Multiple Sclerosis and Related Disorders (2013) 2, 385–387
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
Does natalizumab treatment increase the risk of herpes simplex encephalitis in multiple sclerosis? Case and discussion Kanchan Sharmaa, Samantha A. Ballhama, Kirsty E.A. Inglisa, Shelley Renowdenb, David A. Cottrella,n a
Department of Neurology, Frenchay Hospital, University of Bristol, North Bristol NHS Trust, Bristol BS16 1LE, UK Department of Neuroradiology, Frenchay Hospital, University of Bristol, North Bristol NHS Trust, Bristol BS16 1LE, UK
b
Received 9 September 2012; received in revised form 19 February 2013; accepted 22 February 2013
KEYWORDS
Abstract
Natalizumab; Adverse effects; Herpes simplex encephalitis; Multiple sclerosis; Acyclovir
This report presents the 4th documented case worldwide of herpes simplex encephalitis in multiple sclerosis (MS) patients treated with natalizumab and the first case in the UK. Natalizumab is licensed for relapsing remitting multiple sclerosis in patients with high disease activity despite treatment with interferon-beta and patients with rapidly evolving severe, multiple sclerosis. Natalizumab is a monoclonal antibody targeted against alpha-4 integrin. Its proposed mechanism is attenuation of the migration of immune cells into the central nervous system. Reactivation of the JC virus causing progressive multifocal leucoencephalopathy (PML) and its association with natalizumab is well documented. This case adds support to the suggestion that natalizumab also increases the reactivation risk of CNS herpes simplex infection. A 34 year old woman was admitted with a generalized tonic-clonic seizure, fever and confusion following her 40th infusion of natalizumab. MRI demonstrated increased signal in the medial temporal lobes and EEG showed focal sharp waves over the temporal lobe. CSF PCR later confirmed herpes simplex virus. The patient made an eventual excellent recovery following 21 days of intravenous acyclovir therapy followed by 14 days of oral treatment. Crown Copyright & 2013 Published by Elsevier B.V. All rights reserved.
1. 1.1. n
Corresponding author. Tel.: +44 11 7970 1212. E-mail address: [email protected] (D.A. Cottrell).
Case report Background
MF, a 34 year old female was diagnosed with RRMS in 2005. She was commenced Rebif 44 in April 2007, which was
2211-0348/$ - see front matter Crown Copyright & 2013 Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.02.006
386
K. Sharma et al.
discontinued in November 2007 due to side effects of bruising and neutropenia. She was subsequently commenced on Natalizumab on 04/06/08 due to further severe and frequent relapses. She completed 40 doses with her last infusion on 03/08/11. Her pre treatment EDSS on 03/06/08 was 7.5 and this progressed to 8.0 on 18/08/09 and 8.0 on 27/08/10. However she retained both good upper limb and cognitive function. Co-morbidities included surgically corrected bicuspid aortic valve and coarctation of the aorta. Admission medications included citalopram 20 mg od, the oral contraceptive pill, solifenacin 20 mg od and baclofen 20 mg bd. At the time of admission she was being treated for a UTI by her GP with ciprofloxacin.
1.2.
Patient presentation
MF was admitted on 08/09/11 with two, self terminating, secondary generalized tonic-clonic seizures, confusion and a pyrexia of 38.01 which spiked to 39.8 on the first day. On admission she was haemodynamically stable with an AMMT of 6/10, loosing marks on orientation in time and recall of an address. Admission bloods revealed a WBC 10.0 (neutrophils 8.55), hemoglobin 13.1, platelets 260, CRP 2, normal renal and liver function. Urinalysis revealed ketones, nitrites and blood. An MSU from 01/09/11 sent by her GP grew staph. aureus. She was commenced on ceftriaxone, amoxicillin and acyclovir to cover meningoencephalitis on admission. Her antibiotics were later converted to meropenum on 11/ 09/11 to cover aspiration pneumonia, chest x-ray demonstrating patchy consolidation at the right lung base and raised inflammatory blood markers (WBC 12, CRP 43).
1.3.
Further Investigation
CSF on 09/09/11 had a normal opening pressure, WBC 6 and RBC 116 per mm3, Glucose 3.9 (serum 5.7), protein 0.42. PCR for HSV type 1 was positive. Serum was positive for JC virus IgG antibodies however JC virus CSF PCR was negative. An initial MR brain on 09/09/11 demonstrated no evidence of new pathology. Yet a repeat MR brain on 12/09/11 showed high T2/FLAIR signal in the medial temporal lobes and insular cortex on the right extending to the lentifom nucleus, in keeping with herpes simplex encephalitis (see figure). An EEG on 14/09/11 showed slow, irregular, sharp frontotemporal changes with focal sharp waves over the right temporal lobe.
1.4.
Progression
The patient continued to spike fevers of 38 C which eventually settled after two weeks with no secondary source of infection identified. A trans-thoracic echo on 12/09/11 and transoesophageal echo on 27/09/11 did not reveal any evidence of endocarditis. The patient was treated with 3 weeks of acyclovir IV 500 mg tds and a further 2 weeks of 800 mg bd oral prophylaxis. She was discharged after 32 days and reviewed in clinic one month later having made a good recovery, maintaining
an EDSS of 8.0 on 09/11/11. An Addenbrookes Cognitive Exam on 14/09/11 scored 83/100 (14/18 attention and orientation, 24/16 memory, 7/14 fluency, 26/26 language, visuospatial 12/16) which improved to 98/100 by 15/02/12.
2.
Discussion
This report presents the 4th documented case worldwide of herpes simplex encephalitis (HSE) in a MS patient on natalizumab and the first case in the UK. There are no published details for the first HSE case, reported in the post marketing surveillance, other than it being fatal (Ransohoff, 2007). The second HSE case occurred in a 45 year old female who had received six doses of Natalizumab before becoming unwell with global aphasia, impairment of cognition and drowsiness. HSE was diagnosed two days after the initial symptoms developed, with diagnosis confirmed on CSF HSV PCR (the type was not published). The patient was stable following treatment with 14 days of aciclovir (Haghikia et al., 2011). The third HSE case occurred in a 36 year old female who had received 6 courses of natalizumab before presenting with seizures, confusion and hyperthermia. CSF showed 14 WBC per mm3, lymphocytic predominance with HSV type-1 confirmed on CSF PCR. The patient completed a 21 day course of aciclovir and at five months follow up had persistent and severe episodic memory defect with anosognosia and mild aphasia (Kwiatkowski et al., 2011). There are a further 3 reported cases of herpes simplex meningitis (HSM) associated with multiples sclerosis patients on natalizumab. There are no published details for the first HSM case, reported in the post marketing surveillance (Ransohoff, 2007). The second case of HSM occurred in a 51 year old female who had completed 1 year of natalizumab and then presented with fevers, headache and neck stiffness. Initial CSF studies showed 25 WBC per mm3 with lymphocytic predominance and HSV type 2 was confirmed on CSF PCR. She completed four weeks of IV acyclovir and made a good recovery with mild cognitive sequelae (Shenoy et al., 2011). The third case occurred in a 42-year-old male who had completed two years of Natalizumab treatment before developing fever and meningism. He was diagnosed with type 2 herpes meningoencephalitis; no details of diagnostic investigations have been published (Jelcic et al., 2011). Natalizumab is indicated for relapsing remitting multiple sclerosis in patients with high disease activity despite treatment with interferon-beta and patients with rapidly evolving severe, multiple sclerosis. It works as a monoclonal antibody targeted against alpha-4 integrin, which is present on all leukocytes except neutrophils; with the proposed mechanism of attenuating the migration of lymphocytes into the central nervous system at times of inflammation (Engelhardt and Kappos, 2008). The pathophysiology of HSE is poorly understood (Rozenberg et al., 2011) with 3 possible mechanisms proposed. It could be due to primary infection, reactivation of the virus via axonal spread from the trigeminal ganglion or latent reactivation of the virus in CNS tissue (Steiner, 2011). Under immunocompetent conditions if HSV were to penetrate the CNS, an immune
