- Email: [email protected]
PML risk and natalizumab: more questions than answers
Reflection and Reaction
tuberculosis who received dexamethasone,9 but this factor is not taken into account in the meta-analysis.3 Important differences between the trial in adults in Malawi and the other trials in adults are also evident for age and HIV status. Almost all individuals aged older than 55 years, and HIV-negative adults of all ages, came from trials in Europe and Vietnam, with mortality-related outcomes in both subgroups significantly reduced for patients who received dexamethasone. By contrast with the mortality-related outcomes, any hearing loss in survivors and adverse effects of dexamethasone showed a uniform trend across all studies. The significant reduction in hearing loss in survivors (odds ratio 0·77, 95% CI 0·60–0·99) makes sense if most between-study heterogeneity relates to variables associated with mortality. In the context of treatment decisions, it is also important that studied adverse effects were not different from those in placebo recipients across all trials, with the exception of a significant 4% increase in hyperglycaemia in adults.3 Where does this information leave clinicians who need to make urgent treatment decisions when faced with presumptive bacterial meningitis? By contrast with van de Beek and colleagues,3 I believe that data from Malawi should be considered separately on clinical grounds, particularly given the insensitivity of statistical tests for detecting heterogeneity.4 In my opinion, the high-quality trials from Malawi show convincingly that, in similar settings where delayed presentation or untreated HIV infection is common, the emphasis should be on effective antimicrobial therapy alone, because immune modulation by dexamethasone will usually be too late after delayed presentation or superfluous in untreated HIV infection. The use of glycerol to improve outcomes of meningitis particularly merits further evaluation in such settings.10 In all other settings, a trend to benefit with adjunctive dexamethasone is consistent, although often not significant in individual studies,
with suggestion of greatest benefit in patients who are most at risk for poor outcomes. Such benefits have been shown in real-world practice, when clearly defined protocols specific to local settings are used.11 Because adverse effects related to dexamethasone are similar to those with placebo,3 I believe that, in settings with good access to medical care including HIV treatment, the balance of risks and benefits favours commencing dexamethasone in cases of presumptive pyogenic meningitis outside the neonatal period, with continuing careful assessment for alternative diagnoses. Peter McIntyre Royal Alexandra Hospital for Children, and University of Sydney, Sydney, New South Wales, Australia [email protected] I have no conflicts of interest. 1
2 3
4 5
6
7
8
9
10
11
Murray CJ, Lopez AD, Mathers CD, Stein C. The Global Burden of Disease 2000 project: aims, methods and data sources. World Health Organization, 2001. http://www.who.int/healthinfo/paper36.pdf (accessed 18 Jan, 2010). van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2003; 3: CD004405. van de Beek D, Farrar JJ, de Gans J, et al. Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data. Lancet Neurol 2010; online publication February 4. DOI:10.1016/S14744422(10)70023-5. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Br Med J 2003; 327: 557–60. Molyneux E, Walsh A, Phiri A, Molyneux M. Acute bacterial meningitis in children admitted to the Queen Elizabeth central hospital Blantyre Malawi, 1996–97. Trop Med Int Health 1998; 3: 610–18. Kilpi T, Anttila M, Kallio MJT, Peltola H. Severity of childhood bacterial meningitis and duration of illness before diagnosis Lancet 1991; 338: 406–09. Thwaites GE, Chau TTH, Stepniewska K, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002; 360: 1287–92. Gordon SB, Walsh AL, Chaponda M, et al. Bacterial meningitis in Malawian adults: pneumococcal disease is common, severe and seasonal. Clin Inf Dis 2000; 31: 53–57. Nguyen TH, Tran TH, Thwaites G, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007; 357: 2431–40. Peltola H, Roine I, Fernandez J, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2007; 45: 1277–86. Korshin A, Koster-Rasmussen R, Meyer CN. Adjunctive steroid treatment: local guidelines and patient outcome in adult bacterial meningitis. Scand J Infect Dis 2007; 39: 963–68.
