Subclinical reactivation of varicella zoster virus in all stages of HIV infection

Analysis of 200 paired serum and cerebrospinal fluid (CSF) samples from 180 HIV-positive individuals, 136 of whom had AIDS, revealed intrathecal synthesis of antibodies specific for varicella zoster virus (VZV) in 28 (16%) individuals, measles virus in 15 (8%), herpes simplex virus-1 (HSV-1) in 1 (0.6%), and HSV-2 in none. Of the 28 subjects with a positive VZV antibody specificity index, only 1 had zoster rash at the time of serum and CSF sampling; of the total 180 HIV-positive subjects, 146 (81%) had no history of zoster. Based on an estimated 33.4 million HIV-positive individuals worldwide, subclinical reactivation of VZV in even less than 16% of HIV-positive people suggests the possibility that millions of people have active VZV infection of the central nervous system. In cases of VZV vasculopathy, myelopathy and even zoster sine herpete, the CSF is often positive for anti-VZV antibody, but negative for VZV DNA. To rule out VZV infection of the nervous system, CSF must be tested for VZV DNA and anti-VZV IgG and IgM antibody.     

The protean manifestations of varicella-zoster virus vasculopathy

Varicella-zoster virus (VZV) vasculopathy in the central nervous system (CNS) affects large and small cerebral vessels. Large-vessel disease is most common in immunocompetent individuals, whereas small-vessel disease usually develops in immunocompromised patients. In some patients, both large and small vessels are involved. Neurological features are protean. Neurological disease often occurs months after zoster and sometimes without any history of zoster rash. Magnetic resonance imaging (MRI) scanning, cerebral angiography, and examination of cerebrospinal fluid (CSF) with virological analysis are needed to confirm the diagnosis. VZV vasculopathy patients do not always have VZV DNA in CSF, but diagnosis can be confirmed by finding anti-VZV antibody in CSF, along with reduced serum/CSF ratios of VZV immunoglobulin G (IgG) compared to albumin or total IgG. When VZV vasculopathy develops months after zoster, antiviral treatment is often effective.     

Search for varicella zoster virus and herpes simplex virus-1 in normal human cerebral arteries

Virological confirmation of varicella zoster virus (VZV) vasculopathy is provided by presence of virus in the cerebral arteries, frequently associated with inflammation. Yet, cerebral arteries from normal subjects have never been studied for VZV DNA or antigen. We analyzed 63 human cerebral arteries from 45 subjects for VZV DNA and antigen, control herpes simplex virus (HSV)-1 DNA and antigen, and leukocyte-specific CD45 antigen. No cerebral arteries contained VZV or HSV-1 DNA or antigen; eight arteries from seven subjects contained leukocytes expressing CD45. Thus, the presence of VZV antigen in cerebral arteries of patients with stroke is likely to be clinically significant.     

Acute, chronic, and recurrent varicella zoster virus neuropathy without zoster rash

The authors report three patients with acute, chronic, and recurrent neuropathy associated with varicella zoster virus (VZV) infection but without zoster rash. CSF of all three patients contained VZV immunoglobulin G antibody, but not herpes simplex virus. In two patients, serum/CSF ratios of VZV immunoglobulin G were reduced compared to normal ratios for immunoglobulin G and albumin, and one patient also had VZV immunoglobulin M in CSF. All three patients received antiviral therapy and improved. The diagnosis of nervous system infection by VZV may be confirmed by the presence of antibody to VZV in CSF even without detectable VZV DNA.     

VZV vasculopathy and postherpetic neuralgia: progress and perspective on antiviral therapy

Two serious complications of varicella-zoster virus (VZV) reactivation are vasculopathy and postherpetic neuralgia (PHN). Clinical-virologic analyses have proven that VZV vasculopathy is caused by chronic active virus infection in cerebral arteries. Conclusive evidence that PHN is caused by persistent or productive VZV infection is less compelling because human ganglia are not accessible during life for pathologic and virologic examination. However, the notion that PHN may reflect a smoldering VZV ganglionitis is supported by 1) the detection of VZV DNA and proteins in peripheral blood mononuclear cells of many patients with PHN; 2) studies of multiple patients with zoster sine herpete, which indicate a productive VZV ganglionitis; and 3) a favorable response of some patients with zoster sine herpete and PHN to antiviral treatment. Few studies have used antiviral therapy to manage PHN with conflicting results. Larger, double-blind studies, which give IV antiviral drug, are needed.     