Natalizumab treatment in MS response would mount, clearing the virus, preventing encephalitis. With Natalizumab therapy, HSV clearance within the CNS is impaired as lymphocytes are inhibited from crossing the blood brain barrier allowing HSE to develop. There are 82,732 (195,500 patient years) MS patients on Natalizumab Worldwide (true of 31/12/11) with an incidence of HSE of 1 in 48,875 patient years compared to 1 in 455,000 patient years in the normal population (Hjalmarsson et al., 2007). CSF studies comparing natalizumab treated MS patients with untreated controls demonstrated a significant reduction in certain lymphocyte subsets including CD4 + and CD8 + T cells, creating a CD4 + :CD8 + T ratio similar to that seen in HIV infected controls (St¨ uve et al., 2006). All reported cases to date of CNS herpes infection in MS patients on natalizumab have had a low CSF WBC (6–25), which suggests reduced CNS surveillance and hence increased infection risk in these cases are related to the drug. Natalizumab may also increase susceptibility to non CNS infections. In a Swedish cohort of 1152 patients with natalizumab treated MS surveyed over three and a half years, 14 patients (1.2%) developed herpes simplex or herpes zoster reactivation, giving an annual incidence of et al., 2011). An 3.5 per 1000 patient years (Holmen American cohort observed 4 out of 120 (3.3%) patients on natalizumab developed herpes zoster all within the first year of therapy (Robles et al., 2009). The variation between these two studies suggests further high powered studies are required to enable accurate comparison between the incidence of zoster whilst on natalizumab to zoster in the general population, which is estimated as 4 per 1000 people per year (Chapman et al., 2003). An American observational study recorded a three-fold increase of herpes labialis with natalizumab (Schiess et al., 2009) however the mechanism by which this would occur is unclear as immunocompromise is thought to be selective to the CNS. Reactivation of the JC virus causing progressive multifocal leucoencephalopathy and its association with natalizumab is well documented. This case adds weight to the suggestion that natalizumab also increases the reactivation risk of CNS herpes simplex infection. If further studies replicate this pattern, it would support the use of prophylactic aciclovir as an adjunct to natalizumab. This is the first documented case of HSE associated with natalizumab to have made such a good recovery, likely linked to the early initiation of treatment doses of Aciclovir.
3.
Conclusion
It is important to recognize that patients treated with Natalizumab are not only at risk of PML but also of HSV reactivation both within the CNS and peripherally. Early initiation of IV acyclovir should always be strongly considered in patients on Natalizumab presenting with confusion and seizures.
387
Conflict of interest All authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
References Chapman RS, Cross KW, Fleming DM. The incidence of shingles and its implications for vaccination policy. Vaccine 2003;21:2541–7. Engelhardt B, Kappos L. Natalizumab: targeting alpha4-integrins in multiple sclerosis. Neurodegenerative Disease 2008;5(1):16–22. Haghikia A, Perrech M, Pula B, Ruhrmann S, Potthoff A, Brockmeyer NH, Goelz S,Wiendl H, Lind˚ a H, Ziemssen T, Baranzini SE, K¨ all TB, Bengel D, Olsson T, Gold R, Chan A. Functional energetics of CD4 + -cellular immunity in monoclonal antibody-associated progressive multifocal leukoencephalopathy in autoimmune disorders. PLoS One. 2011 Apr 20;6(4):e18506. http://dx.doi.org/10. 1371/journal.pone.0018506. PubMed PMID: 21533133; PubMed Central PMCID: PMC3080364. Hjalmarsson A, Blomqvist P, Sk¨ oldenberg B. Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality. Clinical Infectious Diseases 2007;45(7):875–80. October 1. C, Piehl F, Hillert J, Fogdell-Hahn A, Lundkvist M, Karlberg E, Holmen Nilsson P, Dahle C, Feltelius N, Svenningsson A, Lycke J, Olsson T. A Swedish national post-marketing surveillance study of natalizumab treatment in multiple sclerosis. Multiple Sclerosis 2011;17(6): 708–19. Jun. Jelcic Ilijas, Nathalie Braun, Fischer Heike, Weller Michael, Linnebank Michael. Favourable outcome of prolonged immune reconstitution inflammatory syndrome in the context of progressive Multifocal Leukoencephalopathy and Herpes Simplex type 2 meningoencephalitis in a patient treated with natalizumab for multiple sclerosis. Conference abstract 5th Joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis Amsterdam, The Netherlands: 19–22.10.2011. Kwiatkowski A, Gallois J, Bilbault N, Calais G, Mackowiak A, Hautecoeur P. Herpes encephalitis during natalizumab treatment in multiple sclerosis. Multiple Sclerosis 2011. November 2. Ransohoff RM. Natalizumab for multiple sclerosis. New England Journal of Medicine 2007;356:2622–9. Robles L, Prieto P, Rivera VM, Hutton GJ. Occurrence of herpes zoster in multiple sclerosis patients treated with natalizumab. International Journal of MS Care 2009;11(Suppl. 2):S43. Rozenberg F, Deback C, Agut H. Herpes simplex encephalitis: from virus to therapy. Infectious Disorders Drug Targets 2011;11(3): 235–50. Schiess N, Zong J, Hayward G, Calabresi P, Nath A. Reactivation of herpes viruses in multiple sclerosis patients on natalizumab therapy. Poster Presentation American Academy of Neurology 61st Annual Meeting; Seattle, WA. April 28 p. P03.163; 2009. Shenoy ES, Mylonakis E, Hurtado RM, Venna N. Natalizumab and HSV meningitis. Journal of NeuroVirology 2011;17:288–90. Steiner I. Herpes simplex virus encephalitis: new infection or reactivation? Current Opinion in Neurology 2011;24(3):268–74. Review. St¨ uve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Hemmer B, Monson NL, Racke MK. Immune surveillance in multiple sclerosis patients treated with natalizumab. Annals of Neurology 2006.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
Does natalizumab treatment increase the risk of herpes simplex encephalitis in multiple sclerosis? Case and discussion Kanchan Sharmaa, Samantha A. Ballhama, Kirsty E.A. Inglisa, Shelley Renowdenb, David A. Cottrella,n a
Department of Neurology, Frenchay Hospital, University of Bristol, North Bristol NHS Trust, Bristol BS16 1LE, UK Department of Neuroradiology, Frenchay Hospital, University of Bristol, North Bristol NHS Trust, Bristol BS16 1LE, UK
b
Received 9 September 2012; received in revised form 19 February 2013; accepted 22 February 2013
KEYWORDS
Abstract
Natalizumab; Adverse effects; Herpes simplex encephalitis; Multiple sclerosis; Acyclovir
This report presents the 4th documented case worldwide of herpes simplex encephalitis in multiple sclerosis (MS) patients treated with natalizumab and the first case in the UK. Natalizumab is licensed for relapsing remitting multiple sclerosis in patients with high disease activity despite treatment with interferon-beta and patients with rapidly evolving severe, multiple sclerosis. Natalizumab is a monoclonal antibody targeted against alpha-4 integrin. Its proposed mechanism is attenuation of the migration of immune cells into the central nervous system. Reactivation of the JC virus causing progressive multifocal leucoencephalopathy (PML) and its association with natalizumab is well documented. This case adds support to the suggestion that natalizumab also increases the reactivation risk of CNS herpes simplex infection. A 34 year old woman was admitted with a generalized tonic-clonic seizure, fever and confusion following her 40th infusion of natalizumab. MRI demonstrated increased signal in the medial temporal lobes and EEG showed focal sharp waves over the temporal lobe. CSF PCR later confirmed herpes simplex virus. The patient made an eventual excellent recovery following 21 days of intravenous acyclovir therapy followed by 14 days of oral treatment. Crown Copyright & 2013 Published by Elsevier B.V. All rights reserved.