PML risk and natalizumab: more questions than answers The availability of natalizumab for the treatment of multiple sclerosis has revolutionised the practice of neurology in at least one salient way: we now spend much more time thinking about progressive multifocal leukoencephalopathy (PML). The reasons for this www.thelancet.com/neurology Vol 9 March 2010
increased attention are not difficult to identify. Many patients with multiple sclerosis have ongoing disease activity while receiving the first-line drugs interferon beta and glatiramer acetate, and natalizumab offers a secondstage medication for these patients.1 However, although
Published Online January 29, 2010 DOI:10.1016/S14744422(10)70025-9 See Articles page 264
231
Reflection and Reaction
there are only isolated occurrences of other opportunistic infections or malignancies in patients who receive natalizumab, these patients are at increased risk of PML.2 Choosing the best treatment option for patients is therefore challenging and risk-benefit analyses3 and thoughtful reviews that offer support to clinicians who make these treatment decisions are most welcome. PML is a complication of treatment with not only natalizumab, but also with other immunomodulatory monoclonal antibodies, some of which are options for treatment of other neurological disorders.4 Fortunately, PML is an active area of research. Treatment strategies for natalizumab-associated PML have been proposed.5,6 Efforts, such as that described by Jilek and colleagues7 in this issue of The Lancet Neurology, are also underway to understand more about PML, mainly so that risk of developing this disorder might be mitigated. Pre-treatment identification of individuals who are at increased risk for PML (beyond those who have recently received potent immunosuppression) could improve the selection of candidates for natalizumab treatment. However, this task is far from easy: asymptomatic infection with the causative agent, a polymovirus called the JC virus is widespread, with estimates that at least half of the adult global population is infected; viral shedding is detected in the urine of about 30% of random samples from healthy individuals.8 There is little detailed understanding of how most infected individuals control JC virus and avoid PML, and there is no suitable animal model in which to test hypotheses. PML remains an uncommon disease and most cases are associated with an implicated causative factor, such as earlier treatment with cytotoxic immunosuppressive drugs or therapeutic monoclonal antibodies, presence of a rheumatic or neoplastic disorder, or immune compromise due to HIV/ AIDS.9,10 In all these circumstances, few of the at-risk individuals develop PML, and the host or viral factors that cause pathogenesis remain unknown. PML is generally presumed, albeit without absolute proof, to be associated with viral reactivation rather than de novo primary infection. Another approach to investigate risk of PML is to search for alterations in immune function11 or viral replication12 in individuals who receive drugs associated with PML risk. Of these individuals, patients with multiple sclerosis who are treated with natalizumab might be the most useful, because the US Food and Drug 232
Administration recommends natalizumab monotherapy and the effects of this drug can therefore be studied in isolation. Furthermore, patients with multiple sclerosis are not characterised by marked abnormalities of circulating immune cells, even when being treated with natalizumab.11 Jilek and colleagues7 report changes in viral replication and immune function over time in a small cohort of patients with multiple sclerosis who are treated with natalizumab (n=24) in comparison with controls receiving interferon-beta (n=16), who showed no changes in the measured variables. The investigators assessed anti-JC virus T-cell proliferation, T-cell cytokine (interferon γ) production, and anti-JC virus antibodies, as well as the presence of JC virus in the plasma, urine, and in blood-derived cells. As controls for anti-viral responses, Epstein-Barr virus was selected because of compelling epidemiology indicating its role in the pathogenesis of multiple sclerosis.13 The investigators also monitored responses to cytomegalovirus, a related herpesvirus that is not involved in the pathogenesis of multiple sclerosis. T-cell responses to two antigens derived from myelin proteins were also evaluated as an investigation