Atypical presentation of varicella-zoster virus encephalitis in an immunocompetent adult

Atypical presentation of varicella-zoster virus encephalitis in an immunocompetent adult Maria Mpaka, MD,a Apostolos H. Karantanas, MD,b and Epaminondas Zakynthinos, MDa

BACKGROUND: Varicella-zoster virus encephalitis is uncommon, but not rare, in immunocompetent adults. Typically, patients develop stroke with hemiplegia caused by large vessel vasculopathy days to weeks after herpes zoster ophthalmicus. METHOD: A previously healthy 66-year-old man developed obtundation deteriorating to coma within 24 hours. He had lymphocytic meningitis and multiple bilateral edematous and hemorrhagic lesions predominantly in the white matter, and intraventricular and subarachnoid hemorrhage. Treatment with acyclovir and dexamethasone was readily administered. The diagnosis of varicella-zoster virus encephalitis was confirmed by polymerase chain reaction analysis of the cerebrospinal fluid. No zosteriform rash preceded or followed encephalitis. Two years later, the patient is in good health, and no relapse or sign of immunosuppression has been reported. CONCLUSION: This is a case of varicella-zoster virus encephalitis in an immunocompetent patient presenting without typical rash and with clinicoradiologic features of multifocal encephalitis, which characterize immunosuppression. (Heart Lung® 2008;37:61– 66.)

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he typical clinical presentations of varicella and herpes zoster are distinctive and readily recognized by most experienced clinicians. However, atypical clinical presentations of these diseases can pose diagnostic and therapeutic challenges. Varicella-zoster virus (VZV) is an alpha herpesvirus found exclusively in humans. Typically, it causes an acute infantile exanthematous illness (varicella or chickenpox). After chickenpox resolves, VZV becomes latent in the neurons of cranial and spinal ganglia of nearly all individuals with no morphologic or functional consequences.1-4 In elderly and in immunocompromised individuals, VZV may reactivate to produce a dermatomal rash with radicular pain (zoster or shingles). Less commonly, viral reactivation may be followed by central nervous system (CNS) involvement, usually by affecting adjacent vessels.3,4 Two distinctive patterns of brain involvement have been described, depending on the

From the aIntensive Care Unit, University of Thessaly, Larissa, Greece; and bDepartment of Radiology, Faculty of Medicine, University of Crete, Crete, Greece. Reprint requests: Epaminondas Zakynthinos, MD, Intensive Care Unit, University Hospital of Larissa, Mezourlo, 41110 Larissa, Greece. 0147-9563/$ – see front matter Copyright © 2008 by Mosby, Inc. doi:10.1016/j.hrtlng.2007.02.009

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immunologic status of the host.4-6 In immunocompetent adults, VZV may spread to the large cerebral arteries of the base of the skull to produce unifocal large-vessel vascular damage, usually presenting with stroke.6,7 In immunocompromised patients, VZV tends to spread to the brain structures with a much deeper tissue penetration, producing a wide variety of syndromes ranging from diffuse smallvessel vasculopathy (multifocal leukoencephalopathy) to meningitis and ventriculitis.4-7 Immunodeficient patients often present with more severe clinical picture and recurrent disease.8-10 The typical zosteriform rash affecting one to three dermatomes of cranial or peripheral nerves usually precedes CNS involvement in both patient groups.4-7 The diagnosis may be missed in cases without typical rash, and therefore treatment might be delayed even in severe VZV infections.7,11-13

CASE REPORT A 66-year-old man was admitted to our tertiary care hospital with mental obtundation. Four days before admission, headache with nausea, vomiting, agitation, and disorientation had rapidly developed in the patient. He was not receiving any medication regularly because he had no known disease. He did not have any recent exanthematous disease and had not been exposed to chickenpox or VZV vacci-

