Varicella zoster virus vasculopathy

INTRODUCTION — Varicella zoster virus (VZV) infection of intra- and extracranial arteries (VZV vasculopathy) may be associated with a granulomatous vasculitis characterized by vessel wall damage and transmural inflammation, with multinucleated giant cells and/or epithelioid macrophages. VZV vasculopathy has previously been called granulomatous angiitis, VZV vasculitis, or post-varicella arteriopathy.

The clinical spectrum of VZV vasculopathy may include intracerebral VZV vasculopathy, giant cell arteritis, and granulomatous aortitis. A subset of patients can have specific ocular and motor findings known as herpes zoster ophthalmicus with delayed contralateral hemiparesis. Intracerebral VZV vasculopathy can occur in patients of all ages after either primary infection with VZV (varicella; chickenpox) or after viral reactivation (zoster; shingles) [1]; however, other forms of VZV vasculopathy (eg, giant cell arteritis) are primarily diseases of older adults.

This topic provides an overview of intracerebral VZV vasculopathy, as well as other forms of vasculopathy associated with VZV. Topic reviews that describe other clinical manifestations and complications of chickenpox and herpes zoster are found elsewhere. (See "Epidemiology of varicella-zoster virus infection: Chickenpox" and "Treatment of varicella (chickenpox) infection" and "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

VIROLOGY — Varicella zoster virus (VZV), a ubiquitous DNA virus, is one of eight known human herpesviruses. Primary infection occurs via aerosols from skin vesicles from an infected person with varicella or zoster, resulting in the characteristic disseminated rash of varicella. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

After primary infection, VZV becomes latent within neurons in cranial nerve, dorsal root, and autonomic ganglia along the entire neuraxis [2-5]. More than 95 percent of the adult population harbors latent VZV. A decline in virus-specific cell-mediated immunity to VZV in older and immunocompromised individuals results in virus reactivation in one or more ganglia. VZV reactivation most commonly manifests as herpes zoster (ie, shingles). (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

PATHOGENESIS OF VASCULOPATHY — Varicella zoster virus (VZV) vasculopathy is associated with productive viral infection in arteries, as evidenced by the presence of multinucleated giant cells, herpesvirus particles, VZV DNA, and VZV antigen in arteries [6].

Direct infection of blood vessels by VZV — VZV infection of intra- and extracranial arteries is associated with a spectrum of inflammatory and noninflammatory pathological changes including thrombosis, necrosis, dissection, and aneurysm formation [7,8]. Animal studies have identified a rich supply of afferent trigeminal and dorsal root ganglionic fibers to intracranial arteries and veins, thus providing an anatomic pathway for transaxonal spread of virus after reactivation from ganglia [9-11]. In autopsy studies of patients who died of intracranial VZV vasculopathy, pathological and virological analyses have revealed herpes virions, VZV DNA, VZV antigen, and multinucleated giant cells within the walls of cerebral arteries (picture 1) [6,12-19].

Role of autoantibodies — Autoantibodies to phospholipids and coagulation proteins (during or after varicella) may play a role in the occlusion of cerebral arteries [20,21]. One report described an adult with varicella who developed a stroke and multiple peripheral thrombotic events associated with a transient protein S deficiency and transient anticardiolipin and anti-beta 2 glycoprotein antibodies [22]. The presence of lupus anticoagulant [23], protein S deficiency [23,24], and anti-protein S antibody [24] in association with varicella infection has also been described.

PATHOLOGY — Very similar pathological changes are seen in intracerebral varicella zoster virus (VZV) vasculopathy, giant cell arteritis (GCA), and granulomatous aortitis, which suggests a common etiology. These changes include vessel wall damage and transmural inflammation with multinucleated giant cells and/or epithelioid macrophages. A common etiology is also supported by the observation that each of the disorders is not restricted to the primary artery involved. As examples:

●In addition to extensive involvement of intracerebral arteries in VZV vasculopathy, extracranial arteries may also be involved.

