninfected and VZV-infected human fibroblast lung cells were used as controls (not shown). Steroids were changed to oral prednisone 60 mg daily. On day 7, brain MRI with gadolinium was negative. On day 9, pain and vision worsened. On day 11, orbital CT and head CT angiography were negative. On day 15, VA was 20/400 OS with relative left APD. On day 17, OS became blind without direct pupillary light reaction; fundus was obscured by vitreous hemorrhage. CSF contained 8 leukocytes/mm3, protein 72 mg/L, and glucose 54 mg/L. CSF cultures for bacteria, fungi, acid-fast bacilli, and cytology were negative. Because asymptomatic temporal artery biopsy was GCA-negative, VZV ischemic optic neuropathy (ION) was considered, and she was treated with IV acyclovir, 10 mg/kg every 8 hours for 7 days. On day 31, CSF contained anti-VZV IgG but not anti-herpes simplex virus IgG antibody, and serum-to-CSF ratio of anti-VZV IgG was reduced (14) compared to ratios for total IgG (121) and albumin (81). Immunohistochemistry and pathology revealed VZV antigen and neutrophils in the original left temporal artery specimen (figure, C). On day 31, she was treated with oral valacyclovir, 1 gram TID for 6 weeks; prednisone was reduced to 20 mg daily and tapered 5 mg/week. Six weeks later, pain resolved, and VA improved to finger counting. Left optic nerve was pale with clear margins and resolution of hemorrhage.

We present a case of spinal cord infarction due to varicella zoster virus (VZV) vasculopathy identified by diffusion-weighted MRI (DWI) and confirmed virologically. An 84-year-old Caucasian woman with a history of breast cancer and essential thrombocythemia developed the apoplectic onset of severe low back pain, numbness and paralysis of both legs, and bowel and bladder incontinence. Initial CSF exam was acellular with protein of 31 mg%. She was treated with oral prednisone (10 mg qid) without improvement and was hospitalized 4 days later. On admission, she was afebrile, blood pressure was 162/73 mm Hg, and heart rate 111 beats/min. Physical exam revealed hepatosplenomegaly and 1+ bilateral lower extremity edema. There was flaccid lower extremity paralysis. Proprioception and vibratory sensation were absent in the feet, although vibration was perceived at the knees, and there was a T7 sensory level to light touch, pinprick, and temperature. Deep tendon reflexes were absent in the legs, and there was no response to plantar stimulation bilaterally. There were 41,000 white blood cells (WBCs) and 550,000 platelets. Flow cytometry of blood WBCs revealed no clonal populations. Serum lactic dehydrogenase and uric acid levels were …

Skin rash and depigmentation are common in patients with meningitis and meningoencephalitis. Skin changes must always be evaluated in conjunction with the clinical symptoms, signs, brain imaging, and laboratory abnormalities, particularly the features of the CSF pleocytosis. The purpose of this montage is to help the clinician identify a specific etiologic agent as early as possible.

Background: Factors that may obscure the diagnosis of varicella zoster virus (VZV) vasculopathy include the absence of rash before TIAs or stroke as well as similar clinical features and imaging, angiographic, and CSF abnormalities to those of other vasculopathies. Diagnosis relies on virologic confirmation that detects VZV DNA, anti-VZV IgG antibody, or both in the CSF.Methods: We reviewed our current 14 cases of patients diagnosed with VZV vasculopathy based on combined clinical, imaging, angiographic, or CSF abnormalities. All CSFs must have been tested for VZV DNA by PCR and for anti-VZV IgG antibody by enzyme immunoassay and found to be positive for either or both. Of the 14 subjects, 8 had a history of recent zoster, whereas 6 had no history of zoster rash before developing vasculopathy.Results: All 14 subjects (100%) had anti-VZV IgG antibody in their CSF, whereas only 4 (28%) had VZV DNA. The detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA (p < 0.001).Conclusions: In varicella zoster virus (VZV) vasculopathy, the diagnostic value of detecting anti-VZV IgG antibody in CSF is greater than that of detecting VZV DNA. Although a positive PCR for VZV DNA in CSF is helpful, a negative PCR does not exclude the diagnosis of VZV vasculopathy. Only when the CSF is negative for both VZV DNA and anti-VZV IgG antibody can the diagnosis of VZV vasculopathy be excluded.

I read with interest the article by Gilden et al.,1 but found myself questioning the reported findings and conclusions. The immunohistochemistry describing the presence of varicella-zoster virus (VZV) protein in the majority of temporal artery biopsies of patients with giant cell arteritis (GCA) is intriguing. However, the findings of VZV antigen staining in the vessel wall, mostly in smooth muscle cells, was not addressed by the authors in other arteries or in other smooth muscle cells. In my experience, the VZV antibodies bind nonspecifically to smooth muscle and skeletal muscle cells, and therefore can be detected in similar frequencies in GCA cases, non-GCA temporal arteries, any other arteries, or even in endometrial leiomyoma. The detection of this staining pattern, similar to the one described,1 is seen without surrounding inflammatory response, supporting …

Raeder paratrigeminal syndrome (painful Horner syndrome with trigeminal nerve involvement) is a poorly recognized complication of multiple disorders including carotid aneurysm, cancer, herpes zoster, maxillary sinusitis, and chronic otitis media. Although brain MRI has revealed carotid artery narrowing,1 dissection,2,3 and aneurysm,4 Raeder syndrome produced by inflammatory disease surrounding the carotid artery has not been verified by brain imaging until now.

This case report illustrates previously undescribed features of chronic active varicella zoster virus (VZV) infection, including a 4-month delay between the onset of zoster and zoster sine herpete, involvement of 9 dermatomes on progression of zoster to zoster sine herpete, and the presence of both VZV DNA and anti-VZV immunoglobulin G (IgG) in the CSF.

Varicella zoster virus (VZV), a ubiquitous human herpesvirus, causes chicken pox on primary infection and then establishes lifelong latency in all cranial nerve, dorsal root, and autonomic ganglia. When VZV-specific cell-mediated immunity declines, such as in elderly and immunocompromised individuals, virus reactivates in one or more ganglia and typically travels peripherally to cause herpes zoster in the corresponding dermatomes. Herpes zoster can be complicated by stroke and has been described clinically as VZV vasculopathy, granulomatous angiitis, post varicella arteriopathy, and herpes zoster ophthalmicus (HZO) with delayed contralateral hemiparesis. The likely mechanism for stroke caused by VZV is direct viral infection of cerebral arteries. This assertion is supported by animal studies identifying afferent fibers from trigeminal and dorsal root ganglia to both intracranial and extracranial blood vessels, providing an anatomic pathway for spread of the virus,1,2 and observations of viral particles, antigens, and DNA in affected arterial vessels in VZV vasculopathy cases.3,4 Several studies have examined varicella and the risk of stroke in children,5,6 but large studies in the adult population regarding the frequency and risk of …

A 21-year-old woman was irradiated after resection of a pituitary adenoma. A few weeks later, she developed right ophthalmic-distribution zoster and right abducens palsy. Zoster rash resolved, but persistent dysesthesias led to constant rubbing and scratching, ultimately leading to ulceration. Skin biopsy was negative for malignancy …