Varicella-zoster virus (VZV) is a double-stranded DNA virus of the Herpesviridae family. Primary VZV infection of mucosal surfaces by droplets, or contact, results in the common childhood infection known as “varicella.” Virions are axonally transported, via dermal sensory nerve endings, to cranial nerve neurons, dorsal root and autonomic ganglia along the neuraxis.1 Here, the virus enters a latency phase, establishing lifelong residency in the host virobiota.
Dermatomal reactivation (zoster) occurs in otherwise healthy individuals but is especially frequent in those with impaired cell-mediated immunity due to primary immune deficiencies, secondary immunocompromise or immunosenescence.2 Neurologic complications of VZV reactivation include dermatomal pain, meningitis, cerebral vasculitis, stroke, myelitis, radiculitis and cranial nerve palsies.1 Craniocervical zoster increases the risk for central nervous system (CNS) complications.3
VZV reactivation, considered a function of endogenous boosting and waning immunity, is uncommon during childhood. Complications involving the CNS are considered rare in pediatric cohorts and are usually associated with primary immune deficiencies, as well as viral exposure in utero, or during the first year of life.1 We hereby report a case series of 3 healthy adolescents, who presented to our institution with neurologic signs and symptoms, resulting in the diagnosis of aseptic meningitis secondary to VZV reactivation.
A 13-year-old, previously well boy presented with abdominal pain and bilious vomiting. He had briefly attended the emergency department (ED) 6 days previously with vomiting and headache after a blunt head injury, attributed to a minor concussion.
He was admitted for dehydration. A fever of 38°C, coinciding with recurrence of headaches and associated photophobia, prompted further investigation. Examination identified mild abdominal tenderness. Neither an exanthem nor meningism was observed. Neurologic examination revealed an unsteady tandem gait. Magnetic resonance imaging (MRI) brain was unremarkable. Complete blood count (CBC), biochemistry and transaminases were normal. C-reactive protein (CRP) remained low (<0.2 mg/L; normal range, 0–5 mg/L). Autoantibody screen was negative. Cerebrospinal fluid (CSF) microscopy showed pleocytosis with 445 white cells/mm3, 96% lymphocytes. CSF protein was markedly raised at 1.5 g/L (normal range, 0.2–0.4 g/L), with a normal glucose value of 2.7 mmol/L (serum glucose, 3.9 mmol/L).
VZV DNA was detected via Biofire Filmarray Meningitis/Encephalitis Panel (bioMérieux, France) polymerase chain reaction (PCR) and confirmed by FTD Viral Meningitis Panel (Fast Track Diagnostics, Luxembourg) PCR, at a cycle threshold (Ct) value of 28.3. Other targets, including enterovirus, parechovirus, herpes simplex virus type 1 and 2 (HSV1/2), mumps and cytomegalovirus, were negative. Intrathecal VZV-specific antibody production was absent.
By history, the patient had chickenpox at 4 years of age. Serology revealed positive VZV-immunoglobulin G (IgG) and negative immunoglobulin M (IgM). He received a 21-day course of intravenous acyclovir. Repeat CSF sampling on day 21 showed 22 white cells/mm3 and protein of 552 mg/L; VZV PCR was negative. He made a full recovery, with no residual neurologic deficit.
A previously healthy, 14-year-old girl presented to the ED with a 5-day history of headache, photophobia, vomiting and a temperature of 38.3°C.
Pronounced hyperreflexia was elicited in all limbs, Hoffman sign was positive, and ankle clonus present bilaterally. Meningism was absent. There was no rash. CBC and inflammatory markers were normal (CRP, <0.8 mg/L). CSF analysis identified 573 white cells/mm3, 99% lymphocytes and a raised protein of 1.3 g/L.
MRI/magnetic resonance angiography of brain, MRI of spinal cord, electroencephalography and ophthalmology assessment were normal. An exotic travel history and subacute presentation resulted in a broad differential, including tuberculous meningitis, autoimmune disease and primary CNS malignancy. Autoimmune panel was negative. Comprehensive investigations for potential causative pathogens, including HIV, human T-lymphocytic virus type 1 and 2, Borrelia burgdorferi, Epstein-Barr virus, cytomegalovirus, Mycoplasma, Brucella and tuberculosis, were all negative. CSF flow cytometry showed predominance of polyclonal T-lymphocytes without markers of malignancy. A published method4 for virus-specific laboratory-developed test PCR confirmed VZV DNA in CSF, at a Ct value of 28.8. Nucleic acid targets for enterovirus, parechovirus and HSV1/2 were not detected.
Her parents reported chickenpox in early childhood, consistent with VZV IgG seropositivity. VZV IgM was negative. She was treated with 21 days of intravenous acyclovir. She also received 7 days of cefotaxime and 5 weeks of antituberculous therapy until extended bacterial and mycobacterial cultures were negative. A repeat MRI/magnetic resonance angiography brain 2 months later was normal. A repeat lumbar puncture now yielded acellular CSF with normal protein and glucose values, negative VZV PCR, and the patient’s hyperreflexia normalized.
A 16-year-old girl presented to the ED with severe headache, neck stiffness and vomiting, preceded by a 2-week history of fatigue, sore throat and coryza.