●In GCA, primary involvement of the temporal artery is frequently accompanied by disease in large arteries such as the aorta, carotid, or subclavian arteries, as well as the smaller retinal arteries.

●In granulomatous aortitis, although the major arteries affected are the aorta, carotid, and subclavian arteries, many patients also have clinical features of GCA, indicating temporal artery disease.

Additional discussions of the pathogenesis of these specific conditions are presented below. (See 'Other types of vasculopathy' below.)

INTRACEREBRAL VZV VASCULOPATHY — Intracerebral varicella zoster virus (VZV) vasculopathy can be seen in both children and adults. Early reports described ischemic large vessel strokes, although it is now appreciated that both large and small arteries are commonly involved. An expanded spectrum of stroke associated with VZV infection is now recognized including aneurysm, subarachnoid and intracerebral hemorrhage, arterial ectasia, and possibly dissection [25-27].

Epidemiology

Children — Varicella is an important risk factor for childhood ischemic stroke [28]. Approximately 1 in 15,000 cases of varicella are associated with subsequent stroke [28]; most occur within 12 months of infection [29]. Furthermore, varicella precedes transient cerebral arteriopathy of childhood in 44 percent of cases [30]. In a large international study of immunocompetent children with stroke, 277 (53 percent) had an arteriopathy, including 19 children (7 percent) with a history of varicella-associated stroke [29]. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".)

Adults — In adults, studies have found an increased risk of stroke after herpes zoster [31-36]. The risk of stroke is greatest in those with ophthalmic-distribution zoster, and is increased soon after zoster, especially within the first three months. However, the risk of stroke can increase for at least one year after herpes zoster [32]. It is unclear if the use of antiviral therapy in patients with herpes zoster prevents stroke [34,35].

Central nervous system (CNS)-associated vasculopathy is more common in immunocompromised individuals [36,37]. Among HIV-infected individuals not receiving antiretroviral therapy, CNS infection caused by VZV was detected at autopsy in 1.5 to 4.4 percent of those with documented vasculopathy and leukoencephalitis [15,16,38-40]; most cases occurred in patients with severe CD4 cell depletion. Cases have also occurred in immunocompromised patients with leukemia, lymphoma, and in those taking immunosuppressive therapies for systemic lupus erythematosus, rheumatoid arthritis, and renal transplantation [41,42].

Select studies that evaluated the risk of stroke in persons with herpes zoster include:

●A study using medical records from the Taiwan National Health Research Institute compared 7760 adults with herpes zoster and 23,280 matched controls without herpes zoster [31]. After adjusting for other cardiovascular risk factors, the adjusted hazard ratio for risk of stroke among persons 45 years or older with a history of herpes zoster was 1.31 (95% CI 1.06-1.63) compared with controls. The incidence of stroke following herpes zoster ophthalmicus was higher compared with patients who had a history of herpes zoster at other cutaneous locations (5.8 versus 1.7 percent).

●An analysis of medical records from a Danish national registry evaluated the risk of stroke in persons with herpes zoster [32]. Individuals were considered to have herpes zoster if they received a prescription for acyclovir at the doses used to treat herpes zoster. Control patients were individuals who did not receive antiviral therapy for herpes zoster. Of the 117,926 zoster patients, 4876 developed stroke during the follow-up period (4.1 percent). Compared with controls, the incidence rate ratio for stroke associated with herpes zoster was 2.3 (95% CI 1.8-2.8) within two weeks after rash, 1.2 (95% CI 1.09-1.24) from two weeks to one year after rash, and 1.05 (95% CI 1.02-1.09) after the first year.

●An analysis of 106,601 cases of herpes zoster and 213,202 controls matched for age, sex, and primary care practice was performed using the United Kingdom Health Improvement Network database [33]. There was a statistically significant increase in transient ischemic attacks and myocardial infarctions in patients with herpes zoster; the increased risk was greatest in zoster patients <40 years of age.

