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15 JANUARY Correspondence 5-HT2a Inhibitors for Progressive Multifocal Leukoencephalopathy: Old Drugs for an Old Disease To the Editor—In the 1 September 2007 issue of the Journal, Verma et al. show that mirtazapine arrested progressive multifocal leukoencephalopathy (PML) in a patient with polycythemia vera [1]. Although this is the first reported case of PML in a patient with polycythemia vera, it is not a first regarding the effectiveness of 5-HT2a antagonists against PML. Actually, after the seminal article by Elphick et al. was published in 2004 [2], we speculated on the possible use of clinically approved antipsychotic drugs for PML [3]. In 2006, our group showed the effectiveness of risperidone (8 mg/day for 10 days) in a 33-year-old haploidentical stem-cell transplant recipient with PML refractory to intravenous cidofovir and donor lymphocyte infusions [4]. We also recently suggested schedules for PML treatment with risperidone, ziprasidone, and olanzapine [5]. Mirtazapine is also not a first for PML treatment. In 2006, Vulliemoz et al. [6] first showed the effectiveness of a 5-day course of intravenous cytarabine (2 mg/ kg/day for 5 days) and an ongoing treatment of mirtazapine at 30 mg/day in a 44-year-old HIV-negative male with dermatomyositis and PML. In 2007, Owczarczyk et al. [7] also showed successful treatment of PML in a 58-year-old white woman after 6 infusions of cidofovir and mirtazapine at 15 mg/day starting after the second infusion of cidofovir. Our group also proposed the monitoring of drops in JC viruria by psychoactive drugs as a surrogate marker for comparing the effectiveness of different 5-HT2a inhibitors against PML [8]. 328 ● JID 2008:197 (15 January) ● We read with interest that the patient reported by Verma [1] et al. had positive JC viremia at diagnosis of PML. In both our HIV-negative PML patients and in the PML patients who received natalizumab [9], JC viremia was usually positive before the onset of symptoms [4] while being normally absent in healthy control subjects and transplant recipients. It is also a far less invasive and expensive test than stereotactic biopsy. These findings also imply that JC virus replication can be 5-HT2a dependent even outside the central nervous system, soliciting investigations for 5-HT2a–positive competent cell types (e.g., white blood cells) that could easily be cultivated, in contrast to adult glial cells. 5. 6. 7. 8. 9. 1,a 4,a Daniele Focosi, Richard Eric Kast, Fabrizio Maggi,2 Giuseppe Lauria,3 Luca Ceccherini-Nelli,2 and Mario Petrini1 1 Department of Oncology, Transplants, and Advances in Medicine, Division of Hematology, and 2 Virology Section and Retrovirus Center, Department of Experimental Pathology, University of Pisa, Pisa, and 3Neuromuscular Diseases Unit, National Neurological Institute “Carlo Besta,” Milan, Italy; 4 Department of Psychiatry, University of Vermont, Burlington ment with risperidone. Antiviral Res 2006; 74: 156 – 8. Kast RE, Focosi D, Petrini M, Altschuler EL. Treatment schedules for 5-HT2A blocking in progressive multifocal leukoencephalopathy using risperidone or ziprasidone. Bone Marrow Transplant 2007; 39:811–2. Vulliemoz S, Lurati-Ruiz F, Borruat F, et al. Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis. J Neurol Neurosurg Psychiatry 2006; 77:1079 – 82. Owczarczyk K, Hilker R, Brunn A, Hallek M, Rubbert A. Progressive multifocal leucoencephalopathy in a patient with sarcoidosis—successful treatment with cidofovir and mirtazapine. Rheumatology (Oxford) 2007; 46:888 –90. Focosi D, Kast RE, Maggi F, Ceccherini-Nelli L, Petrini M. Risperidone-induced reduction in JC viruria as a surrogate marker for efficacy against progressive multifocal leukoencephalopathy and hemorrhagic cystitis. J Clin Virol 2007; 39:63– 4. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005; 353:362– 8. Potential conflicts of interest: none reported. a D.F. and R.E.K. contributed equally to this letter. Reprints or correspondence: Dr. Daniele Focosi, Dept. of Oncology, Transplants, and Advances in Medicine, Div. of Hematology, University of Pisa, via Roma 56, 56100 Pisa, Italy ([email protected]). The Journal of Infectious Diseases 2008; 197:328 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19702-0023$15.00 DOI: 10.1086/524877 References 1. Verma S, Cikurel K, Koralnik IJ, et al. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis 2007; 196:709 –11. 2. Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 2004; 306:1380 –3. 