She was initially drowsy but orientated. A painless, ill-defined patch of nonvesicular erythema was noted over the right dorsolateral thoracic region. She complained of dizziness and was overtly photophobic. The remainder of her neurologic examination was normal, with no demonstrable meningism and no focal neurologic signs. She had an isolated fever on day 2 of her admission. A noncontrast computed tomography brain was unremarkable. CSF analysis showed a raised white cell count of 184/mm3, 100% lymphocytic. Protein value in CSF was high (0.9 g/L), glucose normal at 2.5 mmol/L (serum glucose, 4.5 mmol/L).
CBC, biochemistry, transaminases and CRP (<0.8 mg/L) were within normal range. Serology for HIV and Lyme were negative. VZV DNA was detected in CSF by virus-specific laboratory-developed test PCR4 at a Ct value of 28.2. Enterovirus RNA and HSV1/2 DNA were not detected.
An uncomplicated episode of chickenpox was reported in childhood, consistent with the patient’s serology. She received a 14-day course of intravenous acyclovir and made a full clinical recovery.
While well described in adults, the absence of skin lesions in children is unusual, given most pediatric VZV infection presents as varicella. Table 1 summarizes existing case reports of pediatric meningitis or encephalitis, without zosteriform rash.
CNS complications of primary VZV infection occur in 0.5–1.5 per 1000 pediatric cases.13 Furthermore, CNS manifestations as a consequence of VZV reactivation are infrequently described in the pediatric literature in association with immunocompromise, such as primary or acquired immunodeficiency, malignancy, transplant recipients or rarely due to vaccine strain virus.14 Evidence for immunocompetent children experiencing CNS complications of viral reactivation is emerging, but considering the high prevalence of VZV infections overall, clinical data are scarce.13
This case series identifies striking similarities among the patients, all being unvaccinated adolescents with anamnestic and serologic evidence of prior VZV infection, presenting after a prodrome of several days, without zosteriform rash. Inflammatory markers were completely normal. CSF analyses, however, revealed marked lymphocytic pleocytosis, and highly elevated CSF protein, at levels ordinarily associated with fungal or mycobacterial pathology, which normalized on clinical recovery. This feature of VZV-associated CNS infections may present a diagnostic challenge in countries of high tuberculosis endemicity.
The low viral genetic diversity recently demonstrated in cases of VZV meningitis compared with VZV encephalitis suggests that meningitis, such as we describe here, is a distinct pathologic process resulting from reactivation and replication of virions from very few neurons.15
Adolescents predominate among reported cases, reminiscent of the unique susceptibility to Epstein-Barr-Virus and tuberculosis observed in this age group. Potential interactions of the immune and endocrine systems during this physiologic stage are complex, and changes in sex hormones impact pathogen response.16 Viral reactivation appears to be largely controlled by T cells, which play a key role in immunosurveillance and early virion clearance during reactivation events, thus preventing viral spread.2 Subclinical VZV reactivation in the CNS occurs and is well described in HIV patients17 and can occur without any obvious clinical features.18 Further research into components of neuroimmune and immunoendocrine interactions may delineate the adolescent risk profile for symptomatic and subclinical VZV reactivation and the clinical implications this may have.
Both viral and serologic confirmation is necessary for the diagnosis of VZV reactivation, through viral DNA and antibody detection in CSF. Evidence of one, or both, in the setting of meningitis or encephalitis, without another discernible cause, confers strong evidence of infection.1 Interrogation of alternative etiologies is crucial, as VZV DNA has been interpreted as bystander finding in other neurologic diseases.18 Serology is of little diagnostic value due to high prevalence of seropositivity in the community. In addition, IgM may reemerge during reactivation, appear subclinically and cross-react, reducing its discriminatory value.19 A rise in anti-VZV IgG titers taken on a standardized serologic assay between acute and convalescent sera may assist in confirming the diagnosis.
Indication for, and duration of, antiviral therapy in VZV reactivation is poorly studied.13 Physicians must consider symptom severity and clinical treatment response. Clinical resolution without treatment has been described, raising the possibility that some cases may represent symptomatic, yet transient, viral reactivations.9 Inclusion of VZV DNA targets on multiplex molecular kits may identify cases of VZV reactivation meningitis that would previously have gone undiagnosed, and hence untreated. Contrasting this, data support the notion that pediatric CNS infections from VZV, whether in primary infection or reactivation, may be less benign than previously thought, with one study reporting neurologic sequelae in almost a quarter of patients.20
Hence, lack of data regarding disease burden, frequency of symptomatic reactivations and possibility of subclinical reactivations, conflicting data on the extent of neurologic sequelae and the potential role of VZV in adult stroke21 or neuroinflammatory conditions22 complicate management and prognostic evaluation of VZV reactivation–associated meningitis or encephalitis.
Finally, VZV is vaccine preventable and carries significant disease-associated and economic burden. The identification of 3 cases of VZV meningitis due to reactivation in unvaccinated adolescents in a 3-year period in a catchment area of 550,000 people may suggest a greater disease burden than previously recognized.
The authors thank our patients for their participation in this case series.
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