into how natalizumab might affect the anti-myelin immune reactions that are possibly associated with multiple sclerosis itself. The findings were predominantly negative: there was no evidence for viral reactivation: indeed, no JC virus was detected in any blood samples, and there was no increase in viruria. Importantly, one of the six patients with viruria had antibodies to JC virus at levels below the cutoff for seropositivity, raising concerns about use of serological testing to identify people at low risk for JC virus reactivation. Anti-viral immunity was not compromised, and T-cell responses to JC virus seemed to be increased in some individuals at some time points. Responses to control viruses were overall unchanged. Anti-JC virus T-cell responses were increased above background levels at month 1, but returned to background levels until month 12; at this point, responses were increased again but they returned to background levels at month 18. The changes were seen in only a few patients, although non-parametric statistics enabled significant p value to be attributed to the data. These findings highlight the difficulty of obtaining robust data in human immunology studies and the efforts of the investigators are to be commended. www.thelancet.com/neurology Vol 9 March 2010
Reflection and Reaction
These findings from Jilek and colleagues are not in agreement with those reported recently by Chen and co-workers,12 particularly with regard to the frequency of detection of JC virus in the urine, plasma, and blood cells of patients on natalizumab. The detailed methods used were different, with Chen and co-workers using a more sensitive assay for urine and plasma than Jilek and colleagues, but the assays used for blood cells in both studies had similar levels of detection. The two studies also differed in their assessment of the effects of natalizumab on anti-JC virus immunity, although the two methods were so different that comparisons are hazardous. The results from Jilek and colleagues are more similar to those from earlier reports than are those from Chen and co-workers. Further study and use of a uniform technology are essential to resolve these discrepancies. For non-specialists, the take-home messages are that several groups are asking the correct questions: what are the effects of natalizumab treatment on JC virus replication, and on anti-JC virus immunity? Pathogenic variants and host susceptibility factors (including evidence of previous JC virus infection) are also being sought. Such research should enable future risk-benefit estimations to be based on more and increasingly reliable numbers, and therefore help clinicians to make more informed decisions.
Cleveland Clinic, Mail Code NC30, 9500 Euclid Avenue, Cleveland, OH 44195, USA [email protected] I have received speaker’s honoraria and consulting fees from Biogen-Idec, Teva, Merck-Serono, and Pfizer. 1 2
3 4
5
6
7
8 9 10
11
12 13
Richard M Ransohoff Neuroinflammation Research Center, Lerner Research Institute, Mellen Center for MS Treatment and Research, Neurological Institute, and Cleveland Clinic Lerner College of Medicine,
Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J Med 2007; 356: 2622–29. Linda H, von Heijne A, Major EO, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009; 361: 1081–87. Thompson JP, Noyes K, Dorsey ER, Schwid SR, Holloway RG. Quantitative risk-benefit analysis of natalizumab. Neurology 2008; 71: 357–64. Carson KR, Focosi D, Major EO, et al. 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 2009; 10: 816–24. Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009; 72: 402–09. Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 2009; 361: 1075–80. Jilek S, Jaquiéry E, Hirsch HH, et al. Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study. Lancet Neurol 2010; online publication Jan 29. DOI:10.1016/S1474-4422(10)70006-5. Knowles WA. Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). Adv Exp Med Biol 2006; 577: 19–45. Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006; 60: 162–73. Calabrese LH, Molloy ES, Huang D, Ransohoff RM. Progressive multifocal leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis Rheum 2007; 56: 2116–28. Kivisakk P, Healy BC, Viglietta V, et al. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology 2009; 72: 1922–30. Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009; 361: 1067–74. DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 2006; 63: 839–44.