3. Altschuler E, Kast R. The atypical antipsychotic agents ziprasidone [correction of zisprasidone], risperdone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy. Med Hypotheses 2005; 65:585– 6. 4. Focosi D, Fazzi R, Montanaro D, Emdin M, Petrini M. Progressive multifocal leukoencephalopathy in a haploidentical stem cell transplant recipient: a clinical, neuroradiological and virological response after treat- CORRESPONDENCE Reply to Focosi et al. To the Editor—We read with interest Focosi et al.’s letter [1] in response to our brief report on the role played by mirtazapine in the treatment of progressive multifocal leukoencephalopathy (PML). Although we appreciate the comments, it should be clarified that our article did not claim to be the first report of the potential role of 5-HT2a blockers in the treatment of PML. Our aim was rather to document and highlight the clinical, virological, and radiological improvement in our patient with PML in polycythemia vera. Furthermore, most of the references cited by Focosi et al. were published after our report was submitted [2–5] or were written by one of our coauthors [6]. Focosi et al. note that the diagnosis of PML could have been established on the basis of the detection of JC virus (JCV) DNA in the blood by polymerase chain reaction (PCR) instead of by performing a brain biopsy. The established diagnosis of PML in our patient was based on the brain biopsy performed at another institution before her arrival at our medical center and before PML was considered as a possible diagnosis. Furthermore, JC viremia is present in 16%–38% of immunosuppressed individuals who do not have PML, and JCV PCR is positive in the blood of only 70%– 80% patients with PML [7–10]. Susama Verma,1 Katia Cikurel,1 Igor J. Koralnik,6 Susan Morgello,2 Charlotte Cunningham-Rundles,3 Zelig R. Weinstein,4 Christine Bergmann,5 and David M. Simpson1 Departments of 1Neurology, 2Pathology, 3 Immunobiology, 4Neuroradiology, and 5Psychiatry, The Mount Sinai Medical Center, New York, New York; 6HIV/Neurology Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts References 5. Focosi D, Kast RE, Maggi F, Ceccherini-Nelli L, Petrini M. Risperidone-induced reduction in JC viruria as a surrogate marker for efficacy against progressive multifocal leukoencephalopathy and hemorrhagic cystitis. J Clin Virol 2007; 39:63– 4. 6. Vulliemoz S, Lurati-Ruiz F, Borruat F, et al. Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis. J Neurol Neurosurg Psychiatry 2006; 77:1079 – 82. 7. Tornatore C, Berger JR, Houff SA, et al. Dectection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy. Ann Neurol 1992; 31:454 – 62. 8. Dubois V, Lafon ME, Ragnaud JM, et al. Detection of JC virus DNA in peripheral blood leukocytes of HIV-infected patients. AIDS 1996; 10:353– 8. 9. Ferrante P, Caldarelli-Stefano R, OmodeoZorini E, et al. Comprehensive investigation of the presence of JC virus in AIDS patients with and without progressive multifocal leukoencephalopathy. J Med Virol 1997; 52:235– 42. 10. Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999; 52:253– 60. Potential conflicts of interest: none reported. Financial support: Public Health Service (grants R01 NS/AI 041198 and NS 047029 to I.J.K. and NS002253 to D.M.S.); Ellen R. Cavallo Research Fund; National Institutes of Health (grant R24MH59724 to S.M. and D.M.S.). Reprints or correspondence: Katia Cikurel, 200 E. 69th St., New York, NY 10021 ([email protected]). The Journal of Infectious Diseases 2008; 197:328 –9 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19702-0024$15.00 DOI: 10.1086/524876 1. Focosi D, Kast RE, Maggi F, Lauria G, Ceccherini-Nell L, Petrini M. 5-HT2a inhibitors for progressive multifocal leukoencephalopathy: old drugs for an old disease. J Infect Dis 2008; 197:328 (in this issue). 2. Focosi D, Fazzi R, Montanaro D, Emdin M, Petrini M. Progressive multifocal leukoencephalopathy in a haploidentical stem cell transplant recipient: a clinical, neuroradiological and virological response after treatment with risperidone. Antiviral Res 2007; 74:156 – 8. 3. Kast RE, Focosi D, Petrini M, Altschuler EL. Treatment schedules for 5-HT2A blocking in progressive multifocal leukoencephalopathy using risperidone or ziprasidone. Bone Marrow Transplant 2007; 39:811–2. 4. Owczarczyk K, Hilker R, Brunn A, Hallek MR, Rubbert A. Progressive multifocal leukoencephalopathy in a patient with sarcoidosis—successful treatment with cidofovir and mirtazapine. Rheumatology (Oxford) 2007; 46:888 –90. CORRESPONDENCE ● JID 2008:197 (15 January) ● 329