●The UK General Practice Research Database was used to analyze 6584 individuals from 1987 to 2012 with a first-ever diagnosis of herpes zoster associated with stroke before and after rash [34]. Compared with baseline, the overall rate of strokes was significantly increased in weeks 1 to 4 post-zoster (incidence rate, 1.63; 95% CI 1.32–2.02). The increased rate of stroke extended up to six months post-zoster but diminished over time. For patients with herpes zoster ophthalmicus, the greatest increase in stroke risk was delayed until weeks 5 to 12 after initial presentation. In this analysis, the 3647 zoster patients (55 percent) who received oral antiviral therapy had a reduced risk of stroke compared with the 2937 patients with herpes zoster who did not receive antiviral therapy. However, an earlier study from Taiwan found no effect of antiviral treatment on subsequent stroke among 658 individuals with ophthalmic-distribution herpes zoster [35].

Clinical manifestations

Neurologic manifestations — The clinical presentations of intracerebral VZV vasculopathy can vary widely since VZV affects both large and small arteries and can result in cerebral ischemia or hemorrhage.

●In adults, the classic clinical presentation of VZV vasculopathy is ophthalmic-distribution zoster followed by acute contralateral hemiplegia, whereas in children, primary varicella is followed by onset of acute hemiplegia.

●Other common clinical features of VZV vasculopathy in adults include headache, mental status changes, focal weakness or sensory loss, aphasia, ataxia, and both hemianopia or monocular visual loss [43,44]. Some patients may present with symptoms and signs consistent with encephalitis (eg, mental status changes) followed by a focal deficit [6].

●Less frequently, patients with VZV vasculopathy present with transient ischemic attacks (TIA), aneurysm, subarachnoid or cerebral hemorrhage, carotid dissection, and, rarely, peripheral arterial disease [1,27].

VZV vasculopathy may coexist with other neurologic complications of VZV, such as meningitis, radiculitis, cranial nerve disease, and myelitis or spinal cord infarction [45].

Rash — Approximately two-thirds of patients with VZV vasculopathy have a history of zoster or varicella rash [41]. Although the rash and stroke may develop simultaneously, the average time from rash to neurologic symptoms and signs is 4.1 months [41]. Thus, the absence of rash should not dissuade clinicians from pursuing a diagnostic workup for VZV in the appropriate clinical setting. (See 'Diagnosis' below.)

Cerebrospinal fluid testing — Cerebrospinal fluid (CSF) abnormalities are common in patients with VZV vasculopathy. A modest pleocytosis, usually fewer than 100 cells/microL, predominantly mononuclear cells, is seen in approximately two-thirds of patients with VZV vasculopathy [41]. Many patients also have red blood cells in their CSF. CSF protein is usually elevated while glucose is normal. Oligoclonal bands are frequently present [46]. CSF studies used for diagnosis (eg, VZV antibodies and VZV DNA) are discussed below. (See 'Diagnosis' below.)

Imaging — All patients presenting with a stroke should have imaging studies. This section will discuss findings associated with VZV vasculopathy. The relative advantages of the various imaging modalities for the diagnosis of stroke are discussed elsewhere. (See "Neuroimaging of acute stroke" and "Overview of the evaluation of stroke" and "Initial assessment and management of acute stroke" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".)

Brain imaging — VZV vasculopathy involves both large and small arteries. Mixed large and small artery disease is generally seen more often than pure small artery disease; pure large artery disease occurs least often.

Brain imaging shows ischemic or hemorrhagic infarction in virtually all cases of VZV vasculopathy [41]; most lesions are bland, and some lesions enhance. Although multifocal lesions are common, VZV vasculopathy can also produce single lesions. In early reports, a single large infarct seen in the same location as the cutaneous rash was referred to as "herpes zoster ophthalmicus with contralateral hemiparesis."

