Recognition of multifocal vasculopathy due to varicella-zoster virus (VZV) is often problematic. We describe a human immunodeficiency virus—infected patient who had progressive central nervous system disease for >3 months. Both VZV DNA and antibody were detected in cerebrospinal fluid (CSF) specimens; serial polymerase chain reaction analyses confirmed the diagnosis and guided the duration of therapy. Reduced ratios of VZV antibody in serum to that in CSF were also demonstrate

Bossart, Walter

Gilden, Donald H.

Kronenberg, Andreas

Schuknecht, Bernhard

Schupbach, Reto

Speck, Roberto F.

Weber, Rainer

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330 • CID 2002:35 (1 August) • HIV/AIDSH I V / A I D S B R I E F R E P O R TMultifocal Vasculopathy Dueto Varicella-Zoster Virus (VZV):Serial Analysis of VZV DNAand Intrathecal Synthesis of VZVAntibody in Cerebrospinal FluidAndreas Kronenberg,1,a Reto Schupbach,2,a Bernhard Schuknecht,3Walter Bossart,4 Rainer Weber,1 Donald H. Gilden,5and Roberto F. Speck11Division of Infectious Diseases and Hospital Epidemiology, 2Departmentof Internal Medicine, 3Institute of Neuroradiology, and 4Institute of MedicalVirology, University Hospital Zurich, Switzerland; and 5Departmentsof Neurology and Microbiology, University of Colorado Health SciencesCenter, DenverRecognition of multifocal vasculopathy due to varicella-zos-ter virus (VZV) is often problematic. We describe a humanimmunodeficiency virus–infected patient who had progres-sive central nervous system disease for 13 months. Both VZVDNA and antibody were detected in cerebrospinal fluid (CSF)specimens; serial polymerase chain reaction analyses con-firmed the diagnosis and guided the duration of therapy.Reduced ratios of VZV antibody in serum to that in CSFwere also demonstrated.Multifocal vasculopathy due to varicella-zoster virus (VZV) isoften difficult to recognize because neurological symptoms andsigns can assume many forms and because brain imaging stud-ies reveal multifocal lesions similar to those seen with cerebralemboli, metastases, lymphoma, and toxoplasmosis. We describean HIV-infected patient with progressive CNS disease who wasdetermined to have multifocal vasculopathy due to VZV.Case report. A 28-year-old man who was infected withHIV and hepatitis C virus was hospitalized for progressive diz-ziness of 3 months’ duration and recent-onset left-side weak-ness. Nine months earlier, his CD4 cell count was 13 cells/mLand his HIV load in serum was 92,029 copies/mL. When diz-ziness and vertigo developed, the patient underwent neurolog-Received 26 December 2001; revised 13 March 2002; electronically published 8 July 2002.a These authors contributed equally to this work.Reprints or correspondence: Dr. Andreas Kronenberg, Div. of Infectious Diseases and HospitalEpidemiology, University Hospital, CH-8091 Zurich, Switzerland (andreas.kronenberg@dim.usz.ch).Clinical Infectious Diseases 2002; 35:330–3 2002 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2002/3503-0018$15.00ical examination and CT of brain, the findings of which werenormal. Two weeks before admission, the patient began re-ceiving antiretroviral therapy with lamivudine (150 mg b.i.d.),zidovudine (300 mg b.i.d.), nelfinavir (1250 mg b.i.d.), andtrimethoprim-sulfamethoxazole (160 mg/800 mg 3 times perweek). His medical history was otherwise unremarkable; henever developed cutaneous herpes zoster. On admission, he wasafebrile. Neurological examination revealed left-side mydriasiswithout ptosis or anhidrosis, a left-side hemiparesis and ho-monymous hemianopia, and neglect to the left. Laboratorystudies revealed a hemoglobin level of 9.1 g/dL, a WBC countof 2550 cells/mL, and a normal platelet count. C-reactive proteinand serum electrolyte levels were normal, and the findings ofchest radiography and of liver and renal function studies werenormal.CT of brain revealed contrast-enhancing lesions in the rightoccipitotemporal and parieto-occipital cortices (figure 1A).MRI of the brain corroborated the vascular distribution of thelesions and also revealed prominent subcortical edema (figure1B, 1C); a small