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BMC Neurology

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Open Access 01-12-2013 | Research article

Detection of human herpesviruses in the cerebrospinal fluid from patients diagnosed with or suspected of having progressive multifocal leukoencephalopathy

Authors: Kazuo Nakamichi, Naoki Inoue, Toshio Shimokawa, Ichiro Kurane, Chang-Kweng Lim, Masayuki Saijo

Published in: BMC Neurology | Issue 1/2013

Abstract

Background

Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC virus (JCV), occurs mainly in immunocompromised patients. While JCV DNA is detected in the cerebrospinal fluid (CSF) from a certain proportion of patients suspected of having PML, JCV-negative patients may also develop brain lesions due to other infectious agents. This study assessed the prevalence of six herpesviruses in the CSF from patients diagnosed with or suspected of PML.

Methods

Two hundred and ninety-nine CSF specimens and clinical data were collected from 255 patients, including 31 confirmed PML cases. Quantitative PCR assays were carried out to detect the genomic DNA of JCV, herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6).

Results

Herpesvirus DNAs were detected in the CSF specimens from 29 of 255 patients (11.4%). HSV-1 and CMV were detected in JCV-negative patients, whereas VZV and EBV were detected in both CSF JCV-positive and -negative individuals. The herpesvirus-positive patients had underlying disorders that caused immunosuppression, such as HIV infection, congenital immunodeficiencies, and hematologic malignancies, and presented with neurologic symptoms and MRI lesions, mainly in the cerebral white matter. The median values of CSF cell counts and protein levels in the herpesvirus-positive patients were slightly higher than those in the PML patients.

Conclusions

The results demonstrate that herpesviruses are occasionally detected in the CSF from PML patients and immunocompromised individuals suspected of having PML. Thus, this study provides a significant basis for the diagnosis and treatment of neurological disorders in immunocompromised patients.

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Brew BJ, Davies NW, Cinque P, Clifford DB, Nath A: Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol. 2010, 6: 667-679. 10.1038/nrneurol.2010.164.CrossRefPubMed

Tan CS, Koralnik IJ: Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010, 9: 425-437. 10.1016/S1474-4422(10)70040-5.CrossRefPubMedPubMedCentral

Shishido-Hara Y: Progressive multifocal leukoencephalopathy and promyelocytic leukemia nuclear bodies: a review of clinical, neuropathological, and virological aspects of JC virus-induced demyelinating disease. Acta Neuropathol. 2010, 120: 403-417. 10.1007/s00401-010-0694-x.CrossRefPubMedPubMedCentral

Knowles WA, Pipkin P, Andrews N, Vyse A, Minor P, Brown DW, Miller E: Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol. 2003, 71: 115-123. 10.1002/jmv.10450.CrossRefPubMed

Khanna N, Elzi L, Mueller NJ, Garzoni C, Cavassini M, Fux CA, Vernazza P, Bernasconi E, Battegay M, Hirsch HH: Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis. 2009, 48: 1459-1466. 10.1086/598335.CrossRefPubMed

Major EO: Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med. 2010, 61: 35-47. 10.1146/annurev.med.080708.082655.CrossRefPubMed

Marzocchetti A, Di Giambenedetto S, Cingolani A, Ammassari A, Cauda R, De Luca A: Reduced rate of diagnostic positive detection of JC virus DNA in cerebrospinal fluid in cases of suspected progressive multifocal leukoencephalopathy in the era of potent antiretroviral therapy. J Clin Microbiol. 2005, 43: 4175-4177. 10.1128/JCM.43.8.4175-4177.2005.CrossRefPubMedPubMedCentral

Nakamichi K, Mizusawa H, Yamada M, Kishida S, Miura Y, Shimokawa T, Takasaki T, Lim CK, Kurane I, Saijo M: Characteristics of progressive multifocal leukoencephalopathy clarified through internet-assisted laboratory surveillance in Japan. BMC Neurol. 2012, 12: 121-10.1186/1471-2377-12-121.CrossRefPubMedPubMedCentral

Kleinschmidt-DeMasters BK, Gilden DH: The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol. 2001, 11: 440-451. 10.1111/j.1750-3639.2001.tb00413.x.CrossRefPubMed

10.

Steiner I: Herpes simplex virus encephalitis: new infection or reactivation?. Curr Opin Neurol. 2011, 24: 268-274. 10.1097/WCO.0b013e328346be6f.CrossRefPubMed

11.

Fujimoto H, Asaoka K, Imaizumi T, Ayabe M, Shoji H, Kaji M: Epstein-Barr virus infections of the central nervous system. Intern Med. 2003, 42: 33-40. 10.2169/internalmedicine.42.33.CrossRefPubMed

12.