1. 1.1. n
Corresponding author. Tel.: +44 11 7970 1212. E-mail address: [email protected] (D.A. Cottrell).
Case report Background
MF, a 34 year old female was diagnosed with RRMS in 2005. She was commenced Rebif 44 in April 2007, which was
2211-0348/$ - see front matter Crown Copyright & 2013 Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.02.006
386
K. Sharma et al.
discontinued in November 2007 due to side effects of bruising and neutropenia. She was subsequently commenced on Natalizumab on 04/06/08 due to further severe and frequent relapses. She completed 40 doses with her last infusion on 03/08/11. Her pre treatment EDSS on 03/06/08 was 7.5 and this progressed to 8.0 on 18/08/09 and 8.0 on 27/08/10. However she retained both good upper limb and cognitive function. Co-morbidities included surgically corrected bicuspid aortic valve and coarctation of the aorta. Admission medications included citalopram 20 mg od, the oral contraceptive pill, solifenacin 20 mg od and baclofen 20 mg bd. At the time of admission she was being treated for a UTI by her GP with ciprofloxacin.
1.2.
Patient presentation
MF was admitted on 08/09/11 with two, self terminating, secondary generalized tonic-clonic seizures, confusion and a pyrexia of 38.01 which spiked to 39.8 on the first day. On admission she was haemodynamically stable with an AMMT of 6/10, loosing marks on orientation in time and recall of an address. Admission bloods revealed a WBC 10.0 (neutrophils 8.55), hemoglobin 13.1, platelets 260, CRP 2, normal renal and liver function. Urinalysis revealed ketones, nitrites and blood. An MSU from 01/09/11 sent by her GP grew staph. aureus. She was commenced on ceftriaxone, amoxicillin and acyclovir to cover meningoencephalitis on admission. Her antibiotics were later converted to meropenum on 11/ 09/11 to cover aspiration pneumonia, chest x-ray demonstrating patchy consolidation at the right lung base and raised inflammatory blood markers (WBC 12, CRP 43).
1.3.
Further Investigation
CSF on 09/09/11 had a normal opening pressure, WBC 6 and RBC 116 per mm3, Glucose 3.9 (serum 5.7), protein 0.42. PCR for HSV type 1 was positive. Serum was positive for JC virus IgG antibodies however JC virus CSF PCR was negative. An initial MR brain on 09/09/11 demonstrated no evidence of new pathology. Yet a repeat MR brain on 12/09/11 showed high T2/FLAIR signal in the medial temporal lobes and insular cortex on the right extending to the lentifom nucleus, in keeping with herpes simplex encephalitis (see figure). An EEG on 14/09/11 showed slow, irregular, sharp frontotemporal changes with focal sharp waves over the right temporal lobe.
1.4.
Progression
The patient continued to spike fevers of 38 C which eventually settled after two weeks with no secondary source of infection identified. A trans-thoracic echo on 12/09/11 and transoesophageal echo on 27/09/11 did not reveal any evidence of endocarditis. The patient was treated with 3 weeks of acyclovir IV 500 mg tds and a further 2 weeks of 800 mg bd oral prophylaxis. She was discharged after 32 days and reviewed in clinic one month later having made a good recovery, maintaining
an EDSS of 8.0 on 09/11/11. An Addenbrookes Cognitive Exam on 14/09/11 scored 83/100 (14/18 attention and orientation, 24/16 memory, 7/14 fluency, 26/26 language, visuospatial 12/16) which improved to 98/100 by 15/02/12.
2.