Magnetic resonance imaging (MRI) typically demonstrates both superficial and deep-seated lesions in both gray and white matter and particularly at gray-white matter junctions (image 1). Gray-white matter junction lesions can also be seen in patients with other disorders (eg, metastatic carcinoma and embolic disease); however, VZV vasculopathy should be included in the differential diagnosis. (See 'Differential diagnosis' below.)

Angiographic features — Ischemic or hemorrhagic infarction at gray-white matter junctions should prompt consideration of vascular studies, such as magnetic resonance arteriogram (MRA), computed tomography (CT) angiography, or conventional contrast dye angiography. Typical angiographic changes produced by VZV include segmental constriction, often with poststenotic dilatation (image 1). In addition to arterial occlusion, aneurysm and hemorrhage are also seen. Some of these features can also be seen in patients with other CNS vasculitides. (See "Primary angiitis of the central nervous system in adults".)

Although the presence of stenosis or occlusion is helpful in diagnosing VZV vasculopathy, a negative angiogram does not exclude the diagnosis, most likely because disease in small arteries is not detected as readily as in large arteries. In a series of 30 patients whose CSF tested positive for anti-VZV IgG or VZV DNA , 23 patients underwent vascular studies (conventional angiography or MRA) and 16 (70 percent) had vascular abnormalities [41]. In another report of 25 patients with a variety of infectious vasculopathies, MRI showed enhancement of the arterial wall in two patients with VZV-related disease [47].

Diagnosis

When to suspect VZV — VZV vasculopathy should be suspected in a patient with a recent history of herpes zoster or varicella who presents with a transient ischemic attack, stroke, or altered mental status. VZV vasculopathy should also be considered in patients with a stroke of unknown origin [48], as well as aneurysms, particularly among immunocompromised and HIV-infected patients. Data that support a diagnosis of VZV vasculopathy include:

●A mononuclear pleocytosis in CSF. (See 'Cerebrospinal fluid testing' above.)

●MRI findings consistent with an ischemic or hemorrhagic lesion, particularly at gray-white matter junctions. Suspicion for VZV vasculopathy as the etiology of stroke is increased in the setting of multifocal and/or bilateral strokes, particularly when they accrue over days to weeks. (See 'Brain imaging' above.)

●Focal narrowing and beading in cerebral vessels on angiography. (See 'Angiographic features' above.)

Since both zoster and stroke occur mostly in people over age 60, clinicians might not consider VZV vasculopathy as a cause of transient ischemic attacks or stroke months after presenting with herpes zoster. However, the average time from rash to neurologic symptoms and signs is four months. (See 'Rash' above.)

Laboratory testing — Specific diagnostic testing should be pursued for patients with suspected VZV vasculopathy. A confirmatory laboratory diagnosis is made by demonstrating either the intrathecal production of anti-VZV antibodies or the presence of VZV DNA in CSF using a quantitative polymerase chain reaction (PCR) assay:

●Quantification of virus-specific IgG in the CSF is frequently performed by calculation of a virus-specific antibody index [49]. The presence of intrathecal antibodies and a reduced serum/CSF ratio confirms the diagnosis.

●PCR assays use primers specific for VZV, sensitive enough to detect approximately 100 copies of viral DNA.

Only negative results in both anti-VZV IgG antibody testing and VZV PCR in the CSF would exclude the diagnosis of VZV vasculopathy [50].

Testing for anti-VZV IgG antibody in the CSF generally has a higher yield than testing for VZV DNA. Anti-VZV IgG antibody becomes detectable during the second week after infection [41], whereas VZV DNA may only be present during the first two weeks of infection. This is important since VZV vasculopathy is often unsuspected, and testing may be performed late in the clinical course. However, the yield of VZV DNA testing may be higher in immunocompromised hosts.

The specificity of the enzyme immunoassay test used for detection of VZV antibody appears robust. When this test was performed on more than 1600 CSF samples from subjects with migraine, epilepsy, and other CNS encephalitides (eg, herpes simplex virus, Epstein-Barr virus, West Nile virus), no patient had detectable anti-VZV IgG antibody [50].

The use of antibody testing was supported in a study of patients from multiple institutions in the United States, Europe, and Japan with virologically verified VZV vasculopathy [41]. In this series, 28 of 30 (93 percent) patients with VZV vasculopathy had anti-VZV IgG in the CSF compared with only 30 percent with VZV DNA in CSF; in each of the patients with detectable anti-VZV IgG in CSF, a reduced serum/CSF ratio of VZV IgG confirmed intrathecal synthesis.

Differential diagnosis — VZV is the only human virus that has been shown to replicate in arteries and produce vasculopathy [1]. However, many of the same symptoms, signs, CSF abnormalities (eg, pleocytosis), imaging, and arteriographic abnormalities that occur in VZV vasculopathy are seen in other CNS disorders, such as primary angiitis of the nervous system and granulomatous angiitides of the CNS (eg, sarcoidosis, neurosyphilis, and tuberculous and fungal infections). (See "Primary angiitis of the central nervous system in adults" and "Neurosyphilis", section on 'Meningovascular syphilis' and "Overview of extrapulmonary manifestations of sarcoidosis".)

In addition, hypercoagulable states, multifocal cardiac embolism, and intravascular lymphoma can produce a pattern of multifocal stroke similar to that seen in vasculitis. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Diffuse vasculitis'.)

Treatment

Initial regimen — There are no controlled trials to assess the optimal treatment strategy for patients with intracerebral VZV vasculopathy.

●For patients with suspected intracerebral VZV vasculopathy, we suggest empiric intravenous acyclovir (10 mg/kg intravenously [IV] every eight hours) while awaiting CSF testing for anti-VZV IgG antibody or VZV DNA. (See 'Diagnosis' above.)

●For patients with a confirmed diagnosis of VZV vasculopathy:

•We administer IV acyclovir for 14 days. The duration may need to be extended for those who do not respond to initial treatment. (See 'Monitoring response to treatment' below and 'Patients who do not respond to initial treatment' below.)

•We also suggest a short course of oral prednisone (1 mg/kg daily for five days) without a steroid taper [7]. It is not known if glucocorticoids confer additional benefit to antiviral agents; however, we give a short course of prednisone to minimize the inflammatory response in VZV-infected arteries.

Prompt treatment in suspected cases of VZV vasculopathy may be important to improve treatment outcomes. In the case series of 30 patients described above, individuals were treated with antiviral therapy, steroids, or both [41]; improvement or stabilization of neurologic deficits was seen in 75 percent of those treated with both acyclovir and steroids and in 66 percent of those treated with acyclovir alone.

Monitoring response to treatment — During intravenous antiviral therapy, the patient should be monitored clinically to assess if the neurological deficits have stabilized and if any new strokes have occurred.

Based upon our clinical experience, we suggest a repeat CSF analysis if:

●The patient is not responding clinically within two weeks of intravenous antiviral therapy. This includes patients who have not returned to baseline, especially if they had an initial CSF that contained more than 50 white blood cells/microL.

●Progression of neurologic symptoms associated with new lesions on a repeat MRI. If the patient is stable or improving there is no need for a repeat MRI.

A repeat CSF analysis should include cell count and chemistries, as well as re-evaluation for other concomitant infectious agents, such as mycobacteria, fungi, and Treponema pallidum (the causative agent of neurosyphilis). This is particularly important in patients with AIDS or other significant immunocompromising conditions in which multiple infections may coexist. Repeat testing for VZV is not helpful in this setting. (See 'Differential diagnosis' above.)

Patients who do not respond to initial treatment — Initially, we treat patients for a minimum of 14 days with antiviral therapy. (See 'Initial regimen' above.)