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nees. He had not received a varicella vaccine in adulthood, but records of contagious diseases in his childhood were not available. The computed tomography (CT) scan performed at his district hospital demonstrated a single nonenhancing hypodense lesion in the periphery of the right lobe of the cerebellum and no sign of hemisphere involvement. The cerebrospinal fluid (CSF) was limpid containing 35 nucleated cells/␮L with lymphocytic predominance. CSF glucose was 64 mg/dL (serum glucose of 102 mg/dL), and CSF protein was 380 mg/dL. Intravenous acyclovir (10 mg/kg every 8 hours), dexamethasone (4 mg every 8 hours), and broad-spectrum antibiotics (ceftriaxone, ampicillin/sulbactam) were immediately initiated. In the next 24 hours, his neurologic status continued to deteriorate, and he was transferred to our hospital. In the emergency department, a body temperature of 36.8°C was recorded, along with neck stiffness and coma, with a score of 7 on the Glasgow Coma Scale. No papilledema or gross focal neurologic deficit was observed. No skin lesion or mucosal lesion was present in the oral cavity, external ear canal, and cornea. The patient was intubated and transferred to the intensive care unit. His white blood cell count was 14,000 cells/␮L (79% neutrophils), and serum biochemistry, urinalysis, and chest radiography all showed normal results. At that time, CSF analysis revealed lymphocytic pleocytosis (360 cells/␮L, 93% lymphocytes) with numerous erythrocytes (900 cells/␮L), a glucose level of 68 mg/dL (serum glucose of 112 mg/dL), and a protein level of 560 mg/dL. An urgent CT scan of the brain demonstrated multiple bilateral parenchymal hemorrhagic foci in the frontotemporal regions in addition to the preexisting lesion on the right cerebellar lobe, and intraventricular and subarachnoid hemorrhage (Fig 1). On admission, CSF polymerase chain reaction (PCR) was positive for the VZV genome (Table I), but negative for herpes simplex virus (HSV) 1 and 2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and mycobacterium tuberculosis DNA. At that time, the serum was positive for immunoglobulin (Ig)G antibodies against VZV (Table I), EBV (61 IU; normal values ⬍ 9), and HSV-1 (110 IU; normal values ⬍ 9). Serum anti-VZV IgM antibodies were slightly positive on admission but decreased to normal range levels 2 weeks later, whereas serum anti-VZV IgG increased (Table I). CSF IgG antibodies against VZV remained positive throughout the patient’s intensive care unit stay (Table I). All antibodies were measured using the enzyme-linked immunosorbent assay method. In regard to the CSF, a nested PCR

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Fig 1 Unenhanced CT in the acute setting, at the level of the lateral ventricles, reveals subarachnoid (small arrows) and intraventricular hemorrhage (arrows), and edema in the right frontotemporal area.

assay was performed using oligonucleotide primer pairs specific for the Xbal M region of VZV, the glycoprotein D sequence of HSV-1, the glycoprotein G sequence of HSV-2, the immediate early gene of CMV, the BamHI-W region of EBV, and the gene coding for protein MBP 64 of Mycobacterium tuberculosis. Antibodies against Borrelia burgdorferi, Coxiella burnetii, Mycoplasma pneumoniae, and adenovirus, influenza A and B, parainfluenza 1-3, Coxsackie, ECHO, and CMV viruses were negative. Antinuclear antibodies and thrombophilia screen (protein C and S, partial thromboplastin time, antithrombin III, anticardiolipin antibodies, and lupus anticoagulant) were also negative. CSF cultures for common bacteria were negative. Similarly, acid-fast bacillus stains and mycobacterial cultures of CSF, sputum, and urine were negative. Electroencephalogram showed generalized slow wave activity with “theta” and “delta” basal activity, consistent with diffuse encephalitis. Magnetic resonance imaging (MRI) examination was performed on the 15th day with a Tesla scanner (Philips Intera, Best, The Netherlands) and a head coil applying T1-weighted spin echo, T2-weighted GraSe, FLAIR, and contrast-enhanced T1-weighted spin echo sequences. MRI findings indicated multifocal edematous and hemorrhagic lesions predom-

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Table I Virologic and serologic findings Day after first symptom

VZV PCR in CSF

Titers of VZV antibodiesCSF (IU)

Titers of VZV antibodiesserum† (IU)

