Axonal water fraction as marker of white matter injury in primary-progressive multiple sclerosis: a longitudinal study.

BACKGROUND AND PURPOSE: Diffuse white matter (WM) injury is prominent in primary-progressive multiple sclerosis (PP-MS) pathology and is a potential biomarker of disease progression. Diffusion kurtosis imaging allows the quantification of non-Gaussian water diffusion, providing metrics with high WM pathological specificity. The aim of this study was to characterize the pathological changes occurring in the normal-appearing WM of patients with PP-MS at baseline and at 1-year follow-up and to assess their impact on disability and short-term disease progression. METHODS: A total of 26 patients with PP-MS and 20 healthy controls were prospectively enrolled. Diffusion kurtosis imaging single-shot echo-planar imaging (EPI) was acquired on a 3-T scanner (Philips Achieva, Best, The Netherlands) (voxel size, 2 × 2 × 2 mm3 , 30 directions for each b-value = 1000, 2000 s/mm2 and one b = 0 s/mm2 ). A two-compartment biophysical model of WM tract integrity was used to derive spatial maps of axonal water fraction (AWF), intra-axonal diffusivity, extra-axonal axial and radial diffusivities (De,axial , De,radial ) and tortuosity from the following WM tracts: corpus callosum (CC), corticospinal tract (CST) and posterior thalamic radiation (PTR). RESULTS: At baseline, patients with PP-MS showed a widespread decrease of AWF, tortuosity and De,axial and an increase of De,radial in CC, CST and PTR (P ranging from 0.001 to 0.036). At 1-year follow-up, a significant AWF decrease was detected in the body of CC (P = 0.048), PTR (P = 0.008) and CST (P = 0.044). Baseline AWF values in CST significantly discriminated progressed from non-progressed patients (P = 0.021; area under the curve, 0.854). CONCLUSION: Based on its change over time and its relationship with disease progression, among the analyzed metrics, AWF seems the most sensitive metric of WM tissue damage in PP-MS and therefore it could be considered as a marker for monitoring disease progression.

Looking into cognitive impairment in primary-progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment in primary-progressive multiple sclerosis (PP-MS) is correlated with global brain atrophy. Unfortunately, brain volume computation requires processing resources that are not widely available in clinical practice. Therefore, we decided to test the predictive role of retinal atrophy metrics on cognitive decline, applying them as a proxy of gray matter atrophy in PP-MS. METHODS: Twenty-five patients with PP-MS completed the Brief International Cognitive Assessment for Multiple Sclerosis and underwent spectral-domain optical coherence tomography (OCT) and 3.0-T magnetic resonance imaging. We tested, through a stepwise logistic regression, whether OCT metrics [retinal nerve fiber layer, ganglion cell + inner plexiform layer (GCIPL) and total macular volume] predicted cognitive impairment and explored the role of gray matter atrophy in mediating these correlations. RESULTS: Among OCT metrics, only GCIPL was associated with cognitive impairment (rp = 0.448, P = 0.036) and predictive of objective cognitive impairment (Wald [1] = 4.40, P = 0.036). Controlling for demographics, normalized brain volume and thalamic volume were correlated with GCIPL (rp = 0.427, P = 0.047 and rp = 0.674, P = 0.001, respectively) and cognitive scores (rp = 0.593, P = 0.004 and rp = 0.501, P = 0.017, respectively), with thalamic volume nearly mediating the association between GCIPL and cognition (Sobel z = 1.86, P = 0.063). CONCLUSIONS: The GCIPL thickness is a suitable measure of neurodegeneration. In comparison with brain atrophy, GCIPL offers higher histopathological specificity, being a pure correlate of neuronal loss, and may be a non-invasive, easy-to-perform way to quantitatively evaluate and monitor neuronal loss related to cognitive impairment in PP-MS.

Clinical course in multiple sclerosis patients presenting with a history of progressive disease.

OBJECTIVES: Determine the likelihood of worsening clinical status in the near-term course of progressive MS and evaluate the predictive validity of our diagnostic impression of progressive forms of MS. METHODS: Retrospective review of charts from 175 patients seen between 2000 and 2007 who were diagnosed with either primary or secondary progressive multiple sclerosis. Data extracted included demographic factors, neurological examination findings to determine EDSS, timed 25 foot walk (T25FW) when available, duration of symptoms, clinical course as documented on initial visit, and history of disease-modifying agent (DMA) use. Significant change in EDSS was defined as a change of one point or more from initial to final clinical evaluation. Significant change in T25FW was defined as a ±20% difference from baseline. RESULTS: Of the 175 charts reviewed, 35 patients met criteria and had sufficient documentation to allow for EDSS abstraction. Twenty-four patients (68.6%) showed no significant change in EDSS from baseline while eleven patients (31.4%) worsened and none improved. For those patients that had T25FW data available, 6 out of 20 (30%) patients worsened while 11 (55%) showed no change. Three patients (15%) improved. CONCLUSION: In this observational study at a tertiary care MS center, patients classified as progressive MS did not progress as often, or as rapidly, as previous studies have suggested. Greater than two-thirds of patients in this cohort, did not increase 1 step on the EDSS.