The Pathophysiology of Essential Tremor and Parkinson’s Tremor

Varicella zoster virus (VZV) is an exclusively human neurotropic alphaherpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. With advancing age or immunosuppression, cell-mediated immunity to VZV declines, and the virus reactivates to cause zoster (shingles), dermatomal distribution, pain, and rash. Zoster is often followed by chronic pain (postherpetic neuralgia), cranial nerve palsies, zoster paresis, vasculopathy, meningoencephalitis, and multiple ocular disorders. This review covers clinical, laboratory, and pathological features of neurological complications of VZV reactivation, including diagnostic testing to verify active VZV infection in the nervous system. Additional perspectives are provided by discussions of VZV latency, animal models to study varicella pathogenesis and immunity, and of the value of vaccination of elderly individuals to boost cell-mediated immunity to VZV and prevent VZV reactivation.     

Ischemic Stroke due to Virologically-Confirmed Varicella Zoster Virus Vasculopathy: A Case Series

Background: Limited data are available regarding the characteristics and prognosis of patients with stroke due to varicella zoster virus (VZV) vasculopathy. Methods: We studied 4 patients (2 men and 2 women; age, 38-63 years) from a single center who developed acute ischemic stroke due to VZV vasculopathy. The virological diagnosis was confirmed by detecting VZV DNA and/or the IgG antibody to VZV in the cerebrospinal fluid. Results: Three patients were taking immunosuppressive agents, including prednisolone and/or methotrexate, at baseline. Each patient had a characteristic skin rash prior to stroke, with the interval from rash to stroke onset ranging from 13 to 122 days. Two patients experienced antecedent cranial nerve palsies; one had the third, seventh, ninth, and 10th nerve palsies and the other had the fourth nerve palsy before stroke. Cerebral infarctions were located in the anterior circulation lesion (n?=?1), in the posterior circulation lesion (n?=?2), and in both lesions (n?=?1). Intracranial arterial stenosis was only identified in one patient on magnetic resonance angiography. A high plasma d-dimer level was detected in 1 patient, whereas high β-thromboglobulin and platelet factor 4 levels were detected in 2 patients. As a result of combined therapies with acyclovir, steroid, and antithrombotic agents, neurological symptoms markedly improved in 3 patients, whereas 1 patient was left with moderate hemiplegia. Conclusions: Cranial nerve palsies may be prodromal symptoms of VZV-associated stroke. Increased levels of thrombotic markers may support the use of antithrombotic agents, although the benefit of combined treatment should be determined through larger studies.     

Thrombotic cerebral vasculopathy associated with herpes zoster

We describe the clinical, radiographic, and pathological findings in 3 patients with large-vessel cerebral vasculopathy following herpes zoster. Two of the patients were studied at postmortem examination, and a brain biopsy was performed in the third. Each of the 3 patients suffered thrombotic occlusions of large vessels without notable inflammatory or granulomatous changes following trigeminal or segmental herpes zoster infection. In the 2 autopsied patients, varicella-zoster virus (VZV) antigens were detected by immunoperoxidase staining within the media of the affected cerebral arteries. Little or no inflammation was associated with the foci of the VZV antigens. These studies provide evidence that the vasculopathy following herpes zoster may result from direct VZV infection of the artery and the in situ thrombosis can develop within the infected vessels in the absence of clear inflammatory vasculitis.     

Neurologic manifestations of varicella zoster virus infections

Varicella zoster virus (VZV) causes acute viral exanthema in childhood, becomes latent, and can reactivate years later to produce neurologic disease. Primary VZV infection is associated with acute cerebellitis and stroke, particularly in childhood. VZV reactivation may result in neuropathy, myelitis, stroke, and encephalitis, the latter two syndromes the result of small and large vessel vasculopathy. Prompt diagnosis and treatment are critical to minimize morbidity in herpes zoster as well as morbidity and death in VZV vasculitis and encephalitis. Detection of anti-VZV antibodies in cerebrospinal fluid is the most sensitive method of diagnosing varicella infection of the nervous system. Despite the advent of the VZV vaccine, varicella remains a significant cause of neurologic morbidity.     

Ungewöhnliche Manifestation eines Zoster sine herpete als unilaterales kaudales Hirnnervensyndrom

Multiple lower cranial nerve palsies are a rare complication following varicella zoster virus (VZV) reactivation, especially if typical herpetic eruptions are lacking. We report a case of a 45-year-old, immunocompetent male with unilateral involvement of the cranial nerves VIII, IX, X, and XI without skin lesions. Cerebrospinal fluid (CSF) studies revealed mononuclear pleocytosis with intrathecal antibody synthesis against VZV, while polymerase chain reaction (PCR) did not detect VZV or HSV (herpes simplex virus). The patient almost completely recovered after aciclovir administration. VZV reactivation without rash (zoster sine herpete) may lead to multiple cranial nerve palsies. PCR is a useful tool to detect VZV-DNA in CSF, but negative results do not exclude a reactivation. In case of multiple cranial nerve palsies of unknown etiology with mononuclear pleocytosis in CSF tumors of the skull base, meningitis tuberculosis, and meningeosis have to be excluded, and antiviral therapy should be discussed.     

VZV vasculopathy associated with myelo-radiculoganglio-meningo-encephalitis: an autopsy case of an immunocompetent 66-year-old male

Encephalitis is the most severe manifestation of central nervous system (CNS) infection by Varicella-Zoster-Virus (VZV). VZV associated encephalitis is now recognized to be a vasculopathy that affects large or small cerebral arteries. This report describes an autopsy case of an immunocompetent 66-year-old male who developed a progressive small vessel vasculopathy and clinically presented with a zosteriform rash and myelo-radiculoganglio-meningo-encephalitis followed by subarachnoid bleeding. This is an extremely rare manifestation of VZV vasculopathy associated with widespread CNS damage, and what is more, the spinal lesions were different from those of the cerebrum, brainstem and cerebellum, where the former were predominantly demyelinative changes and the latter were ischemic. To the best of our knowledge, few cases have been described pathologically in an immunocompetent individual. Further studies are needed to investigate the pathogenesis and treatment of VZV vasculopathy.     

Disseminated cutaneous herpes zoster and multiple cerebral infarcts in an adult with diabetes mellitus

Ischemic stroke is a rare complication of varicella-zoster virus (VZV) infection. We present the case of a patient with a medical history of type 2 diabetes mellitus (DM) who experienced disseminated cutaneous VZV infection followed by multiple cerebral infarcts associated with VZV vasculopathy. Brain magnetic resonance imaging revealed multiple hyperintense lesions over the bilateral deep white matter and basal ganglia. A skin biopsy revealed small-vessel leukocytoclastic vasculitis with neutrophilic, lymphocytic, and eosinophilic infiltration. This case report describes the rare finding of cutaneous leukocytoclastic vasculitis in VZV infection and highlights that VZV infection is an uncommon but critical etiology of cryptogenic stroke in patients with DM.     

Polymerase chain reaction analysis and oligoclonal antibody in the cerebrospinal fluid from 34 patients with varicella-zoster virus infection of the nervous system

Objective

To study cerebrospinal fluid (CSF) and serum samples from 34 consecutive patients suspected of having varicella‐zoster virus (VZV) infection of the central nervous system (CNS).

Population and methods

The patients were divided into three groups. The first group consisted of 27 patients with a rash in one to three dermatomes and clinical suspicion of meningitis and radiculitis; among them, three subgroups were distinguished according to the affected dermatome: ophthalmicus (n = 9), oticus (n = 11) and cervico‐thoraco‐lumbar zoster (n = 7). Four cases of zoster sine herpete (ZSH) were included in the second group: these patients presented with either radiculitis (n = 2) or meningoencephalitis (n = 2), without cutaneous eruption. The third group consisted of three patients with a generalised rash and encephalitis. A polymerase chain reaction (PCR) for VZV DNA and antigen‐driven immunoblots for oligoclonal anti‐VZV antibodies were carried out on all CSF samples.

Results

PCR of the CSF was positive in 44% of the patients from the first group, mainly within the first 7 days after eruption. In addition, intrathecal synthesis of anti‐VZV antibodies was detected in 37% of patients, always after an interval of 7 days (p<0.0001). Among the four patients with ZSH, a positive VZV PCR was detected in three patients and CSF‐specific oligoclonal anti‐VZV antibodies in two. PCR was also positive in the CSF of two of the three patients with generalised rash and encephalitis; local production of anti‐VZV antibodies was seen in a second CSF sample in one patient, and was also present in the third patient.