We typically extend the duration of intravenous acyclovir for an additional two to four weeks if the patient does not improve clinically, develops new lesions by MRI, or has a persistent pleocytosis after two weeks. Unlike most acute viral encephalitides, VZV vasculopathy is often chronic and protracted. We have encountered multiple patients with VZV vasculopathy who continue to have new neurologic symptoms such as focal weakness and altered mental status after intravenous acyclovir treatment; most of these patients were HIV infected.

OTHER TYPES OF VASCULOPATHY

VZV vasculopathy with temporal artery infection — Varicella zoster virus (VZV) may be associated with a multifocal vasculopathy that presents with the clinical and laboratory features of giant cell arteritis (GCA) and temporal artery infection (table 1). As with other types of VZV vasculopathy, a history of a zoster rash is not always present [51,52]. A more detailed discussion of the clinical manifestations of GCA are presented elsewhere. (See "Clinical manifestations of giant cell arteritis".)

Patients with VZV vasculopathy and temporal artery infection may develop visual loss associated with VZV infection of the ophthalmic and/or retinal arteries. Due to the multifocal nature of VZV vasculopathy and the rich innervation of the vascular supply to the optic nerve and retina, VZV vasculopathy may produce a spectrum of ischemic injuries such as anterior and posterior ischemic optic neuropathy (ION), retinal necrosis, and central retinal artery occlusion [51,53].

When extensive serial sections of temporal artery biopsies are examined, virtually identical pathological changes are seen in the arteries of patients with intracerebral VZV vasculopathy and VZV vasculopathy associated with temporal artery infection. The pathology is characterized by granulomatous vasculitis, in which inflammation, often transmural, is seen with necrosis, usually in the arterial media, accompanied by multinucleated giant cells, epithelioid macrophages, or both. (See 'Pathogenesis of vasculopathy' above.)

In addition, virological analysis of temporal arteries have shown that VZV is present in most GCA-positive and GCA-negative temporal artery biopsies, mostly in skip areas that correlate with adjacent GCA pathology [51,53-57]. The prevalence of VZV in the temporal arteries of patients with clinically suspected GCA is similar, independent of whether biopsy is negative or positive pathologically [53,58].

A retrospective analysis evaluated archived formalin-fixed, paraffin-embedded GCA-positive and GCA-negative temporal artery biopsies (50 sections/temporal artery) from subjects >50 years across 13 centers in the United States, Canada, Iceland, France, Germany, and Israel, who were reported to have clinical manifestations and laboratory features of GCA [57]. Immunohistochemical analyses showed VZV antigen in 73 of 104 (70 percent) of GCA-positive and 58 of 100 (58 percent) of GCA-negative temporal arteries, compared with 11 of 61 (18 percent) of arteries that were removed postmortem from age-matched controls. Overall, VZV antigen was 3.89-fold more likely to be present in GCA-positive temporal arteries than normal temporal arteries (95% CI 2.38-7.24), and 3.22 times more likely to be present in GCA-negative than normal temporal arteries (95% CI 1.94-6.03). In addition, GCA-negative temporal artery biopsies were found to contain VZV antigen in five of seven (71 percent) patients with anterior ischemic optic neuropathy (AION). VZV DNA was readily detected in 18 of 45 (40 percent) of GCA-positive/VZV antigen-positive temporal arteries; 6 of 10 (60 percent) VZV antigen-positive skeletal muscles; and 1 VZV antigen-positive normal temporal artery, despite formalin fixation.

Despite the association of VZV infection and GCA described above, some experts feel direct pathogenetic evidence of a causal role for VZV in GCA is still insufficient. (See "Pathogenesis of giant cell arteritis".)