The CombiRx trial of combined therapy with interferon and glatiramer acetate in relapsing remitting MS: Design and baseline characteristics.

BACKGROUND: Interferon-ß1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective. OBJECTIVE: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA. METHODS: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0-5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio. RESULTS: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2ml, and 40% of the participants had enhancing lesions. CONCLUSION: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy.

Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis.

BACKGROUND: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies. OBJECTIVES: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS. METHODS: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005. RESULTS: Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted. CONCLUSIONS: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.

Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks.

BACKGROUND AND OBJECTIVES: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed. METHODS: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab. RESULTS: At baseline, the cohort's mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test-retest correlations were high for both SDMT (range 0.89 for weeks 0-4 to 0.96 for weeks 44-48) and MSNQ (0.82 for weeks 0-4 to 0.93 for weeks 44-48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2). CONCLUSIONS: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.

Rapid disease course in African Americans with multiple sclerosis.

OBJECTIVE: To investigate utility of a Multiple Sclerosis Severity Scale (MSSS)-based classification system for comparing African American (AA) and white American (WA) multiple sclerosis (MS) subpopulations in the New York State Multiple Sclerosis Consortium (NYSMSC) database. MSSS is a frequency-rank algorithm relating MS disability to disease duration in a large, untreated reference population. Design/ METHODS: Distributions of patients in 6 MSSS-based severity grades were calculated for AA and WA registrants. RESULTS: There were 419 AA and 5,809 WA patients in the NYSMSC, who had EDSS recorded during years 1-30 since symptom onset. Median EDSS was not different in AA and WA (3.5 vs 3.0, p = 0.60), whereas median MSSS in AA was higher than in WA (6.0 vs 4.8, p = 0.001). AA patients were overrepresented in the 2 most severe grades (41.5% vs 29.3% for WA) and underrepresented in the 2 lowest grades (23.4% vs 35.4%; p < 0.001). In multivariable analysis (ordered logistic and median regression), MSSS for AA remained significantly higher than in WA after adjusting for age, gender, disease duration, disease type distribution, and treatment with disease-modifying therapies. CONCLUSIONS: The 6-tiered MSSS grading system is a powerful tool for comparing rate of disease progression in subpopulations of interest. MSSS-based analysis demonstrates that African ancestry is a risk factor for a more rapidly disabling disease course.

Assessing disability progression with the Multiple Sclerosis Functional Composite.

BACKGROUND: The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event. OBJECTIVE: Evaluate a new method for analyzing disability progression using the MSFC. METHODS: MSFC progression was defined as worsening from baseline on scores of at least one MSFC component by 20% (MSFC Progression-20) or 15% (MSFC Progression-15), sustained for >or=3 months. Progression rates were determined using data from natalizumab clinical studies (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]). Correlations between MSFC progression and other clinical measures were determined, as was sensitivity to treatment effects. RESULTS: Substantial numbers of patients met MSFC progression criteria, with MSFC Progression-15 being more sensitive than MSFC Progression-20, at both 1 and 2 years. MSFC Progression-20 and MSFC Progression-15 were related significantly to Expanded Disability Status Scale (EDSS) score change, relapse rate, and the SF-36 Physical Component Summary (PCS) score change. MSFC Progression-20 and MSFC Progression-15 at 1 year were predictive of EDSS progression at 2 years. Both MSFC progression end points demonstrated treatment effects in AFFIRM, and results were replicated in SENTINEL. CONCLUSION: MSFC Progression-20 and MSFC Progression-15 are sensitive measures of disability progression; correlate with EDSS, relapse rates, and SF-36 PCS; and are capable of demonstrating therapeutic effects in randomized, controlled clinical studies.

Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a.

BACKGROUND: Findings from a small clinical study suggested that statins may counteract the therapeutic effects of interferon beta (IFNbeta) in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We conducted a post hoc analysis of data from the Safety and Efficacy of Natalizumab in Combination With IFNbeta-1a in Patients With Relapsing-Remitting Multiple Sclerosis (SENTINEL) study to determine the effects of statins on efficacy of IFNbeta. SENTINEL was a prospective trial of patients with RRMS treated with natalizumab (Tysabri, Biogen Idec, Inc., Cambridge, MA) plus IM IFNbeta-1a (Avonex, Biogen Idec, Inc.) 30 microg compared with placebo plus IM IFNbeta-1a 30 microg. Clinical and MRI outcomes in patients treated with IM IFNbeta-1a only (no-statins group, n = 542) were compared with those of patients taking IM IFNbeta-1a and statins at doses used to treat hyperlipidemia (statins group, n = 40). RESULTS: No significant differences were observed between treatment groups in adjusted annualized relapse rate (p = 0.937), disability progression (p = 0.438), number of gadolinium-enhancing lesions (p = 0.604), or number of new or enlarging T2-hyperintense lesions (p = 0.802) at 2 years. More patients in the statins group reported fatigue, extremity pain, muscle aches, and increases in hepatic transaminases compared with patients in the no-statins group. Statin treatment had no ex vivo or in vitro effect on induction of IFN-stimulated genes. CONCLUSIONS: Statin therapy does not appear to affect clinical effects of IM interferon beta-1a in patients with relapsing-remitting multiple sclerosis or the primary molecular response to interferon beta treatment.