4*

Positive

IgG 105 IgM 5.2

IgG 85 IgM 13.5

7

Positive

IgG 152 IgM 4.7

IgG 135 IgM 11.7

Negative

IgG 145 IgM 2.47

IgG 132 IgM 6.96

16

VZV, Varicella-zoster virus; PCR, polymerase chain reaction; CSF, cerebrospinal fluid; Ig, Immunoglobin. *Commencement of treatment with acyclovir on day 3. Overall treatment for 3 wk. †Normal values ⬍ 9 IU.

inately in the white matter and deep-seated areas both supra- and infratentorially (Fig 2A-C). Evidence of hemosiderin deposition was obvious on T2weighted images. In addition, enhancement indicated active encephalitis. Antibacterial agents were discontinued as soon as VZV genome was isolated in the patient’s CSF. Acyclovir administration was continued for 3 weeks in total, and dexamethasone was tapered off after the first week of treatment.14 The patient’s neurologic status further deteriorated during the first days despite treatment (acyclovir), which was commenced 24 hours before admission to our unit. However, it gradually improved, and he was transferred to the medical ward after 30 days of intensive care unit treatment. By that time, he had no movement deficit but presented aphasia and disorientation in time and space. The patient was discharged from the hospital 2 weeks later; his ability to nominate objects and recognize persons was improved, but he was still disoriented. He fully recovered 6 months later. No zosteriform exanthema, enanthema, or radicular pain was reported on admission with encephalitis, and they were not observed during the 2-year follow-up. Human immunodeficiency virus test was negative in two separate examinations. No immunodeficiency or neoplastic syndrome was made evident in the 2-year period.

DISCUSSION The diagnosis of acute encephalitis is suspected in febrile patients who present with altered con-

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sciousness and signs of diffuse cerebral dysfunction.15 Nevertheless, in any patient who presents with altered mental status or personality change, one should consider the possibility of an infectious cause regardless of the absence of fever,15,16 as was the case of our patient on admission in our hospital. HSV, enteroviruses, EBV, mumps, measles, and VZV are responsible for most cases of acute viral encephalitis in the Western world.15,17,18 HSV encephalitis, considered the commonest viral encephalitis, may have an abrupt onset and may occur in immunocompetent patients with or without mucocutaneous lesions.15-19 HSV CNS infection has a high mortality rate if untreated, whereas early therapy with acyclovir significantly improves the outcome.15 In our patient, lymphocytic meningitis with intracranial hemorrhagic and edematous lesions dictated the need for immediate acyclovir treatment, because “herpetic meningoencephalitis” was the most probable diagnosis. VZV encephalitis was confirmed by detection of the viral genome in the CSF by PCR and presence of intrathecal anti-VZV antibodies. The patient we describe is a rare case of severe VZV encephalitis presenting significant deviation from the expected clinical and laboratory presentation: (1) Brain involvement by VZV usually occurs in immunosuppressed, mainly those with acquired immune deficiency syndrome,20 and is uncommon in immunocompetent patients.4,8,21,22 (2) Encephalitis from VZV is now recognized to be a vasculopathy affecting large or small vessels. However, large-vessel arterial disease (granulomatous arteritis) occurs

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Fig 2 MRI performed 2 weeks after onset of clinical symptoms. A: Axial T2-weighted GraSe MRI shows edematous lesions in both temporal lobes (white arrows), old hemorrhage with hemosiderin deposition in the anterior left temporal lobe (black arrow), and peripheral hemosiderin deposition at the site of previous parenchymal hemorrhage (small black arrows). B: T1-weighted turbo-spin echo MRI shows a high-intensity area corresponding to parenchymal hemorrhage (arrow). C: Enhanced T1-weighted turbo-spin echo MRI shows abnormal enhancement in the left temporal lobe (arrows).

predominantly in immunocompetent patients, and encephalitis mediated by small vessels multifocal leukoencephalopathy is found virtually exclusively in immunodeficient patients. Typically, large-vessel encephalitis is characterized by acute focal deficit (stroke) that develops days to months after zoster of contralateral trigeminal distribution with predominant ocular involvement (herpes zoster ophthalmicus);4-6,23 the internal carotid artery or its branches ipsilateral to the zoster are usually affected with resultant vessel thrombosis and large brain infarctions.4,5 In our case, the progression of the disease to coma without gross focal neurologic deficit and the radiologic findings of multiple bilateral edematous and hemorrhagic lesions (Figs 1 and 2) are compatible with small vessel, or mixed small and large vessel, arteriopathy characteristic of immunodeficiency.3-6 (3) In our case, no rash indicative of zoster was reported before or after CNS involvement on the follow-up of 2 years. The typical rash has been reported to precede encephalitis by up to 10 months or occur after encephalitis for up to 6 months.3-5 Encephalitis related to VZV without

