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Predictors and characteristics of seizures in survivors of progressive multifocal leukoencephalopathy

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Abstract

This study aims to determine the risk factors for epileptogenesis and characteristics of seizures in patients with progressive multifocal leukoencephalopathy (PML) who survive more than 1 year from onset of neurological symptoms (PML survivors). We reviewed clinical data including seizure history and MR imaging studies from PML survivors evaluated at our institution between 1997 and 2014. PML progressors who passed away within 1 year and patients with a history of seizures prior to PML diagnosis were excluded from the analysis. Of 64 PML survivors, 28 (44 %) developed seizures. The median time from the onset of PML symptoms to the first seizure was 5.4 months (range 0–159) and 64 % of patients with seizures had them within the first year. The presence of juxtacortical PML lesions was associated with a relative risk of seizures of 3.5 (p < 0.02; 95 % confidence interval (CI) 1.3–9.4) in multivariate analyses. Of all seizure types, 86 % were focal and 60 % most likely originated from the frontal lobes. Among seizure patients, 89 % required treatment, including one (54 %), two (25 %), or three (10.5 %) antiepileptic drugs. Seizures are a frequent complication in PML and can develop throughout the entire course of the disease. However, late onset seizures did not signify PML relapse. Seizures may require treatment with multiple antiepileptic medications and are a significant co-morbidity in PML.

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References

  • Bartsch T, Rempe T, Wrede A, Leypoldt F, Adams O, Rohr A, Jansen O, Bruck W, Wuthrich C, Deuschl G, Koralnik IJ (2015) Progressive hemiparesis in a psoriasis patient treated with dimethyl fumarate. Ann Neurol 78:501–14

    Article  CAS  PubMed  Google Scholar 

  • Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, Tomson T, Hauser WA (2010) Recommendation for a definition of acute symptomatic seizure. Epilepsia 51:671–675

    Article  PubMed  Google Scholar 

  • Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer IE (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51:676–685

    Article  PubMed  Google Scholar 

  • Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, Bartt R, Major EO, Nath A (2013) PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology 80:1430–1438

    Article  PubMed  PubMed Central  Google Scholar 

  • Carson KR, Focosi D, Major EO, Petrini M, Richey EA, West DP, Bennett CL (2009) Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 10:816–824

    Article  CAS  PubMed  Google Scholar 

  • Casado JL, Corral I, Garcia J, Martinez-San Millan J, Navas E, Moreno A, Moreno S (2014) Continued declining incidence and improved survival of progressive multifocal leukoencephalopathy in HIV/AIDS patients in the current era. Eur J Clin Microbiol Infect Dis 33:179–187

    Article  CAS  PubMed  Google Scholar 

  • Clifford DB, De Luca A, Simpson DM, Arendt G, Giovannoni G, Nath A (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 9:438–446

    Article  CAS  PubMed  Google Scholar 

  • Collazos J, Mayo J, Martinez E, Blanco MS (1999) Contrast-enhancing progressive multifocal leukoencephalopathy as an immune reconstitution event in AIDS patients. Aids 13:1426–1428

    Article  CAS  PubMed  Google Scholar 

  • Dahlhaus S, Hoepner R, Chan A, Kleiter I, Adams O, Lukas C, Hellwig K, Gold R (2013) Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 84:1068–1074

    Article  PubMed  PubMed Central  Google Scholar 

  • Dammeier N, Schubert V, Hauser TK, Bornemann A, Bischof F (2015) Case report of a patient with progressive multifocal leukoencephalopathy under treatment with dimethyl fumarate. BMC Neurol 15:108

    Article  PubMed  PubMed Central  Google Scholar 

  • Du Pasquier RA, Koralnik IJ (2003) Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 9(Suppl 1):25–31

    Article  PubMed  Google Scholar 

  • Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55:475–482

    Article  PubMed  Google Scholar 

  • Gadzia J, Turner J (2010) Progressive multifocal leukoencephalopathy in two psoriasis patients treated with efalizumab. J Drugs Dermatol 9:1005–1009

    PubMed  Google Scholar 

  • Gheuens S, Bord E, Kesari S, Simpson DM, Gandhi RT, Clifford DB, Berger JR, Ngo L, Koralnik IJ (2011) Role of CD4+ and CD8+ T-cell responses against JC virus in the outcome of patients with progressive multifocal leukoencephalopathy (PML) and PML with immune reconstitution inflammatory syndrome. J Virol 85:7256–7263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gheuens S, Ngo L, Wang X, Alsop DC, Lenkinski RE, Koralnik IJ (2012a) Metabolic profile of PML lesions in patients with and without IRIS: an observational study. Neurology 79:1041–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gheuens S, Smith DR, Wang X, Alsop DC, Lenkinski RE, Koralnik IJ (2012b) Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS. Neurology 78:1390–1393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gray F, Bazille C, Adle-Biassette H, Mikol J, Moulignier A, Scaravilli F (2005) Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol 11(Suppl 3):16–22

    Article  PubMed  Google Scholar 

  • Hoepner R, Ahlbrecht J, Faissner S, Schneider R, Dahlhaus S, Adams O, Raab P, Lukas C, Chan A, Stangel M, Gold R (2014) Clinical and paraclinical findings in natalizumab-associated infratentorial progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 85:1177–1178

    Article  CAS  PubMed  Google Scholar 

  • Hoffmann C, Horst HA, Albrecht H, Schlote W (2003) Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 74:1142–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khatri BO, Garland J, Berger J, Kramer J, Sershon L, Olapo T, Sesing J, Dukic M, Rehn E (2015) The effect of dimethyl fumarate (Tecfidera) on lymphocyte counts: a potential contributor to progressive multifocal leukoencephalopathy risk. Mult Scler Relat Disord 4:377–379

    Article  PubMed  Google Scholar 

  • Khoury MN, Alsop DC, Agnihotri SP, Pfannl R, Wuthrich C, Ho ML, Hackney D, Ngo L, Anderson MP, Koralnik IJ (2014) Hyperintense cortical signal on magnetic resonance imaging reflects focal leukocortical encephalitis and seizure risk in progressive multifocal leukoencephalopathy. Ann Neurol 75:659–669

    Article  PubMed  PubMed Central  Google Scholar 

  • Korman BD, Tyler KL, Korman NJ (2009) Progressive multifocal leukoencephalopathy, efalizumab, and immunosuppression: a cautionary tale for dermatologists. Arch Dermatol 145:937–942

    Article  PubMed  Google Scholar 

  • Kotecha N, George MJ, Smith TW, Corvi F, Litofsky NS (1998) Enhancing progressive multifocal leukoencephalopathy: an indicator of improved immune status? Am J Med 105:541–543

    Article  CAS  PubMed  Google Scholar 

  • Kothary N, Diak IL, Brinker A, Bezabeh S, Avigan M, Dal Pan G (2011) Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients. J Am Acad Dermatol 65:546–551

    Article  CAS  PubMed  Google Scholar 

  • Lima MA, Koralnik IJ (2005) New features of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy and natalizumab. J Neurovirol 11(Suppl 3):52–57

    Article  CAS  PubMed  Google Scholar 

  • Lima MA, Drislane FW, Koralnik IJ (2006) Seizures and their outcome in progressive multifocal leukoencephalopathy. Neurology 66:262–264

    Article  PubMed  Google Scholar 

  • Marousi S, Travasarou M, Karageorgiou CE, Gheuens S, Koralnik IJ (2012) Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS. Neurology 79:2160, author reply 2160

    Article  PubMed  Google Scholar 

  • Martinez JV, Mazziotti JV, Efron ED, Bonardo P, Jordan R, Sevlever G, Martinez M, Verbanaz SC, Salazar ZS, Pardal MF, Reisin R (2006) Immune reconstitution inflammatory syndrome associated with PML in AIDS: a treatable disorder. Neurology 67:1692–1694

    Article  CAS  PubMed  Google Scholar 

  • Miralles P, Berenguer J, Lacruz C, Cosin J, Lopez JC, Padilla B, Munoz L, Garcia-de-Viedma D (2001) Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy. Aids 15:1900–1902

    Article  CAS  PubMed  Google Scholar 

  • Moll NM, Rietsch AM, Ransohoff AJ, Cossoy MB, Huang D, Eichler FS, Trapp BD, Ransohoff RM (2008) Cortical demyelination in PML and MS: similarities and differences. Neurology 70:336–343

    Article  CAS  PubMed  Google Scholar 

  • Nita DA, Cisse Y, Timofeev I, Steriade M (2006) Increased propensity to seizures after chronic cortical deafferentation in vivo. J Neurophysiol 95:902–913