Gluten sensitivity: an emerging issue behind neurological impairment? Coeliac disease is regarded as an autoimmune small bowel disorder that is triggered by the ingestion of wheat gliadins and other cereal prolamins in genetically susceptible individuals.1 Although the small bowel is one of the main targets of the disease, increasing evidence indicates that coeliac disease can affect other organs, including the nervous system, thus changing the clinical scenario from what was once thought of as an intestinal disorder to a broader systemic disease. In this context, the term gluten sensitivity was coined to take into account the various www.thelancet.com/neurology Vol 9 March 2010
extraintestinal gluten-dependent manifestations, even in patients with an apparently normal intestinal mucosa.2 In this issue of The Lancet Neurology, Hadjivassiliou and colleagues3 review the association between gluten sensitivity and neurological impairment. The most frequent manifestations of such an association are cerebellar ataxia and peripheral neuropathy. Gluten can also be involved in the pathogenesis of epilepsy, as there is robust evidence that drug-resistant seizures (mostly of the complex partial type) and epilepsy with 233
tuberculosis who received dexamethasone,9 but this factor is not taken into account in the meta-analysis.3 Important differences between the trial in adults in Malawi and the other trials in adults are also evident for age and HIV status. Almost all individuals aged older than 55 years, and HIV-negative adults of all ages, came from trials in Europe and Vietnam, with mortality-related outcomes in both subgroups significantly reduced for patients who received dexamethasone. By contrast with the mortality-related outcomes, any hearing loss in survivors and adverse effects of dexamethasone showed a uniform trend across all studies. The significant reduction in hearing loss in survivors (odds ratio 0·77, 95% CI 0·60–0·99) makes sense if most between-study heterogeneity relates to variables associated with mortality. In the context of treatment decisions, it is also important that studied adverse effects were not different from those in placebo recipients across all trials, with the exception of a significant 4% increase in hyperglycaemia in adults.3 Where does this information leave clinicians who need to make urgent treatment decisions when faced with presumptive bacterial meningitis? By contrast with van de Beek and colleagues,3 I believe that data from Malawi should be considered separately on clinical grounds, particularly given the insensitivity of statistical tests for detecting heterogeneity.4 In my opinion, the high-quality trials from Malawi show convincingly that, in similar settings where delayed presentation or untreated HIV infection is common, the emphasis should be on effective antimicrobial therapy alone, because immune modulation by dexamethasone will usually be too late after delayed presentation or superfluous in untreated HIV infection. The use of glycerol to improve outcomes of meningitis particularly merits further evaluation in such settings.10 In all other settings, a trend to benefit with adjunctive dexamethasone is consistent, although often not significant in individual studies,
with suggestion of greatest benefit in patients who are most at risk for poor outcomes. Such benefits have been shown in real-world practice, when clearly defined protocols specific to local settings are used.11 Because adverse effects related to dexamethasone are similar to those with placebo,3 I believe that, in settings with good access to medical care including HIV treatment, the balance of risks and benefits favours commencing dexamethasone in cases of presumptive pyogenic meningitis outside the neonatal period, with continuing careful assessment for alternative diagnoses. Peter McIntyre Royal Alexandra Hospital for Children, and University of Sydney, Sydney, New South Wales, Australia [email protected] I have no conflicts of interest. 1
2 3
4 5
6
7
8
9
10
11
Murray CJ, Lopez AD, Mathers CD, Stein C. The Global Burden of Disease 2000 project: aims, methods and data sources. World Health Organization, 2001. http://www.who.int/healthinfo/paper36.pdf (accessed 18 Jan, 2010). van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2003; 3: CD004405. van de Beek D, Farrar JJ, de Gans J, et al. Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data. Lancet Neurol 2010; online publication February 4. DOI:10.1016/S14744422(10)70023-5. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Br Med J 2003; 327: 557–60. Molyneux E, Walsh A, Phiri A, Molyneux M. Acute bacterial meningitis in children admitted to the Queen Elizabeth central hospital Blantyre Malawi, 1996–97. Trop Med Int Health 1998; 3: 610–18. Kilpi T, Anttila M, Kallio MJT, Peltola H. Severity of childhood bacterial meningitis and duration of illness before diagnosis Lancet 1991; 338: 406–09. Thwaites GE, Chau TTH, Stepniewska K, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002; 360: 1287–92. Gordon SB, Walsh AL, Chaponda M, et al. Bacterial meningitis in Malawian adults: pneumococcal disease is common, severe and seasonal. Clin Inf Dis 2000; 31: 53–57. Nguyen TH, Tran TH, Thwaites G, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007; 357: 2431–40. Peltola H, Roine I, Fernandez J, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2007; 45: 1277–86. Korshin A, Koster-Rasmussen R, Meyer CN. Adjunctive steroid treatment: local guidelines and patient outcome in adult bacterial meningitis. Scand J Infect Dis 2007; 39: 963–68.