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skin manifestations has been described mainly in patients with HIV and other immunocompromised patients,3,12,24 but rare cases have also been reported in previously healthy patients.3,7,13,25 (4) In our case, specific antibodies were detected in the CSF with the onset of symptoms (Table I), probably referring to early subclinical CNS involvement. Typically, the immune response in the CSF is expected 10 to 12 days from the onset of the CNS disease.26,27 (5) Subarachnoid and intraventricular hemorrhages are rare findings in VZV encephalitis. To our knowledge, only four cases of subarachnoid hemorrhage have been published, and no cases of intraventricular hemorrhage have been published.28-31 These hemorrhagic complications have probably contributed to the initial worsening of the patient’s status, which continued to deteriorate despite treatment. On admission, the severity of the clinical image indicated a bacterial origin of the disease rather than a viral one.32 Thus, broad-spectrum antibiotics were discontinued only when CSF PCR results were available.

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PCR for viral DNA amplification has significantly facilitated the diagnosis of infective encephalitis. CSF PCR is diagnostic for encephalitis because of HSV 1 and 2, VZV, CMV, and EBV. PCR for the HSV and VZV genomes in experienced laboratories is virtually 100% specific, and the sensitivity of this test exceeds 90%.33,34 The results of PCR assays of the CSF must be cautiously interpreted: They may be negative if the CSF is collected after the emergence of intrathecal antibodies or after acyclovir therapy.34 False-negative results may also occur if hemoglobin or heparin is present in the CSF, if the sample is processed too late, or if it was inappropriately stored.34 CSF PCR analysis for VZV DNA has been critical in identifying VZV as a causative factor in cases of CNS infections that may be clinically confusing as cases without skin manifestations.11,20,24,34,35 In viral encephalitis, intrathecal IgG antibodies are measured in the post-acute stage from day 7 to day 12 of the disease, reach maximum values on day 20, and then persist for several years.17 Intrathecal immune response may be further delayed or even absent when antiviral treatment is started early.36 Therefore, the measurement of intrathecal antibodies does not serve as a primary diagnostic tool for the diagnosis of viral encephalitis; yet, it allows confirming the clinical diagnosis in an acceptable percentage of prolonged and chronic cases or when antiviral therapy has been initiated several days earlier.26,37 Occasionally, IgG antibodies against VZV in the CSF may be detected early in the course of the encephalitis (Table I), because VZV infection of the nervous system is often protracted, especially in immunocompromised patients.4 CSF anti-VZV IgM antibodies are positive in a minority of patients, reaching up to 15% of patients with proved CNS VZV infection.27 The analysis of serum anti-VZV IgG antibodies is of no value because VZV antibodies persist in the serum of nearly all adults.4,38 The elevated level of IgM antibodies in the serum, especially the progressive decrease over the course of the disease (Table I), strongly supports a VZV cause.27 MRI is the imaging of choice in acute encephalitis, although it may be easier to obtain a CT on an urgent basis. Characteristic neuroimaging changes may offer clues as to the specific infective cause, for example, frontotemporal changes in HSV and thalamic hemorrhage in Japanese encephalitis.17 The bilateral edematous and hemorrhagic lesions, as well as the enhanced lesions, in our patient are

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characteristic of VZV multifocal leukoencephalitis consistent with small vessel viral angiopathy.4,8

CONCLUSION This is a rare case of VZV encephalitis in an immunocompetent patient who presented with severe complications and a clinicoradiologic presentation typical of immunosuppression. Clinicians must bear in mind that multifocal leukoencephalitis even without zosteriform rash should prompt the investigation for CNS VZV disease in both immunocompetent and immunocompromised patients.38

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