Discussion
This report presents the 4th documented case worldwide of herpes simplex encephalitis (HSE) in a MS patient on natalizumab and the first case in the UK. There are no published details for the first HSE case, reported in the post marketing surveillance, other than it being fatal (Ransohoff, 2007). The second HSE case occurred in a 45 year old female who had received six doses of Natalizumab before becoming unwell with global aphasia, impairment of cognition and drowsiness. HSE was diagnosed two days after the initial symptoms developed, with diagnosis confirmed on CSF HSV PCR (the type was not published). The patient was stable following treatment with 14 days of aciclovir (Haghikia et al., 2011). The third HSE case occurred in a 36 year old female who had received 6 courses of natalizumab before presenting with seizures, confusion and hyperthermia. CSF showed 14 WBC per mm3, lymphocytic predominance with HSV type-1 confirmed on CSF PCR. The patient completed a 21 day course of aciclovir and at five months follow up had persistent and severe episodic memory defect with anosognosia and mild aphasia (Kwiatkowski et al., 2011). There are a further 3 reported cases of herpes simplex meningitis (HSM) associated with multiples sclerosis patients on natalizumab. There are no published details for the first HSM case, reported in the post marketing surveillance (Ransohoff, 2007). The second case of HSM occurred in a 51 year old female who had completed 1 year of natalizumab and then presented with fevers, headache and neck stiffness. Initial CSF studies showed 25 WBC per mm3 with lymphocytic predominance and HSV type 2 was confirmed on CSF PCR. She completed four weeks of IV acyclovir and made a good recovery with mild cognitive sequelae (Shenoy et al., 2011). The third case occurred in a 42-year-old male who had completed two years of Natalizumab treatment before developing fever and meningism. He was diagnosed with type 2 herpes meningoencephalitis; no details of diagnostic investigations have been published (Jelcic et al., 2011). Natalizumab is indicated for relapsing remitting multiple sclerosis in patients with high disease activity despite treatment with interferon-beta and patients with rapidly evolving severe, multiple sclerosis. It works as a monoclonal antibody targeted against alpha-4 integrin, which is present on all leukocytes except neutrophils; with the proposed mechanism of attenuating the migration of lymphocytes into the central nervous system at times of inflammation (Engelhardt and Kappos, 2008). The pathophysiology of HSE is poorly understood (Rozenberg et al., 2011) with 3 possible mechanisms proposed. It could be due to primary infection, reactivation of the virus via axonal spread from the trigeminal ganglion or latent reactivation of the virus in CNS tissue (Steiner, 2011). Under immunocompetent conditions if HSV were to penetrate the CNS, an immune
Natalizumab treatment in MS response would mount, clearing the virus, preventing encephalitis. With Natalizumab therapy, HSV clearance within the CNS is impaired as lymphocytes are inhibited from crossing the blood brain barrier allowing HSE to develop. There are 82,732 (195,500 patient years) MS patients on Natalizumab Worldwide (true of 31/12/11) with an incidence of HSE of 1 in 48,875 patient years compared to 1 in 455,000 patient years in the normal population (Hjalmarsson et al., 2007). CSF studies comparing natalizumab treated MS patients with untreated controls demonstrated a significant reduction in certain lymphocyte subsets including CD4 + and CD8 + T cells, creating a CD4 + :CD8 + T ratio similar to that seen in HIV infected controls (St¨ uve et al., 2006). All reported cases to date of CNS herpes infection in MS patients on natalizumab have had a low CSF WBC (6–25), which suggests reduced CNS surveillance and hence increased infection risk in these cases are related to the drug. Natalizumab may also increase susceptibility to non CNS infections. In a Swedish cohort of 1152 patients with natalizumab treated MS surveyed over three and a half years, 14 patients (1.2%) developed herpes simplex or herpes zoster reactivation, giving an annual incidence of et al., 2011). An 3.5 per 1000 patient years (Holmen American cohort observed 4 out of 120 (3.3%) patients on natalizumab developed herpes zoster all within the first year of therapy (Robles et al., 2009). The variation between these two studies suggests further high powered studies are required to enable accurate comparison between the incidence of zoster whilst on natalizumab to zoster in the general population, which is estimated as 4 per 1000 people per year (Chapman et al., 2003). An American observational study recorded a three-fold increase of herpes labialis with natalizumab (Schiess et al., 2009) however the mechanism by which this would occur is unclear as immunocompromise is thought to be selective to the CNS. Reactivation of the JC virus causing progressive multifocal leucoencephalopathy and its association with natalizumab is well documented. This case adds weight to the suggestion that natalizumab also increases the reactivation risk of CNS herpes simplex infection. If further studies replicate this pattern, it would support the use of prophylactic aciclovir as an adjunct to natalizumab. This is the first documented case of HSE associated with natalizumab to have made such a good recovery, likely linked to the early initiation of treatment doses of Aciclovir.