signal of uncertain significance, which waspossibly ischemic, was also seen close to the right lateral ven-tricle (figure 1B). The findings of magnetic resonance angiog-raphy were normal.Analysis of CSF specimens obtained from the patient re-vealed 11 WBCs/mm3 (95% mononuclear), a protein level of135 mg/dL, and a normal glucose level. The results of VenerealDisease Research Laboratory testing of CSF specimens werenegative; culture of CSF specimens revealed no bacteria, in-cluding mycobacteria; and no cryptococcal antigen or Toxo-plasma-specific IgG was detected. Serum was also negative forIgG antibody to Toxoplasma. PCR analysis of CSF specimenswith primers specific for bacterial 16S RNA [1] and Toxo-plasma species, cytomegalovirus, Epstein-Barr virus, herpessimplex virus types I and II, and JC virus DNA were negative.However, PCR with primers specific for VZV glycoprotein Igene (open-reading frame 67) amplified VZV DNA. PCR wasdone with use of TaqMan chemistry and the following se-quences: 5′-ACAGCTTGTCTTTATTGGAGAGCAA-3′ as theforward primer, 5′-GCCACCGTATCCGCGTATA-3′ as the re-verse primer, and 5′-(FAM)-ACCTACCGGGACAAACTATA-GCGGAACACTG-(TAMRA)-3′ as the probe. Furthermore,VZV antibody analysis indicated a decrease in the ratio ofVZV-specific IgG in serum to that in CSF to 0.89, comparedwith ratios of 39 for albumin and 44 for total IgG, which isconsistent with intrathecal synthesis of VZV-specific IgG [2].Because encephalitis due to Toxoplasma species could not beHIV/AIDS • CID 2002:35 (1 August) • 331Figure 1. A, Contrast-enhanced CT of the brain of a patient with varicella-zoster virus multifocal vasculopathy showing contrast-enhancing lesions(arrows) in right occipitotemporal and parieto-occipital cortices. B, MRI of brain showing 2 lesions (arrows) in right occipitotemporal and parieto-occipital cortices. A small contrast-enhancing lesion, which is possibly ischemic, is visible close to right lateral ventricle (arrowhead). C, T2-weightedMRI showing subcortical edema (arrow) extending into optic radiation and a small area of increased signal adjacent to internal capsule and frontalhorn (arrowhead). D, T2-weighted MRI from 5 months after treatment revealing residual right posterior hemispheric infarcts (arrows) and a small CSF-filled infarct close to lateral ventricle (arrowhead).excluded initially, the patient was treated empirically with sul-fadiazine (1500 mg q.i.d.) and pyrimethamine (75 mg q.d.).On detection of both VZV-specific DNA and antibody in CSFspecimens, the diagnosis of VZV multifocal vasculopathy wasconfirmed, and the patient was treated with intravenous acy-clovir (10 mg/kg t.i.d.) for 24 days. Treatment efficacy wasmonitored by serial real-time PCR analysis of CSF specimens.A 4-log reduction in the number of VZV DNA copies (from104 copies/mL [day 0] to copies/mL [day 14] and to15 10!101 copies/mL [day 21]) was observed when all CSF sampleswere analyzed in parallel. After receiving intravenous acyclovirtreatment for 21 days, the patient had no neurological symp-toms, and the results of PCR of CSF specimens for VZV DNAwere negative. Acyclovir therapy was discontinued 3 days later,and a 4-week course of oral valacyclovir (2000 mg t.i.d.) wasbegun. Five months after the initiation of valacyclovir therapy,the findings of a neurological examination were normal, andMRI performed at this time showed residual cortical infarcts(figure 1D).Discussion. In the past decade, the protean clinical features332 • CID 2002:35 (1 August) • HIV/AIDSof VZV multifocal vasculopathy have been well characterized[3]. Most, but not all, patients are immunocompromised, usu-ally because of AIDS, and disease is often protracted and mayprogress without rash [4–7]. Symptoms and signs include com-binations of headache, fever, mental status changes, seizures,and focal deficit. Brain imaging studies reveal both large andsmall infarcts of both cortical and subcortical gray and whitematter; infarcts are usually ischemic [8, 9] but may also behemorrhagic [10]. In this regard, the diagnosis of VZV vas-culopathy might have been recognized earlier for our patienthad contrast-enhanced