Conclusion

Amplification of VZV DNA by PCR in the CSF and antigen‐driven immunoblots have important diagnostic value in suspected VZV infection, although their presence depends on the timing of the CSF sampling. VZV is thought to be a causative agent in unexplained cases of meningitis associated with radiculitis or focal CNS symptoms, even in the absence of skin manifestations. In such patients, rapid diagnosis by this combined approach permits early antiviral treatment.Varicella‐zoster virus (VZV), an exclusively human herpesvirus, causes chickenpox (varicella), becomes latent in the cranial nerve and dorsal root ganglia, and may reactivate decades later in 10–20% of the population to produce shingles (zoster).¹ Shingles is characterised by unilateral radicular pain and a vesicular rash that is generally limited to one to three contiguous dermatomes. The annualised incidence of shingles is about 1.5–3 cases per 1000 people, but increases to 11 cases per 1000 in the population >60 years of age.² VZV can also cause neurological complications, very rarely during the primary infection (most often a varicella cerebellitis) and more often during the reactivation phase. The main complication is post‐herpetic neuralgia, a neuropathic pain syndrome that persists after the dermatomal rash has healed. Acute neurological complications may, however, occur, and affect either the peripheral nervous system (cranial neuropathies, motor radiculopathies of the arm or the leg, bladder and bowel dysfunction) or the central nervous system (CNS; meningitis, myelitis and vasculitic encephalitis). The same neurological complications may be observed in zoster sine herpete (ZSH), which is defined by a dermatomal pain without antecedent rash.³Cerebrospinal fluid (CSF) analysis is a key tool in the diagnosis of CNS infection with VZV. The amplification of VZV DNA by polymerase chain reaction (PCR) and the detection of intrathecal synthesis (ITS) of anti‐VZV‐specific antibodies are the most reliable ways of establishing a definite diagnosis of VZV CNS infection.⁴ We present a retrospective study on CSF samples collected from 34 consecutive patients suspected of harbouring CNS VZV infection. Our population included four cases with ZSH and three with disseminated rash with meningoencephalitis. We discuss correlations between the CSF results, the timing of CSF samples and the clinical picture.     

Recurrent varicella zoster virus myelopathy

Myelopathy is an uncommon complication of VZV infection and may develop in the absence of rash. We report the rare recurrence of myelopathy in an immunocompetent adult who initially developed myelopathy after ophthalmic-distribution zoster. Recurrent myelopathy two years later caused by VZV was verified by the presence of new-onset clinical symptoms and signs consistent with myelopathy, new lesions in the spinal cord detected by MRI, and evidence of intrathecal synthesis of anti-VZV IgG antibody in CSF. After virological verification and antiviral therapy, myelopathy did not recur and anti-VZV IgG antibody could not be detected in CSF. In contrast to earlier cases of recurrent VZV myelopathy in immunocompetent adults that developed weeks to months after the first episode of myelopathy, this is the first instance of recurrence years later.     

Diplopia as isolated presentation of varicella zoster central nervous system reactivation

Here, we report a patient who developed diplopia secondary to a right cranial nerve III and IV palsy, as well as fever and headache. Cerebrospinal fluid analysis (CSF) showed high varicella-zoster virus (VZV)-DNA viral load (>300,000,000 copies/ml). VZV antibodies in CSF was ≥1:16. Diagnosis of neurological reactivation of VZV infection was made without the presence of characteristic vesicular rash. Quantitative real-time PCR for VZV and intrathecal dosage of VZV IgM and IgG should be performed in cases suspected for viral encephalitis and also in all patients with not otherwise attributable cranial nerve lesions.     

Review: The neurobiology of varicella zoster virus infection

Varicella zoster virus (VZV) is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. Although VZV cannot be isolated from human ganglia, nucleic acid hybridization and, later, polymerase chain reaction proved that VZV is latent in ganglia. Declining VZV-specific host immunity decades after primary infection allows virus to reactivate spontaneously, resulting in shingles (zoster) characterized by pain and rash restricted to one to three dermatomes. Multiple other serious neurological and ocular disorders also result from VZV reactivation. This review summarizes the current state of knowledge of the clinical and pathological complications of neurological and ocular disease produced by VZV reactivation, molecular aspects of VZV latency, VZV virology and VZV-specific immunity, the role of apoptosis in VZV-induced cell death and the development of an animal model provided by simian varicella virus infection of monkeys.