Proof of concept studies for tissue-protective agents in multiple sclerosis.

BACKGROUND: There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). METHODS AND OBJECTIVES: We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. RESULTS: Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. CONCLUSIONS: The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials.

GLANCE: results of a phase 2, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the safety and tolerability of natalizumab when added to glatiramer acetate (GA) in patients with relapsing multiple sclerosis. The primary outcome assessed whether this combination would increase the rate of development of new active lesions on cranial MRI scans vs GA alone. METHODS: This phase 2, randomized, double-blind, placebo-controlled study included patients aged 19 to 55 years who were treated with GA for at least 1 year before randomization and experienced at least one relapse during the previous year. Patients received IV natalizumab 300 mg (n = 55) or placebo (n = 55) once every 4 weeks plus GA 20 mg subcutaneously once daily for < or = 20 weeks. RESULTS: The mean rate of development of new active lesions was 0.03 with combination therapy vs 0.11 with GA alone (p = 0.031). Combination therapy resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p = 0.020) and new/newly enlarging T2-hyperintense lesions (0.5 vs 1.3, p = 0.029). The incidence of infection and infusion reactions was similar in both groups; no hypersensitivity reactions were observed. One serious adverse event occurred with combination therapy (elective hip surgery). With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone. CONCLUSION: The combination of natalizumab and glatiramer acetate seemed safe and well tolerated during 6 months of therapy.

Differential diagnosis of suspected multiple sclerosis: a consensus approach.

BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial.

OBJECTIVE: Several studies have reported a reduction of relapses after the long-term administration of IV immunoglobulin (IVIG) to patients with relapsing-remitting multiple sclerosis (RRMS), but they were mostly small and differed in terms of predefined outcome variables and treatment regimen. We therefore set out to test two different doses of a new formulation of immunoglobulin termed IGIV-C 10% for suppression of both clinical and MRI disease activity as well as safety. METHODS: One hundred twenty-seven patients with RRMS participated in this multicenter, randomized, double-blind, placebo-controlled trial. Forty-four and 42 patients received treatment with 0.2 and 0.4 g/kg of IGIV-C 10%, and 41 patients received an equal volume of placebo (0.1% albumin) every 4 weeks for 48 weeks. The primary endpoint was the proportion of relapse-free patients. The main secondary endpoint was lesion activity assessed by 6-weekly MRI. RESULTS: Baseline variables were similar in IVIG- and placebo-treated groups. After 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%), and there was no difference regarding the cumulative number of unique newly active MRI lesions (median numbers: IVIG 0.2 g/kg: 8.0; IVIG 0.4 g/kg: 5.0; placebo: 7.2) after 48 weeks. There were no significant between-group differences in the rates of adverse events. CONCLUSION: Although IV immunoglobulin (IVIG) treatment was well tolerated, this study did not substantiate a beneficial effect of IVIG in doses ranging from 0.2 to 0.4 g/kg. This result seriously questions the utility of IVIG for the treatment of relapsing-remitting multiple sclerosis.

Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL.

OBJECTIVE: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. METHODS: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INF beta]1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies (>or=0.5 microg/mL) at a single time point or "persistently positive" if they had antibodies at two or more time points >or=6 weeks apart. RESULTS: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p

MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS.

BACKGROUND: In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] study), involving 942 patients with relapsing multiple sclerosis (MS), natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study. METHODS: The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years. RESULTS: Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients. CONCLUSION: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.

Natalizumab reduces visual loss in patients with relapsing multiple sclerosis.

OBJECTIVE: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). METHODS: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%). RESULTS: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups. CONCLUSIONS: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

Reactivation of JC virus and development of PML in patients with multiple sclerosis.

The attention of researchers and clinicians specializing in both multiple sclerosis (MS) and JC virus (JCV), the etiologic agent of progressive multifocal leukoencephalopathy (PML), was rekindled by the development of PML in two patients with MS enrolled in a clinical trial of combination therapy with natalizumab (Tysabri) and interferon beta-1A (Avonex) in recent years. PML had not been previously reported with either MS or treatment with interferon beta alone. This occurrence of PML with alpha4beta1-integrin inhibition in MS raised a number of issues in terms both of the scientific understanding of these diseases and for the future of immunomodulatory treatment for MS. In this review, we examine the current status of knowledge of the virus, its molecular biology, life cycle, and pathogenetic mechanisms, and how this relates to the basic science and clinical perspectives of MS. A better understanding of the specific steps from JCV infection to the development of PML is key to this issue. Other critical issues for further investigation include the role of alpha4beta1-integrin inhibition by natalizumab in the re-expression of JCV from latent sites and in the inhibition of entry into the brain and peripheral sites.