MRI initially been performed insteadof CT. Testing of CSF specimens usually yields nonspecific re-sults, showing increased WBC count (predominantly mono-nuclear cells), with elevated protein and normal glucose levels.Although diagnosis can be difficult to make when the patientlacks a history of rash, it is important to recognize that rashis often absent from patients with CNS disease caused by VZV.A retrospective analysis of 34 HIV-infected patients with ce-rebral VZV infection showed that 17.6% of the patients neverdeveloped rash [11]. Nevertheless, the multifocal changes de-tected on brain imaging studies should mandate the need forvirological analysis to confirm that VZV is the cause of disease.In the aforementioned clinical setting, the detection of VZVDNA and/or antibody to VZV in CSF specimens verifies thediagnosis of VZV-induced multifocal vasculopathy [12]. Similarvirological analyses have shown that VZV also causes acute,chronic, and recurrent myelitis [13], as well as acute, chronic,and recurrent neuropathies [14], often without rash, includingchronic radicular pain without rash (the so-called “zoster sineherpete”) [15].In our patient, both VZV DNA and antibody to VZV weredetected in CSF specimens. Also, serial PCR analyses to monitorVZV DNA in CSF over time not only confirmed the diagnosis,but they also guided the duration of therapy, which led to abeneficial outcome for our patient. As described elsewhere ina study of 3 children with VZV-associated cerebral vasculitis[16], decreased ratios of antibody to VZV in serum to that inCSF were demonstrated, providing definitive evidence for theviral etiology of disease in our patient. Detection of reducedratios of antibody to VZV in serum/CSF has been critical forthe diagnosis of VZV autonomic neuropathy [17] and VZVmyelitis [18, 19]. Previous antibody studies of cases of VZVvasculopathy revealed high titers of antibody to VZV in CSFspecimens, which emphasizes the diagnostic value of detectingVZV antibody in CSF, even when viral DNA is not present[19]. However, the ability to demonstrate reduced ratios ofantibody in serum to that in CSF in our patient was the linchpinin our diagnosis that VZV caused the multifocal vasculopathy.No controlled studies have addressed the duration of anti-viral treatment necessary to treat VZV multifocal vasculopathy.The duration of treatment for HIV-infected patients has rangedfrom 7 to 60 days [11]. Monitoring of VZV DNA in CSF andof intrathecal antibody production should help to establishguidelines for the duration of antiviral treatment to protectpatients from recurrent disease. It is unlikely that antiretroviraltherapy contributed essentially to the recovery in our patient,because antiretroviral therapy was initiated only 2 weeks beforeacyclovir therapy.Finally, clinicians must be alert to the clinical manifestationsof VZV multifocal vasculopathy, the characteristic abnormal-ities visible on MRIs, and the importance of confirming thediagnosis by virological analysis of CSF specimens. Althoughmultiple areas of the brain are affected, VZV-induced multifocalvasculopathy is not a primary encephalitis (i.e., parenchymalinfection) but rather a productive VZV infection, mostly orexclusively restricted to cerebral arteries [6, 9, 20–23]. This factemphasizes the need for rapid diagnosis and antiviral treatmentto eradicate virus in arteries and to prevent further stroke. Thefailure of clinicians to recognize the entity of VZV-inducedmultifocal vasculopathy was evident in a recent review in whichthe causes of focal neurological disease in patients with AIDSwere listed as Toxoplasma gondii, progressive multifocal leu-koencephalopathy, cytomegalovirus, and Epstein-Barr virus–related CNS lymphoma, without any mention of VZV multi-focal vasculopathy [24].References1. Goldenberger D, Kunzli A, Vogt P, Zbinden R, Altwegg M. Moleculardiagnosis of bacterial endocarditis by broad-range PCR amplificationand direct sequencing. J Clin Microbiol 1997; 35:2733–9.2. Reiber H, Lange P. Quantification of virus-specific antibodies in cer-ebrospinal fluid and serum: sensitive and specific detection of antibodysynthesis in brain. Clin Chem 1991; 37:1153–60.3. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, MahalingamR, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med 2000; 342:635–45.4. Aygun N, Finelli DA, Rodgers MS, et al. Multifocal varicella-zostervirus leukoencephalitis in a patient with AIDS: MR findings. Am JNeuroradiol 1998; 19:1897–9.5. Gilden DH, Murray RS, Wellish M, Kleinschmidt-DeMasters BK, VafaiA. Chronic progressive varicella-zoster virus encephalitis in an AIDSpatient. Neurology 1988; 38:1150–3.6. Gilden DH, Kleinschmidt-DeMasters BK, Wellish M, Hedley-WhyteET, Rentier B, Mahalingam R. Varicella zoster virus, a cause of waxingand waning vasculitis: NEJM case 5-1995 revisited. Neurology 1996;47:1441–6.7. Picard O, Brunereau L, Pelosse B, et al. Cerebral infarction associatedwith vasculitis due to varicella zoster virus in patients infected withthe human immunodeficiency virus. Biomed Pharmacother 1997; 51:449–54.8. Amlie-Lefond C, Kleinschmidt-DeMasters BK, Mahalingam R, DavisLE, Gilden DH. The vasculopathy of varicella zoster virus encephalitis.Ann Neurol 1995; 37:784–90.9. Eidelberg D, Sotrel A, Horoupian DS, Neumann PE, Pumarola-SuneT, Price RW. Thrombotic cerebral vasculopathy associated with herpeszoster. Ann Neurol 1986; 19:7–14.10. Elble RJ. Intracerebral hemorrhage with herpes zoster ophthalmicus.Ann Neurol 1983; 14:591–2.11. De La Blanchardiere A, Rozenberg F, Caumes E, et al. NeurologicalHIV/AIDS • CID 2002:35 (1 August) • 333complications of varicella-zoster virus infection in adults with humanimmunodeficiency virus infection. Scand J Infect Dis 2000; 32:263–9.12. Kleinschmidt-DeMasters BK, Gilden DH. Varicella zoster virus infec-tions of the nervous system—clinical and pathologic correlates. ArchPathol Lab Med 2001; 125:770–80.13. Gilden DH, Wright RR, Schneck SA, Gwaltney JM Jr, Mahalingam R.Zoster sine herpete, a clinical variant. Ann Neurol 1994; 35:530–3.14. Fox RJ, Galetta SL, Mahalingam R, Wellish M, Forghani B, Gilden DH.Acute, chronic, and recurrent varicella zoster virus neuropathy withoutzoster rash. Neurology 2001; 57:351–4.15. Gilden DH, Beinlich BR, Rubinstien EM, et al. Varicella-zoster virusmyelitis: an expanding spectrum. Neurology 1994; 44:1818–23.16. Ha¨usler MG, Ramaekers VT, Reul J, et al. Early and late onset man-ifestations of cerebral vasculitis related to varicella zoster. Neuro-pediatrics 1998; 29:202–7.17. Bennett JL, Mahalingam R, Wellish MC, Gilden DH. Epstein-Barr vi-rus–associated acute autonomic neuropathy. Ann Neurol 1996; 40:453–5.18. de Silva SM, Mark AS, Gilden DH, et al. Zoster myelitis: improvementwith antiviral therapy in two cases. Neurology 1996; 47:929–31.19. Gilden DH, Bennett JL, Kleinschmidt-DeMasters BK, Song DD, YeeAS, Steiner I. The value of cerebrospinal fluid antiviral antibody in thediagnosis of neurologic disease produced by varicella zoster virus. JNeurol Sci 1998; 159:140–4.20. Horten B, Price RW, Jimenez D. Multifocal varicella-zoster virus leu-koencephalitis temporally remote from herpes zoster. Ann Neurol1981; 9:251–6.21. Fukumoto S, Kinjo M, Hokamura K, Tanaka K. Subarachnoid hem-orrhage and granulomatous angiitis of the basilar artery: demonstrationof the varicella-zoster-virus in the basilar artery lesions. Stroke 1986;17:1024–8.22. Melanson M, Chalk C, Georgevich L, et al. Varicella-zoster virus DNAin CSF and arteries in delayed contralateral hemiplegia: evidence forviral invasion of cerebral arteries. Neurology 1996; 47:569–70.23. Morgello S, Block GA, Price RW, Petito CK. Varicella-zoster virusleukoencephalitis and cerebral vasculopathy. Arch Pathol Lab Med1988; 112:173–7.24. Skiest DJ. Focal neurological disease in patients with acquired im-munodeficiency syndrome. Clin Infect Dis 2002; 34:103–15.

Multifocal Vasculopathy Due to Varicella-Zoster Virus (VZV): Serial Analysis of VZV DNA and Intrathecal Synthesis of VZV Antibody in Cerebrospinal Fluid

Multifocal Vasculopathy Due to Varicella-Zoster Virus (VZV): Serial Analysis of VZV DNA and Intrathecal Synthesis of VZV Antibody in Cerebrospinal Fluid

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