3.
Conclusion
It is important to recognize that patients treated with Natalizumab are not only at risk of PML but also of HSV reactivation both within the CNS and peripherally. Early initiation of IV acyclovir should always be strongly considered in patients on Natalizumab presenting with confusion and seizures.
387
Conflict of interest All authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
References Chapman RS, Cross KW, Fleming DM. The incidence of shingles and its implications for vaccination policy. Vaccine 2003;21:2541–7. Engelhardt B, Kappos L. Natalizumab: targeting alpha4-integrins in multiple sclerosis. Neurodegenerative Disease 2008;5(1):16–22. Haghikia A, Perrech M, Pula B, Ruhrmann S, Potthoff A, Brockmeyer NH, Goelz S,Wiendl H, Lind˚ a H, Ziemssen T, Baranzini SE, K¨ all TB, Bengel D, Olsson T, Gold R, Chan A. Functional energetics of CD4 + -cellular immunity in monoclonal antibody-associated progressive multifocal leukoencephalopathy in autoimmune disorders. PLoS One. 2011 Apr 20;6(4):e18506. http://dx.doi.org/10. 1371/journal.pone.0018506. PubMed PMID: 21533133; PubMed Central PMCID: PMC3080364. Hjalmarsson A, Blomqvist P, Sk¨ oldenberg B. Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality. Clinical Infectious Diseases 2007;45(7):875–80. October 1. C, Piehl F, Hillert J, Fogdell-Hahn A, Lundkvist M, Karlberg E, Holmen Nilsson P, Dahle C, Feltelius N, Svenningsson A, Lycke J, Olsson T. A Swedish national post-marketing surveillance study of natalizumab treatment in multiple sclerosis. Multiple Sclerosis 2011;17(6): 708–19. Jun. Jelcic Ilijas, Nathalie Braun, Fischer Heike, Weller Michael, Linnebank Michael. Favourable outcome of prolonged immune reconstitution inflammatory syndrome in the context of progressive Multifocal Leukoencephalopathy and Herpes Simplex type 2 meningoencephalitis in a patient treated with natalizumab for multiple sclerosis. Conference abstract 5th Joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis Amsterdam, The Netherlands: 19–22.10.2011. Kwiatkowski A, Gallois J, Bilbault N, Calais G, Mackowiak A, Hautecoeur P. Herpes encephalitis during natalizumab treatment in multiple sclerosis. Multiple Sclerosis 2011. November 2. Ransohoff RM. Natalizumab for multiple sclerosis. New England Journal of Medicine 2007;356:2622–9. Robles L, Prieto P, Rivera VM, Hutton GJ. Occurrence of herpes zoster in multiple sclerosis patients treated with natalizumab. International Journal of MS Care 2009;11(Suppl. 2):S43. Rozenberg F, Deback C, Agut H. Herpes simplex encephalitis: from virus to therapy. Infectious Disorders Drug Targets 2011;11(3): 235–50. Schiess N, Zong J, Hayward G, Calabresi P, Nath A. Reactivation of herpes viruses in multiple sclerosis patients on natalizumab therapy. Poster Presentation American Academy of Neurology 61st Annual Meeting; Seattle, WA. April 28 p. P03.163; 2009. Shenoy ES, Mylonakis E, Hurtado RM, Venna N. Natalizumab and HSV meningitis. Journal of NeuroVirology 2011;17:288–90. Steiner I. Herpes simplex virus encephalitis: new infection or reactivation? Current Opinion in Neurology 2011;24(3):268–74. Review. St¨ uve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Hemmer B, Monson NL, Racke MK. Immune surveillance in multiple sclerosis patients treated with natalizumab. Annals of Neurology 2006.
