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ARTICLES: M. A. Nagel, R. J. Cohrs, R. Mahalingam, M. C. Wellish, B. Forghani, A. Schiller, J. E. Safdieh, E. Kamenkovich, L. W. Ostrow, M. Levy, B. Greenberg, A. N. Russman, I. Katzan, C. J. Gardner, M. Häusler, R. Nau, T. Saraya, H. Wada, H. Goto, M. de Martino, M. Ueno, W. D. Brown, C. Terborg, and D. H. Gilden The varicella zoster virus vasculopathies: Clinical, CSF, imaging, and virologic features Neurology 2008; 70: 853-860 [Abstract] [Full text] [PDF]

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The varicella zoster virus vasculopathies: Clinical, CSF, imaging, and virologic features

Mitchell SV Elkind   (4 June 2008)

Reply from the authors

Maria A. Nagel, Donald H. Gilden   (4 June 2008)

The varicella zoster virus vasculopathies: Clinical, CSF, imaging, and virologic features 4 June 2008
Mitchell SV Elkind, Columbia University 710 West 168th Street, NY, NY 10032 Send Correspondence to journal: Re: The varicella zoster virus vasculopathies: Clinical, CSF, imaging, and virologic features mse13{at}columbia.edu Mitchell SV Elkind	Nagel and colleagues are to be congratulated on their collaborative review characterizing varicella zoster virus (VZV) vasculopathy in a series of 30 patients. [1] However, they may have overstated their estimate of the sensitivity of virologic testing, particularly that for anti-VZV IgG antibody in the CSF which was 93.3%. The case definition they used for VZV vasculopathy was based on the presence in CSF of VZV DNA by PCR or anti-VZV IgG antibody, or both. Because there was no independent “gold standard,” such as biopsy evidence of virus or inflammation in brain vessels, against which their presumptive diagnosis was being compared, the calculation of sensitivity of these CSF findings may be interpreted as the result of circular reasoning and should be treated with caution. It would be impossible to know whether some of their diagnoses represented false positives. It is plausible that some cases represented patients in whom intrathecal anti-VZV antibody synthesis occurred secondary to recent zoster, but in whom stroke or vasculopathy had an alternative cause, including atherosclerosis, dissection, or other etiology. Both stroke and zoster are common enough that the two may occur coincidentally. One third of their cases had no evidence of pleocytosis, making inflammatory vasculopathy less likely. Three cases (10%), did not have rash, pleocytosis, or VZV DNA and so alternative, non-inflammatory vasculopathies remain plausible. There is evidence that elevations in leukocyte count, and recent (up to 90 days) infections of several types may provoke cerebrovascular and cardiovascular events, so the attribution of causality to VZV in particular remains uncertain. [2,3,4] Further analytic studies, including age-matched control groups tested for these same antibodies and DNA, are needed to better define the diagnostic role of these virologic findings and the magnitude of association of recent VZV infection with stroke. References 1. Nagel MA, Cohrs RJ, Mahalingam R, et al. The varicella zoster virus vasculopathies. Clinical, CSF, imaging, and virologic features. Neurology 2008;70:853-860. 2 . Elkind MSV, Sciacca R, Boden-Albala B, et al. Relative Elevation in Leukocyte Count Predicts First Cerebral Infarction. Neurology 2005;64:2121-2125. 3. Grau AJ, Buggle F, Becher H, et al. Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia. Neurology 1998;50:196-203. 4. Smeeth L, Thomas SL, Hall AJ, et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611-2618. Disclosure: The author reports no disclosures.
Reply from the authors 4 June 2008
Maria A. Nagel, Department of Neurology, Mail Stop B182, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262, Donald H. Gilden Send Correspondence to journal: Re: Reply from the authors Don.Gilden{at}UCHSC.edu Maria A. Nagel, et al.	Our earlier paper discussed Dr. Elkind's concerns. [5] Ideally, the accuracy of a test is determined by comparison with a gold standard. In HSV encephalitis, the diagnostic value of PCR could be compared to brain biopsies. Unfortunately, biopsy is not performed in VZV vasculopathy because the virus is usually restricted to cerebral arteries. [1] Consequently, confirmation requires testing CSF for VZV DNA and anti-VZV IgG antibody. In addition, we rigorously demonstrated intrathecal synthesis of anti-VZV IgG antibody in every case, eliminating the possibility that CSF was contaminated by anti-VZV IgG antibody in blood. Furthermore, we failed to detect anti-HSV-1 IgG antibody in our cases. Finally, we always looked for more common causes of stroke including atherosclerosis or dissection. Dr. Elkind questions whether anti-VZV IgG antibody in patients with stroke after zoster reflects antibody produced after zoster, and that the stroke had another cause. This is certainly possible. However, our patients with VZV vasculopathy almost always had a progressive course, gray-white matter junction lesions, and often CSF pleoctytosis, none of which are characteristic of atherosclerotic stroke. Furthermore, patients were evaluated for other inflammatory and non-inflammatory causes of stroke. Dr. Elkind also notes that three patients did not have rash, pleocytosis, or VZV DNA. First, we hasten to emphasize that a spectrum of vascular involvement exists, ranging from necrotizing arteritis to modest, chronic vascular inflammation, to thrombosis without inflammation, to remote vascular occlusion resembling atherosclerosis. [6] More specifically, of those three cases, one (case 15) was an immunocompromised patient with chronic progressive disease with multi-focal angiographic abnormalities and characteristic gray-white matter junction lesions, reduced serum/CSF ratios of anti-VZV IgG, and a favorable response to antiviral agents months after disease onset. The second patient (case 17) had large artery disease without evidence of atherosclerosis or dissection, typical gray-white matter lesions and evidence of intrathecal synthesis of anti-VZV IgG antibody. The third patient was a healthy, 25-year-old woman without evidence of atherosclerosis, fibromuscular dysplasia or dissection who had multifocal vasculopathy and evidence of intrathecal synthesis of anti-VZV IgG. These three cases are reminiscent of the prototypic case of progressive fatal VZV vasculopathy presented in 1995 [7], a 73-year-old immunocompetent man with no history of rash, whose diagnosis of VZV vasculopathy was confirmed at autopsy by the presence of VZV DNA and antigen in cerebral arteries corresponding to areas of infarction. [8] References 5. Nagel MA, Forghani B, Mahalingam R, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology 2007;68:1069-1073. 6. Kleinschmidt-DeMasters, Gilden DH. Varicella-zoster virus infections of the nervous system – clinical and pathological correlates. Arch Pathol Lab Med 2001;125:770-780. 7. Case Records of the Massachusetts General Hospital (Case 5-1995). N Engl J Med 1995;332:452-459. 8. Gilden DH, Kleinschmidt-DeMasters BK, Wellish M, Hedley-Whyte ET, Rentier B, Mahalingam R. Varicella zoster virus, a cause of waxing and waning vasculitis. Neurology 1996;47:1441-1446. Disclosure: The authors report no disclosures.