VZV-associated granulomatous aortitis — VZV may be associated with granulomatous aortitis. Granulomatous aortitis should be suspected in patients with back or abdominal pain, as well as symptoms and signs of aortic insufficiency, particularly if patients also have features consistent with GCA. Other common complaints included shortness of breath, chest pain, diplopia, weight loss, nausea, and fatigue. One study detected VZV infection in the aortas of 11 patients with granulomatous aortitis; most subjects had aortic aneurysm (some with aortic stenosis or dilatation) and coronary artery disease [59].

Conventional angiography may show luminal abnormalities, but computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are preferred since they can show stenosis, dilatation, and inflammation of the aortic wall. Abdominal ultrasonography may show thickening of the vessel wall and a halo sign reflective of inflammation. Other testing used in the diagnosis of vasculitis, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated in patients with granulomatous aortitis, but these findings are nonspecific. (See "Overview of and approach to the vasculitides in adults", section on 'Diagnostic approach'.)

Management considerations — There are no controlled trials evaluating the use of antiviral therapy for the treatment of VZV-associated temporal artery infection or granulomatous aortitis. Although some experts endorse antiviral therapy since the risk of treatment is low, most providers do not routinely administer antiviral therapy to such patients. (See "Treatment of giant cell arteritis" and "Overview of the management of vasculitis in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Varicella-zoster virus".)

SUMMARY AND RECOMMENDATIONS

●Varicella zoster virus (VZV), a ubiquitous DNA virus, is one of eight known human herpesviruses. After primary varicella infection (chickenpox), VZV becomes latent within neurons in cranial nerves, dorsal roots, and autonomic ganglia along the entire neuraxis. Herpes zoster (shingles) results from virus reactivation in one or more ganglia. (See 'Virology' above.)

●VZV is associated with vasculopathy, as evidenced by the presence of multinucleated giant cells, herpesvirus particles, VZV DNA, and VZV antigen in arteries. (See 'Pathogenesis of vasculopathy' above.)

●Intracerebral VZV vasculopathy can be seen in both children and adults (see 'Intracerebral VZV vasculopathy' above):

•In adults, the classic clinical presentation of VZV vasculopathy is ophthalmic-distribution zoster followed by acute contralateral hemiplegia; whereas in children, primary varicella may be followed by onset of acute hemiplegia. The average time from rash to neurologic symptoms and signs is approximately four months. (See 'Clinical manifestations' above.)

•VZV can affect both large and small arteries and can result in cerebral ischemia or hemorrhagic lesions, particularly at gray-white matter junctions. Suspicion for VZV vasculopathy as the etiology of stroke is increased in the setting of multifocal and/or bilateral strokes, particularly when they accrue over days to weeks. (See 'Imaging' above.)

•A laboratory diagnosis of VZV vasculopathy is made by demonstrating either the intrathecal production of anti-VZV antibodies or the presence of VZV DNA in cerebrospinal fluid (CSF) using a quantitative polymerase chain reaction assay (PCR). Testing for anti-VZV IgG antibody in the CSF generally has a higher yield than testing for VZV DNA. (See 'Diagnosis' above.)

•For patients with suspected intracerebral VZV vasculopathy, we suggest empiric intravenous acyclovir while awaiting their CSF laboratory test results (Grade 2C). A reasonable regimen is 10 mg/kg every 8 hours. (See 'Initial regimen' above.)

•For patients with a confirmed diagnosis of VZV vasculopathy, we administer intravenous acyclovir for 14 days. For such patients, we also suggest a short course of oral prednisone (1 mg/kg daily for five days) without a steroid taper (Grade 2C). (See 'Initial regimen' above.)

•The course of acyclovir can be extended for patients who do not respond initially. (See 'Monitoring response to treatment' above and 'Patients who do not respond to initial treatment' above.)

●VZV may be associated with a multifocal vasculopathy that presents with the clinical and laboratory features of giant cell arteritis (GCA) and temporal artery infection. It may also be associated with granulomatous aortitis. (See 'Other types of vasculopathy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Donald H Gilden, MD (deceased), who contributed to earlier versions of this topic review.