Varicella Zoster meningitis as a mimicker of pseudotumor cerebri in an immunocompetent patient: A case report and literature review

Varicella-zoster (VZ) meningitis is uncommon in patients with immunocompetence and usually presents with typical rash and fever. However, VZ meningitis can rarely present with symptoms of intracranial hypertension without the classic manifestations. Herein, we describe a 17-year-old female teen who presented with intractable headache and vomiting and diagnosed with VZ meningitis. Her symptoms remarkably improved after a lumbar puncture and acyclovir therapy.


INTRODUCTION
Varicella-zoster virus (VZV) remains latent in the cranial ganglia and dorsal root ganglia after the resolution of the primary infectionvaricella (chickenpox); virus reactivation in tissues causes zoster (shingles) disease and manifests commonly with fever and rash. 1 The central nervous system (CNS) complications of VZV include aseptic meningitis, encephalitis, cerebral infarcts secondary to concomitant granulomatous vasculitis, myelitis, and multiple cranial neuropathies. 2 Aseptic meningitis is a rare entity. CNS manifestations of VZV infection in patients with immunocompetence are usually detected in cerebrospinal fluid (CSF) samples by polymerase chain reaction (PCR). 3 Contrary to its common clinical presentation in association with a vesicular rash (exanthem), we herein present an atypical scenario of VZV meningitis manifesting with intracranial hypertension in a young female patient with immunocompetence.
A 17-year-old female patient, with unknown chronic illnesses, presented three times within 10 days with a history of a progressive, throbbing holo-cranial headache that progressed rapidly from mild to severe with nausea and repetitive vomiting. It was persistent and had minimal response to simple analgesia (acetaminophen and ibuprofen). She had no fever, rash, visual changes, hearing problems, or any focal neurological symptoms. She had no previous medical or surgical history and had never received regular medications. Family history was noncontributory. She had up-to-date immunizations; however, she was unsure if she received a vaccination against VZV. She was also unsure about prior history of chickenpox infection. On admission, she was in pain of 10/10 in severity, afebrile with normal blood pressure of 117/78 mmHg, and heart rate of 89 beat/minute. Physical examination revealed normal neurological findings and negative meningeal signs (Kernig's/ Brudzinski's), whereas fundoscopy was not performed (was missed). Laboratory test results were normal (Table 1). Magnetic resonance imaging and magnetic resonance venography of the head did not detect signs of venous sinus stenosis or radiological features of intracranial hypertension.
Lumbar puncture revealed clear CSF with elevated opening pressure (29 cm-water). The procedure was performed in the lateral recumbent position, and the needle was inserted between L3 and L4. Then, the manometer tube was connected. Subsequently, the pressure was measured after the nadir of fluid meniscus was oscillating at the level of 29 cm-water. Approximately 45 mL of CSF was collected. The patient mentioned a remarkable improvement in her headache after the procedure. CSF analysis showed lymphocytic predominant pleocytosis ( Table 1). The diagnosis of VZ meningitis was established based on the positive PCR result of the CSF. Based on expert opinion, the patient received a 10-day course of acyclovir 750 mg 8-hourly administered intravenously (IV) with remarkable improvement.

DISCUSSION
VZV reactivation causes various neurologic manifestations including acute retinal necrosis, herpes zoster ophthalmicus, post-herpetic neuralgia, myelitis, meningoencephalitis, and VZV vasculopathy. 4 An elevated intracranial pressure secondary to viral infection is a rare presentation of viral meningitis. 5 It is distinguished primarily from idiopathic intracranial hypertension (pseudotumor cerebri) by characteristic pleocytosis in the CSF sample, which defies the diagnostic modified Dandy's criteria for pseudotumor cerebri. 6 Subclinical meningeal irritation secondary to VZV reactivation occurs in 40% -50% of cases reported. The increasing incidence is attributed to the development of diagnostic methods and frequent clinical suspicion even in the absence of common  8 The immune system plays a significant role; specifically, memory T cells mediate cellular immunity against various microorganisms, which declines with aging and immune suppression causing viral renaissance. 9 Only a few reports have described VZV meningitis mimicking idiopathic intracranial hypertension in patients with immunocompetence in the absence of cutaneous manifestations ( Table 2). Headache is the chief presenting complaint in all cases. The diagnosis of viral meningitis was established by viral PCR from CSF samples with negative cultures. Moreover, pleocytosis in CSF was observed in all samples. In VZV, although PCR analysis of CSF is considered very sensitive in the first 7-10 days after infection with specificity of 95%, 10 virus-specific antibodies become readily detectable after this period, and PCR analysis may reveal negative results instead. 11 All cases demonstrated increased CSF opening pressure, i.e., between 29 and 60 cm in water, establishing a diagnosis of intracranial hypertension in association with VZV meningitis. 12 -15 The first case report has demonstrated a false localizing sign of 6th nerve palsy and papilledema in association with intracranial hypertension in comparison with other cases reported in the literature including our case ( Table 2). The association of elevated intracranial pressure in cases of bacterial meningitis, CNS tuberculous, and fungal infections is well-described in the literature in comparison with viral meningitis. 12 Although current literature lacks a summative list of the common viral etiologies leading to increased ICP, human immunodeficiency virus, measles, VZV, and very rarely enterovirus are the commonly described agents in a survey of existing case reports. 13 However, the mechanism is poorly understood. This is possibly attributed to one of the proposed theories, as suggested by Lo et al., i.e., post-infective or "allergic" response and diffuse brain swelling due to VZV meningitis or as super-imposed phenomena on a baseline subclinical pseudotumor cerebri. 16 Patients with elevated ICP and a CSF profile of infectious picture, but has no well-known infectious causes, may represent a subgroup of nonspecific viral syndrome, as referred to by Ravid et al. 17 Acetazolamide is the standard treatment for pseudotumor cerebri, as it decreases CSF production with efficacy up to 75% 18 ; however, its use is often limited because of side effects, which include paresthesia, polyuria, and fatigue. 19 Adjunctive second-line therapies include topiramate, furosemide, and corticosteroids. A symptomatic control is achieved in) IIH mimickers secondary to viral etiology with a treatment regimen of acetazolamide and appropriate antiviral drugs administered intravenously or orally. 20 A slightly different treatment approach was used by the four reported cases compared with our case. 12 -15 Notably, antiviral therapy given intravenously has resulted in complete recovery, as compared with oral antiviral therapy where partial recovery was demonstrated in one patient using acyclovir intravenously as reported by Kiefer et al. However, in all other reported cases including our case, 12 -14 antiviral therapy administered intravenously resulted in complete recovery, acyclovir was given intravenously in three cases 12,13 and ganciclovir was administered in one case. 14 Only two reported cases 12,13 have received acetazolamide in combination with antiviral therapy; Ibrahim et al. used a dose of 250 mg PO BID. By contrast, antiviral therapy alone was used in the other reported cases, which were comparable to our case, and similar clinical outcomes were obtained (Table 2).

CONCLUSIONS
Despite its rarity, VZV can cause meningitis in patients with immunocompetence as in our case. The typical rash and fever might be absent in some patients who may present with only headache and vomiting. The present case suggests a possible association between VZV and intracranial hypertension; however, more studies are warranted to delineate a better understanding of this pathophysiology. This case highlights the clinical and scientific importance of CSF viral PCR testing in the evaluation of headache syndromes in the case of elevated ICP.

Declaration of Competing Interest
The authors report no conflict of interest.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors.