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Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment
Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case Report
Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment Marzena J. Fabis-Pedrini a,1, Wen Xu a,b,1, Jason Burton a, William M. Carroll a, Allan G. Kermode a,c,⇑ a Centre for Neuromuscular and Neurological Disorders, Western Australian Neuroscience Research Institute, The University of Western Australia, Sir Charles Gairdner Hospital, 4th Floor, A Block, QEII Medical Centre, Verdun Street, Nedlands, WA 6009, Australia b Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China c Institute of Immunology and Infectious Diseases, Murdoch University, Murdoch, WA 6150, Australia
a r t i c l e
i n f o
Article history: Received 2 February 2015 Accepted 9 August 2015 Available online xxxx Keywords: Immune reconstitution inflammatory syndrome Multiple sclerosis Natalizumab Progressive multifocal leukoencephalopathy
a b s t r a c t We report a case of asymptomatic progressive multifocal leukoencephalopathy (PML) detected on regular MRI screening in a 40-year-old patient with subsequent benign course with 12 months follow-up. The patient had a history of aggressive inflammatory multiple sclerosis, prior mitoxantrone therapy, Stratify John Cunningham Virus test positivity (Quest Diagnostics, Madison, NJ, USA), and 5 years of natalizumab monotherapy. The initial MRI detection of PML was both atypical and subtle. Early diagnosis and intervention, and pre-emptive treatment for immune reconstitution inflammatory syndrome with high dose steroids, as well as empirical mirtazapine and mefloquine, were associated with a benign PML disease course and outcome. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
2. Case report
Natalizumab (NTZ) is an effective widely used diseasemodifying therapy in multiple sclerosis (MS) [1]. NTZ is a selective monoclonal antibody against the alpha 4 subunit of alpha 4 beta 1 integrin and significantly inhibits the ability of activated T cells to migrate across the blood–brain barrier into the central nervous system [1]. Decision-making around its use however has been dominated by the infrequent occurrence of progressive multifocal leukoencephalopathy (PML), which is caused by the John Cunningham virus (JCV) [2]. Unlike other clinical contexts in which PML may occur, cessation and removal of NTZ from the circulation in MS patients permits their immune surveillance to return to its baseline state. It appears that the immune reconstitution inflammatory syndrome (IRIS) after cessation of NTZ therapy may be a key determinant, if not the major determinant, of prognosis in this complication [3]. Here we report a case of asymptomatic PML detected on regular screening in a patient with secondary progressive MS at high risk of development of PML, with subsequent benign course of resolution and outcome.
A patient was diagnosed with relapsing remitting MS in 1996 at the age of 24 years. The same year she commenced subcutaneous interferon b1-b, but continued to experience frequent relapses requiring intravenous methylprednisolone (IVMP). In November 2003 she started treatment with mitoxantrone 12 mg/m2 and 1 g of IVMP every 3 months for 1 year, followed by ongoing interferon therapy. Since other disease modifying agents were ineffective, concurrent with the development of a tumefactive lesion accompanied by status epilepticus and Expanded Disability Status Scale (EDSS) score of 6.0, in 2008 the patient commenced on NTZ 300 mg monthly. Gadolinium-enhanced MRI performed every 6 months were unchanged for the following 54 months and she remained stable and relapse free. However, in August 2011 she was JCV antibody positive (using a two-step anti–JCV antibody assay, Stratify JCV, Quest Diagnostics, Madison, NJ, USA). The risks and benefits of NTZ treatment were discussed and therapy continued. In February 2013, a PML surveillance MRI demonstrated subtle patchy signal change in the left cerebral peduncle and pons (Fig. 1). NTZ was discontinued and cerebrospinal fluid (CSF) examination confirmed JCV DNA presence. The leukocyte count was 0 * 106/L and proteins were 0.44 g/L. EDSS score remained at 6.0. The patient was admitted to hospital and received five sessions of plasmapheresis with addition of oral mefloquine loading, mirtazapine
⇑ Corresponding author. Tel.: +61 8 93881865; fax: +61 8 93882149. 1
E-mail address: [email protected] (A.G. Kermode). These authors contributed equally to this study.
http://dx.doi.org/10.1016/j.jocn.2015.08.027 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fabis-Pedrini MJ et al. Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.08.027
2
Case Report / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Fig. 1. Neuroimaging of asymptomatic progressive multifocal leukoencephalopathy. Patient positive for John Cunningham virus (August 2011) continued natalizumab therapy for the following 17 months without new symptoms. (A) Parasagittal fluid-attenuated inversion recovery MRI performed in February 2013 according to the scheduled follow-up without any signs of PML clinically and (B) T1-weighted gadolinium enhanced MRI shows interval development of multiple small patchy foci of high signal within the left side of the brain stem, cerebral peduncle, pontine tegmentum and left brachium points (white arrows). (C) Several lesions faintly enhance following gadolinium administration on axial T2-weighted fast spin echo MRI.
treatment resulted with rapid improvement. JCV was undetectable in CSF. Following steroid treatment, dimethyl fumarate therapy was commenced. Follow up MRI in December 2013 showed significant interval improvement and cessation of enhancement. Similarly MRI in January and July 2014 showed extensive white matter disease with the previously demonstrated foci of parenchymal enhancement having resolved. Summary of the disease course, treatments and corresponding radiological features are presented in Table 1.
15 mg note, and IVMP 500 mg daily for 5 days, then continued mirtazapine, prednisolone 50 mg/kg orally, and weekly mefloquine 250 mg. Repeat CSF examination showed quantitative polymerase chain raction for JCV of 63,910 copies/mL, but leukocyte count was 0 * 106/L with proteins 0.33 g/L. The oral prednisolone was reduced to 37.5 mg after 3 weeks, then to 25 mg after 5 weeks. Follow-up MRI (March and April 2013) showed subtle enhancement in some lesions only, suggestive of mild IRIS but the patient did not have any worsening neurological signs. Two months later (May 2013), MRI demonstrated interval development of multiple new areas of signal abnormality and faint nodular enhancement, yet EDSS score remained 6.0. In August 2013 prednisolone had tapered to 6.25 mg in the morning based on CSF and imaging results. CSF examination showed JCV as fewer than 30 copies/mL. In October 2013 the patient felt more unbalanced but could still walk with a single elbow crutch (EDSS score 6.0). MRI demonstrated extensive multiple new enhancing foci in the posterior fossa, and in the supratentorial compartment new enhancing lesions with the characteristics of MS lesions were also seen. IVMP
3. Discussion PML is a subacute demyelinating disease caused by JCV infection in immunosuppressed patients. Known risk factors for the development of PML in MS patients include JCV positivity, length of NTZ treatment above 2 years and prior use of immunosuppressive medications [2]. Our patient was JCV positive, had 4.5 years of treatment with NTZ and had been treated with mitoxantrone prior to NTZ therapy. Considering the risk of NTZ therapy, it is
Table 1 Summary of the disease course of our patient with progressive multifocal leukoencephalopathy demonstrating diagnostic and therapeutic procedures as well as the corresponding MRI and its description EDSS Examination date JCV status MRI
MRI date
Treatment
6.0 Aug 2011 Feb 2012 Aug 2012 Positive blood Stable, no evidence of PML
6.0 Feb 2013
6.0 Mar 2013
6.0 Apr 2013
6.0 May 2013
6.0 Aug 2013
6.0 Oct 2013
Positive CSF Subtle patchy foci of contrast enhancement (PML)
63,910c CSF Interval resolution of the previously demonstrated enhancing foci
–
– Interval development of multiple new areas of nodular enhancement in left mid-brain, pons and cerebellum consistent with IRIS
Aug 2011 Feb 2012 Aug 2012 NTZ
Feb 2013
Mar 2013
Several existing brain stem and cerebral lesions show subtle enhancement suspicious for IRIS Apr 2013
<30c CSF Unchanged
May 2013
Jun 2013 Aug 2013
Undetectable CSF Multiple new enhancing foci in supratentorial and infratentorial compartments, suggestive of active MS Oct 2013
NTZ stop PLEX Mefloquine Mirtazapine IVMP Prednisolone
Prednisolone Mefloquine Mirtazapine
Prednisolone
Prednisolone
Prednisolone
IVMP Dimethyl fumarate
6.0 Dec 2013 Jan 2014 Jul 2014 – Interval improvement with resolution of enhancement and reduction in lesion T2 volumes Dec 2013 Jan 2014 Jul 2014 Dimethyl fumarate
c = copies/ml, CSF = cerebrospinal fluid, EDSS = Expanded Disability Status Scale, IRIS = immune reconstitution inflammatory syndrome, IVMP = intravenous methylprednisolone, JCV = John Cunningham virus, MS = multiple sclerosis, NTZ = natalizumab, PLEX = plasma exchange, PML = progressive multifocal leukoencephalopathy.
Please cite this article in press as: Fabis-Pedrini MJ et al. Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.08.027
Case Report / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
important to remember that NTZ can reduce the risk of the progression and the rate of relapse in MS patients [1]. Thus, although the small risk of PML exists, it must be balanced against the inevitable risk of MS progression, which can be limited by effective therapies such as NTZ. Patients who develop PML may present with various neurological symptoms, such as cognitive impairment, apraxia, visual deficits and motor disability and seizures [4,5]. Our patient was diagnosed with PML based on MRI and CSF findings but did not experience any new symptoms. After plasma exchange, the patient was treated with mefloquine (able to inhibit JCV replication in vitro), mirtazapine (can inhibit viral spread by blocking the 5-HT2 receptor) [5], and IVMP. IRIS in NTZ-associated PML occurs after removal of the drug resulting in return of immunocompetence [3]. The immune system reconstitution leads to infiltration of lymphocytes in the PML lesions. We treated our patient with IVMP followed by oral steroids preemptively prior to the development of IRIS, resulting in a benign PML disease course and clinical outcome. Any new changes on MRI during NTZ treatment should prompt the neurologist to consider PML as a possible cause [6]. Early investigation in suspected PML is warranted, and if confirmed, early intervention coupled with pre-emptive management to reduce IRIS may permit a benign PML disease course and clinical outcomes. IRIS management may need to be very prolonged, in this case continuing beyond 10 months. Conflicts of Interest/Disclosures Jason Burton has received speaker honoraria and membership of scientific advisory boards from Bayer Schering, Biogen-Idec,
3
Novartis, Merck Serono and Sanofi-Genzyme. William M. Carroll received speaker honoraria and membership of scientific advisory boards from Bayer Schering, Novartis, Merck Serono, Sanofi, Biogen-Idec and CSL. Allan G. Kermode received speaker honoraria and scientific advisory board fees from Bayer, Biogen-Idec, Novartis, Sanofi-Aventis, Merck, Sanofi-Genzyme, Innate Immunotherapeutics and CSL. The other authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements Dr Xu’s research was supported by Sun Yat Sen University Occupational Training Scholarship, International Project Fund of 985 Project, Sun Yat Sen University. References [1] Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354: 899–910. [2] Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–80. [3] Tan IL, McArthur JC, Clifford DB, et al. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011;77:1061–7. [4] Hohlfeld R. Natalizumab-induced PML: can the beast be tamed? J Neurol Neurosurg Psychiatry 2013;84:1065. [5] Dahlhaus S, Hoepner R, Chan A, et al. Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2013;84: 1068–74. [6] Wattjes MP, Richert ND, Killestein J, et al. The chameleon of neuroinflammation: magnetic resonance imaging characteristics of natalizumab-associated progressive multifocal leukoencephalopathy. Mult Scler 2013;19:1826–40.
Please cite this article in press as: Fabis-Pedrini MJ et al. Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.08.027
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case Report
Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment Marzena J. Fabis-Pedrini a,1, Wen Xu a,b,1, Jason Burton a, William M. Carroll a, Allan G. Kermode a,c,⇑ a Centre for Neuromuscular and Neurological Disorders, Western Australian Neuroscience Research Institute, The University of Western Australia, Sir Charles Gairdner Hospital, 4th Floor, A Block, QEII Medical Centre, Verdun Street, Nedlands, WA 6009, Australia b Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China c Institute of Immunology and Infectious Diseases, Murdoch University, Murdoch, WA 6150, Australia
a r t i c l e
i n f o
Article history: Received 2 February 2015 Accepted 9 August 2015 Available online xxxx Keywords: Immune reconstitution inflammatory syndrome Multiple sclerosis Natalizumab Progressive multifocal leukoencephalopathy
a b s t r a c t We report a case of asymptomatic progressive multifocal leukoencephalopathy (PML) detected on regular MRI screening in a 40-year-old patient with subsequent benign course with 12 months follow-up. The patient had a history of aggressive inflammatory multiple sclerosis, prior mitoxantrone therapy, Stratify John Cunningham Virus test positivity (Quest Diagnostics, Madison, NJ, USA), and 5 years of natalizumab monotherapy. The initial MRI detection of PML was both atypical and subtle. Early diagnosis and intervention, and pre-emptive treatment for immune reconstitution inflammatory syndrome with high dose steroids, as well as empirical mirtazapine and mefloquine, were associated with a benign PML disease course and outcome. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
2. Case report
Natalizumab (NTZ) is an effective widely used diseasemodifying therapy in multiple sclerosis (MS) [1]. NTZ is a selective monoclonal antibody against the alpha 4 subunit of alpha 4 beta 1 integrin and significantly inhibits the ability of activated T cells to migrate across the blood–brain barrier into the central nervous system [1]. Decision-making around its use however has been dominated by the infrequent occurrence of progressive multifocal leukoencephalopathy (PML), which is caused by the John Cunningham virus (JCV) [2]. Unlike other clinical contexts in which PML may occur, cessation and removal of NTZ from the circulation in MS patients permits their immune surveillance to return to its baseline state. It appears that the immune reconstitution inflammatory syndrome (IRIS) after cessation of NTZ therapy may be a key determinant, if not the major determinant, of prognosis in this complication [3]. Here we report a case of asymptomatic PML detected on regular screening in a patient with secondary progressive MS at high risk of development of PML, with subsequent benign course of resolution and outcome.
A patient was diagnosed with relapsing remitting MS in 1996 at the age of 24 years. The same year she commenced subcutaneous interferon b1-b, but continued to experience frequent relapses requiring intravenous methylprednisolone (IVMP). In November 2003 she started treatment with mitoxantrone 12 mg/m2 and 1 g of IVMP every 3 months for 1 year, followed by ongoing interferon therapy. Since other disease modifying agents were ineffective, concurrent with the development of a tumefactive lesion accompanied by status epilepticus and Expanded Disability Status Scale (EDSS) score of 6.0, in 2008 the patient commenced on NTZ 300 mg monthly. Gadolinium-enhanced MRI performed every 6 months were unchanged for the following 54 months and she remained stable and relapse free. However, in August 2011 she was JCV antibody positive (using a two-step anti–JCV antibody assay, Stratify JCV, Quest Diagnostics, Madison, NJ, USA). The risks and benefits of NTZ treatment were discussed and therapy continued. In February 2013, a PML surveillance MRI demonstrated subtle patchy signal change in the left cerebral peduncle and pons (Fig. 1). NTZ was discontinued and cerebrospinal fluid (CSF) examination confirmed JCV DNA presence. The leukocyte count was 0 * 106/L and proteins were 0.44 g/L. EDSS score remained at 6.0. The patient was admitted to hospital and received five sessions of plasmapheresis with addition of oral mefloquine loading, mirtazapine
⇑ Corresponding author. Tel.: +61 8 93881865; fax: +61 8 93882149. 1
E-mail address: [email protected] (A.G. Kermode). These authors contributed equally to this study.
http://dx.doi.org/10.1016/j.jocn.2015.08.027 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fabis-Pedrini MJ et al. Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.08.027
2
Case Report / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Fig. 1. Neuroimaging of asymptomatic progressive multifocal leukoencephalopathy. Patient positive for John Cunningham virus (August 2011) continued natalizumab therapy for the following 17 months without new symptoms. (A) Parasagittal fluid-attenuated inversion recovery MRI performed in February 2013 according to the scheduled follow-up without any signs of PML clinically and (B) T1-weighted gadolinium enhanced MRI shows interval development of multiple small patchy foci of high signal within the left side of the brain stem, cerebral peduncle, pontine tegmentum and left brachium points (white arrows). (C) Several lesions faintly enhance following gadolinium administration on axial T2-weighted fast spin echo MRI.
treatment resulted with rapid improvement. JCV was undetectable in CSF. Following steroid treatment, dimethyl fumarate therapy was commenced. Follow up MRI in December 2013 showed significant interval improvement and cessation of enhancement. Similarly MRI in January and July 2014 showed extensive white matter disease with the previously demonstrated foci of parenchymal enhancement having resolved. Summary of the disease course, treatments and corresponding radiological features are presented in Table 1.
15 mg note, and IVMP 500 mg daily for 5 days, then continued mirtazapine, prednisolone 50 mg/kg orally, and weekly mefloquine 250 mg. Repeat CSF examination showed quantitative polymerase chain raction for JCV of 63,910 copies/mL, but leukocyte count was 0 * 106/L with proteins 0.33 g/L. The oral prednisolone was reduced to 37.5 mg after 3 weeks, then to 25 mg after 5 weeks. Follow-up MRI (March and April 2013) showed subtle enhancement in some lesions only, suggestive of mild IRIS but the patient did not have any worsening neurological signs. Two months later (May 2013), MRI demonstrated interval development of multiple new areas of signal abnormality and faint nodular enhancement, yet EDSS score remained 6.0. In August 2013 prednisolone had tapered to 6.25 mg in the morning based on CSF and imaging results. CSF examination showed JCV as fewer than 30 copies/mL. In October 2013 the patient felt more unbalanced but could still walk with a single elbow crutch (EDSS score 6.0). MRI demonstrated extensive multiple new enhancing foci in the posterior fossa, and in the supratentorial compartment new enhancing lesions with the characteristics of MS lesions were also seen. IVMP
3. Discussion PML is a subacute demyelinating disease caused by JCV infection in immunosuppressed patients. Known risk factors for the development of PML in MS patients include JCV positivity, length of NTZ treatment above 2 years and prior use of immunosuppressive medications [2]. Our patient was JCV positive, had 4.5 years of treatment with NTZ and had been treated with mitoxantrone prior to NTZ therapy. Considering the risk of NTZ therapy, it is
Table 1 Summary of the disease course of our patient with progressive multifocal leukoencephalopathy demonstrating diagnostic and therapeutic procedures as well as the corresponding MRI and its description EDSS Examination date JCV status MRI
MRI date
Treatment
6.0 Aug 2011 Feb 2012 Aug 2012 Positive blood Stable, no evidence of PML
6.0 Feb 2013
6.0 Mar 2013
6.0 Apr 2013
6.0 May 2013
6.0 Aug 2013
6.0 Oct 2013
Positive CSF Subtle patchy foci of contrast enhancement (PML)
63,910c CSF Interval resolution of the previously demonstrated enhancing foci
–
– Interval development of multiple new areas of nodular enhancement in left mid-brain, pons and cerebellum consistent with IRIS
Aug 2011 Feb 2012 Aug 2012 NTZ
Feb 2013
Mar 2013
Several existing brain stem and cerebral lesions show subtle enhancement suspicious for IRIS Apr 2013
<30c CSF Unchanged
May 2013
Jun 2013 Aug 2013
Undetectable CSF Multiple new enhancing foci in supratentorial and infratentorial compartments, suggestive of active MS Oct 2013
NTZ stop PLEX Mefloquine Mirtazapine IVMP Prednisolone
Prednisolone Mefloquine Mirtazapine
Prednisolone
Prednisolone
Prednisolone
IVMP Dimethyl fumarate
6.0 Dec 2013 Jan 2014 Jul 2014 – Interval improvement with resolution of enhancement and reduction in lesion T2 volumes Dec 2013 Jan 2014 Jul 2014 Dimethyl fumarate
c = copies/ml, CSF = cerebrospinal fluid, EDSS = Expanded Disability Status Scale, IRIS = immune reconstitution inflammatory syndrome, IVMP = intravenous methylprednisolone, JCV = John Cunningham virus, MS = multiple sclerosis, NTZ = natalizumab, PLEX = plasma exchange, PML = progressive multifocal leukoencephalopathy.
Please cite this article in press as: Fabis-Pedrini MJ et al. Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.08.027
Case Report / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
important to remember that NTZ can reduce the risk of the progression and the rate of relapse in MS patients [1]. Thus, although the small risk of PML exists, it must be balanced against the inevitable risk of MS progression, which can be limited by effective therapies such as NTZ. Patients who develop PML may present with various neurological symptoms, such as cognitive impairment, apraxia, visual deficits and motor disability and seizures [4,5]. Our patient was diagnosed with PML based on MRI and CSF findings but did not experience any new symptoms. After plasma exchange, the patient was treated with mefloquine (able to inhibit JCV replication in vitro), mirtazapine (can inhibit viral spread by blocking the 5-HT2 receptor) [5], and IVMP. IRIS in NTZ-associated PML occurs after removal of the drug resulting in return of immunocompetence [3]. The immune system reconstitution leads to infiltration of lymphocytes in the PML lesions. We treated our patient with IVMP followed by oral steroids preemptively prior to the development of IRIS, resulting in a benign PML disease course and clinical outcome. Any new changes on MRI during NTZ treatment should prompt the neurologist to consider PML as a possible cause [6]. Early investigation in suspected PML is warranted, and if confirmed, early intervention coupled with pre-emptive management to reduce IRIS may permit a benign PML disease course and clinical outcomes. IRIS management may need to be very prolonged, in this case continuing beyond 10 months. Conflicts of Interest/Disclosures Jason Burton has received speaker honoraria and membership of scientific advisory boards from Bayer Schering, Biogen-Idec,
3
Novartis, Merck Serono and Sanofi-Genzyme. William M. Carroll received speaker honoraria and membership of scientific advisory boards from Bayer Schering, Novartis, Merck Serono, Sanofi, Biogen-Idec and CSL. Allan G. Kermode received speaker honoraria and scientific advisory board fees from Bayer, Biogen-Idec, Novartis, Sanofi-Aventis, Merck, Sanofi-Genzyme, Innate Immunotherapeutics and CSL. The other authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements Dr Xu’s research was supported by Sun Yat Sen University Occupational Training Scholarship, International Project Fund of 985 Project, Sun Yat Sen University. References [1] Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354: 899–910. [2] Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–80. [3] Tan IL, McArthur JC, Clifford DB, et al. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011;77:1061–7. [4] Hohlfeld R. Natalizumab-induced PML: can the beast be tamed? J Neurol Neurosurg Psychiatry 2013;84:1065. [5] Dahlhaus S, Hoepner R, Chan A, et al. Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2013;84: 1068–74. [6] Wattjes MP, Richert ND, Killestein J, et al. The chameleon of neuroinflammation: magnetic resonance imaging characteristics of natalizumab-associated progressive multifocal leukoencephalopathy. Mult Scler 2013;19:1826–40.
Please cite this article in press as: Fabis-Pedrini MJ et al. Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.08.027