    Article  PubMed  Google Scholar 

  • Nuttall JJ, Wilmshurst JM, Ndondo AP, Yeats J, Corcoran C, Hussey GD, Eley BS (2004) Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case of immune reconstitution inflammatory syndrome. Pediatr Infect Dis J 23:683–685

    Article  PubMed  Google Scholar 

  • Okulicz JF, Grandits GA, French JA, George JM, Simpson DM, Birbeck GL, Ganesan A, Weintrob AC, Crum-Cianflone N, Lalani T, Landrum ML (2011) Virologic outcomes of HAART with concurrent use of cytochrome P450 enzyme-inducing antiepileptics: a retrospective case control study. AIDS Res Ther 8:18

    Article  PubMed  PubMed Central  Google Scholar 

  • Siddiqi O, Birbeck GL (2013) Safe treatment of seizures in the setting of HIV/AIDS. Curr Treat Options Neurol 15:529–543

    Article  PubMed  PubMed Central  Google Scholar 

  • Silva MT, Pacheco MC Jr, Vaz B (2006) Inflammatory progressive multifocal leukoencephalopathy after antiretroviral treatment. Aids 20:469–471

    Article  PubMed  Google Scholar 

  • Tan K, Roda R, Ostrow L, McArthur J, Nath A (2009) PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 72:1458–1464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan IL, McArthur JC, Clifford DB, Major EO, Nath A (2011) Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 77:1061–1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Topolnik L, Steriade M, Timofeev I (2003) Partial cortical deafferentation promotes development of paroxysmal activity. Cereb Cortex 13:883–893

    Article  PubMed  Google Scholar 

  • Wuthrich C, Koralnik IJ (2012) Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol 71:54–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong, W., Ping, X., Gao, J., Jin, X., 2011. Preparing undercut model of posttraumatic epileptogenesis in rodents. J Vis Exp

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Authors’ contributions

Dr. Miskin was involved in the conceptualization or design of the study, acquisition, analysis, and interpretation of the data and drafting of the manuscript. Dr. Herman was involved in the conceptualization or design of the study, analysis, and interpretation of the data and drafting and critical revision of the manuscript. Dr. Ngo was involved in the analysis and interpretation of the data, critical revision of the manuscript, and statistical analysis. Dr. Koralnik was involved in the conceptualization of the study, analysis and interpretation of the data, critical revision of the manuscript, obtaining funding, and supervision.

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Authors and Affiliations

  1. Division of Neuro-Immunology, Department of Neurology, Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA

    Dhanashri P. Miskin & Igor J. Koralnik

  2. Division of Epilepsy, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA

    Susan T. Herman

  3. Division of General Medicine and Primary Care Section for Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA

    Long H. Ngo

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  1. Dhanashri P. Miskin
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Correspondence to Dhanashri P. Miskin.

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Funding

This study was supported by NIH grants R01NS 047029 and 074995.

Conflict of interest

Dr. Miskin reports no disclosures or conflicts of interest. Dr. Herman is funded by NIH grants R01 047029 and 074409; received research grants from UCB Pharma, Sage Pharmaceuticals, Acorda Therapeutics, and the Epilepsy Therapy Development Project; received consulting fees from Eisai, Inc. and Biotie, Inc. Dr. Ngo is funded by NIH grant R01 047029. Dr. Koralnik is funded by NIH grants R01 047029 and 074995; has received a research grant from Biogen Idec and the National Multiple Sclerosis Society; served on scientific advisory boards for Hoffmann La Roche, GlaxoSmithKline, Merck Serono, and MedImmune; received consulting fees from Bristol Myers Squibb, Ono Pharmaceuticals, Merck Serono, Hoffmann La Roche, GlaxoSmithKline, Perseid Therapeutics, Vertex Pharmaceuticals, and Johnson & Johnson; is an Associate Editor for the Annals of Neurology; and receives royalties from UpToDate for topics on the management of HIV and CNS mass lesions and on PML.

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Miskin, D.P., Herman, S.T., Ngo, L.H. et al. Predictors and characteristics of seizures in survivors of progressive multifocal leukoencephalopathy. J. Neurovirol. 22, 464–471 (2016). https://doi.org/10.1007/s13365-015-0414-3

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  • DOI: https://doi.org/10.1007/s13365-015-0414-3

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