Ivers LC, Kim AY, Sax PE: Predictive value of polymerase chain reaction of cerebrospinal fluid for detection of Epstein-Barr virus to establish the diagnosis of HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2004, 38: 1629-1632. 10.1086/420934.CrossRefPubMed

13.

Weber T, Frye S, Bodemer M, Otto M, Luke W: Clinical implications of nucleic acid amplification methods for the diagnosis of viral infections of the nervous system. J Neurovirol. 1996, 2: 175-190. 10.3109/13550289609146880.CrossRefPubMed

14.

Nakamichi K, Kurane I, Saijo M: Evaluation of a quantitative real-time PCR assay for the detection of JC polyomavirus DNA in cerebrospinal fluid without nucleic acid extraction. Jpn J Infect Dis. 2011, 64: 211-216.PubMed

15.

Nakamichi K, Kishida S, Tanaka K, Suganuma A, Sano Y, Sano H, Kanda T, Maeda N, Kira J, Itoh A, Kato N, Tomimoto H, Kurane I, Lim CK, Mizusawa H, Saijo M: Sequential changes in the non-coding control region sequences of JC polyomaviruses from the cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. Arch Virol. 2013, 158: 639-650. 10.1007/s00705-012-1532-3.CrossRefPubMed

16.

Hawrami K, Breuer J: Development of a fluorogenic polymerase chain reaction assay (TaqMan) for the detection and quantitation of varicella zoster virus. J Virol Methods. 1999, 79: 33-40. 10.1016/S0166-0934(98)00176-1.CrossRefPubMed

17.

Ogawa H, Suzutani T, Baba Y, Koyano S, Nozawa N, Ishibashi K, Fujieda K, Inoue N, Omori K: Etiology of severe sensorineural hearing loss in children: independent impact of congenital cytomegalovirus infection and GJB2 mutations. J Infect Dis. 2007, 195: 782-788. 10.1086/511981.CrossRefPubMed

18.

Weinberg A, Bloch KC, Li S, Tang YW, Palmer M, Tyler KL: Dual infections of the central nervous system with Epstein-Barr virus. J Infect Dis. 2005, 191: 234-237. 10.1086/426402.CrossRefPubMed

19.

Corcoran C, Rebe K, van der Plas H, Myer L, Hardie DR: The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons. J Clin Virol. 2008, 42: 433-436. 10.1016/j.jcv.2008.03.017.CrossRefPubMed

20.

Kannangai R, Sachithanandham J, Mahadevan A, Abraham AM, Sridharan G, Desai A, Ravi V, Shankar SK: Association of neurotropic viruses in HIV-infected individuals who died of secondary complications of tuberculosis, cryptococcosis, or toxoplasmosis in South India. J Clin Microbiol. 2013, 51: 1022-1025. 10.1128/JCM.03321-12.CrossRefPubMedPubMedCentral

21.

d’Arminio Monforte A, Cinque P, Vago L, Rocca A, Castagna A, Gervasoni C, Terreni MR, Novati R, Gori A, Lazzarin A, Moroni M: A comparison of brain biopsy and CSF-PCR in the diagnosis of CNS lesions in AIDS patients. J Neurol. 1997, 244: 35-39.CrossRefPubMed

22.

Davies NW, Brown LJ, Gonde J, Irish D, Robinson RO, Swan AV, Banatvala J, Howard RS, Sharief MK, Muir P: Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections. J Neurol Neurosurg Psychiatry. 2005, 76: 82-87. 10.1136/jnnp.2004.045336.CrossRefPubMedPubMedCentral

23.

Cinque P, Vago L, Dahl H, Brytting M, Terreni MR, Fornara C, Racca S, Castagna A, Monforte AD, Wahren B, Lazzarin A, Linde A: Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients. AIDS. 1996, 10: 951-958. 10.1097/00002030-199610090-00004.CrossRefPubMed

24.

Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ: The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008, 47: 303-327. 10.1086/589747.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/200/prepub

Title: Detection of human herpesviruses in the cerebrospinal fluid from patients diagnosed with or suspected of having progressive multifocal leukoencephalopathy
Authors: Kazuo Nakamichi
Naoki Inoue
Toshio Shimokawa
Ichiro Kurane
Chang-Kweng Lim
Masayuki Saijo
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: BMC Neurology / Issue 1/2013
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/1471-2377-13-200

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Detection of human herpesviruses in the cerebrospinal fluid from patients diagnosed with or suspected of having progressive multifocal leukoencephalopathy

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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