PML risk and natalizumab: more questions than answers The availability of natalizumab for the treatment of multiple sclerosis has revolutionised the practice of neurology in at least one salient way: we now spend much more time thinking about progressive multifocal leukoencephalopathy (PML). The reasons for this www.thelancet.com/neurology Vol 9 March 2010
increased attention are not difficult to identify. Many patients with multiple sclerosis have ongoing disease activity while receiving the first-line drugs interferon beta and glatiramer acetate, and natalizumab offers a secondstage medication for these patients.1 However, although
Published Online January 29, 2010 DOI:10.1016/S14744422(10)70025-9 See Articles page 264
231
Reflection and Reaction
there are only isolated occurrences of other opportunistic infections or malignancies in patients who receive natalizumab, these patients are at increased risk of PML.2 Choosing the best treatment option for patients is therefore challenging and risk-benefit analyses3 and thoughtful reviews that offer support to clinicians who make these treatment decisions are most welcome. PML is a complication of treatment with not only natalizumab, but also with other immunomodulatory monoclonal antibodies, some of which are options for treatment of other neurological disorders.4 Fortunately, PML is an active area of research. Treatment strategies for natalizumab-associated PML have been proposed.5,6 Efforts, such as that described by Jilek and colleagues7 in this issue of The Lancet Neurology, are also underway to understand more about PML, mainly so that risk of developing this disorder might be mitigated. Pre-treatment identification of individuals who are at increased risk for PML (beyond those who have recently received potent immunosuppression) could improve the selection of candidates for natalizumab treatment. However, this task is far from easy: asymptomatic infection with the causative agent, a polymovirus called the JC virus is widespread, with estimates that at least half of the adult global population is infected; viral shedding is detected in the urine of about 30% of random samples from healthy individuals.8 There is little detailed understanding of how most infected individuals control JC virus and avoid PML, and there is no suitable animal model in which to test hypotheses. PML remains an uncommon disease and most cases are associated with an implicated causative factor, such as earlier treatment with cytotoxic immunosuppressive drugs or therapeutic monoclonal antibodies, presence of a rheumatic or neoplastic disorder, or immune compromise due to HIV/ AIDS.9,10 In all these circumstances, few of the at-risk individuals develop PML, and the host or viral factors that cause pathogenesis remain unknown. PML is generally presumed, albeit without absolute proof, to be associated with viral reactivation rather than de novo primary infection. Another approach to investigate risk of PML is to search for alterations in immune function11 or viral replication12 in individuals who receive drugs associated with PML risk. Of these individuals, patients with multiple sclerosis who are treated with natalizumab might be the most useful, because the US Food and Drug 232
Administration recommends natalizumab monotherapy and the effects of this drug can therefore be studied in isolation. Furthermore, patients with multiple sclerosis are not characterised by marked abnormalities of circulating immune cells, even when being treated with natalizumab.11 Jilek and colleagues7 report changes in viral replication and immune function over time in a small cohort of patients with multiple sclerosis who are treated with natalizumab (n=24) in comparison with controls receiving interferon-beta (n=16), who showed no changes in the measured variables. The investigators assessed anti-JC virus T-cell proliferation, T-cell cytokine (interferon γ) production, and anti-JC virus antibodies, as well as the presence of JC virus in the plasma, urine, and in blood-derived cells. As controls for anti-viral responses, Epstein-Barr virus was selected because of compelling epidemiology indicating its role in the pathogenesis of multiple sclerosis.13 The investigators also monitored responses to cytomegalovirus, a related herpesvirus that is not involved in the pathogenesis of multiple sclerosis. T-cell responses to two antigens derived from myelin proteins were also evaluated as an investigation into how natalizumab might affect the anti-myelin immune reactions that are possibly associated with multiple sclerosis itself. The findings were predominantly negative: there was no evidence for viral reactivation: indeed, no JC virus was detected in any blood samples, and there was no increase in viruria. Importantly, one of the six patients with viruria had antibodies to JC virus at levels below the cutoff for seropositivity, raising concerns about use of serological testing to identify people at low risk for JC virus reactivation. Anti-viral immunity was not compromised, and T-cell responses to JC virus seemed to be increased in some individuals at some time points. Responses to control viruses were overall unchanged. Anti-JC virus T-cell responses were increased above background levels at month 1, but returned to background levels until month 12; at this point, responses were increased again but they returned to background levels at month 18. The changes were seen in only a few patients, although non-parametric statistics enabled significant p value to be attributed to the data. These findings highlight the difficulty of obtaining robust data in human immunology studies and the efforts of the investigators are to be commended. www.thelancet.com/neurology Vol 9 March 2010
Reflection and Reaction
These findings from Jilek and colleagues are not in agreement with those reported recently by Chen and co-workers,12 particularly with regard to the frequency of detection of JC virus in the urine, plasma, and blood cells of patients on natalizumab. The detailed methods used were different, with Chen and co-workers using a more sensitive assay for urine and plasma than Jilek and colleagues, but the assays used for blood cells in both studies had similar levels of detection. The two studies also differed in their assessment of the effects of natalizumab on anti-JC virus immunity, although the two methods were so different that comparisons are hazardous. The results from Jilek and colleagues are more similar to those from earlier reports than are those from Chen and co-workers. Further study and use of a uniform technology are essential to resolve these discrepancies. For non-specialists, the take-home messages are that several groups are asking the correct questions: what are the effects of natalizumab treatment on JC virus replication, and on anti-JC virus immunity? Pathogenic variants and host susceptibility factors (including evidence of previous JC virus infection) are also being sought. Such research should enable future risk-benefit estimations to be based on more and increasingly reliable numbers, and therefore help clinicians to make more informed decisions.
Cleveland Clinic, Mail Code NC30, 9500 Euclid Avenue, Cleveland, OH 44195, USA [email protected] I have received speaker’s honoraria and consulting fees from Biogen-Idec, Teva, Merck-Serono, and Pfizer. 1 2
3 4
5
6
7
8 9 10
11
12 13
Richard M Ransohoff Neuroinflammation Research Center, Lerner Research Institute, Mellen Center for MS Treatment and Research, Neurological Institute, and Cleveland Clinic Lerner College of Medicine,
Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J Med 2007; 356: 2622–29. Linda H, von Heijne A, Major EO, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009; 361: 1081–87. Thompson JP, Noyes K, Dorsey ER, Schwid SR, Holloway RG. Quantitative risk-benefit analysis of natalizumab. Neurology 2008; 71: 357–64. Carson KR, Focosi D, Major EO, et al. 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 2009; 10: 816–24. Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009; 72: 402–09. Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 2009; 361: 1075–80. Jilek S, Jaquiéry E, Hirsch HH, et al. Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study. Lancet Neurol 2010; online publication Jan 29. DOI:10.1016/S1474-4422(10)70006-5. Knowles WA. Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). Adv Exp Med Biol 2006; 577: 19–45. Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006; 60: 162–73. Calabrese LH, Molloy ES, Huang D, Ransohoff RM. Progressive multifocal leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis Rheum 2007; 56: 2116–28. Kivisakk P, Healy BC, Viglietta V, et al. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology 2009; 72: 1922–30. Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009; 361: 1067–74. DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 2006; 63: 839–44.
Gluten sensitivity: an emerging issue behind neurological impairment? Coeliac disease is regarded as an autoimmune small bowel disorder that is triggered by the ingestion of wheat gliadins and other cereal prolamins in genetically susceptible individuals.1 Although the small bowel is one of the main targets of the disease, increasing evidence indicates that coeliac disease can affect other organs, including the nervous system, thus changing the clinical scenario from what was once thought of as an intestinal disorder to a broader systemic disease. In this context, the term gluten sensitivity was coined to take into account the various www.thelancet.com/neurology Vol 9 March 2010
extraintestinal gluten-dependent manifestations, even in patients with an apparently normal intestinal mucosa.2 In this issue of The Lancet Neurology, Hadjivassiliou and colleagues3 review the association between gluten sensitivity and neurological impairment. The most frequent manifestations of such an association are cerebellar ataxia and peripheral neuropathy. Gluten can also be involved in the pathogenesis of epilepsy, as there is robust evidence that drug-resistant seizures (mostly of the complex partial type) and epilepsy with 233