Use and cost of disease-modifying therapies by Sonya Slifka Study participants: has anything really changed since 2000 and 2009?

BACKGROUND: Disease-modifying therapies benefit individuals with relapsing forms of multiple sclerosis, but their utility remains unclear for those without relapses. OBJECTIVE: To determine disease-modifying therapy use and costs in 2009, compare use in 2009 and 2000, and examine compliance with evidence-based guidelines. METHODS: We determined the extent and characteristics of disease-modifying therapy use by participants in the Sonya Slifka Longitudinal Multiple Sclerosis Study (Slifka) in 2000 (n=2156) and 2009 (n=2361) and estimated out-of-pocket and total (payer) costs for 2009. Two multivariable logistic regressions predicted disease-modifying therapy use. RESULTS: Disease-modifying therapy use increased from 55.3% in 2000 to 61.5% in 2009. In 2009, disease-modifying therapy use was reported by 76.5% of participants with relapsing-remitting multiple sclerosis, 73.2% with progressive-relapsing multiple sclerosis, 62.5% with secondary progressive multiple sclerosis, and 41.8% with primary progressive multiple sclerosis. Use was significantly associated with relapsing-remitting multiple sclerosis, shorter duration of illness, one to two relapses per year, non-ambulatory symptoms, using a cane, younger age, higher family income, and having health insurance. Average annual costs in 2009 were US$939-3101 for patients and US$16,302-18,928 for payers. CONCLUSION: Use rates were highest for individuals with relapsing-remitting multiple sclerosis, but substantial for those with progressive courses although clinical trials have not demonstrated significant benefits for them.

Disease-related determinants of quality of life 10 years after clinically isolated syndrome.

BACKGROUND: The main clinical determinants of quality of life (QOL) 5 years after clinically isolated syndrome (CIS) are Expanded Disability Status Scale (EDSS) score and conversion to clinically definite multiple sclerosis (CDMS). The aim of this study was to determine the demographic, clinical, and magnetic resonance imaging (MRI) factors associated with QOL 10 years after CIS. METHODS: Controlled High Risk Avonex® Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance (CHAMPIONS) 10-year patients were assessed for CDMS, EDSS score, MRI T2 activity, brain parenchymal fraction, and patient-reported QOL. Associations were evaluated using analysis of variance models. RESULTS: A second clinical event consistent with CDMS and higher EDSS scores at years 5 and 10 were associated with lower 36-item Short Form Health Status Survey (SF-36) Physical Component Summary scores at year 10 (P < .01). Patients with earlier onset of CDMS had worse patient-reported Physical Component Summary, SF-36 Mental Component Summary, fatigue, and pain scores at year 10 than patients with later or no onset of CDMS. Neither initial randomization group nor any MRI metrics assessed at baseline or during follow-up were associated with QOL at 10 years. CONCLUSIONS: These results support the development of therapies for patients with CIS that significantly reduce the risk of conversion to CDMS and the progression of physical disability to milestones as low as EDSS scores of 2.0.

Ten-year follow-up of the 'minimal MRI lesion' subgroup from the original CHAMPS Multiple Sclerosis Prevention Trial.

BACKGROUND: Patients with clinically isolated syndrome (CIS) and characteristic magnetic resonance imaging (MRI) lesions are at high risk for multiple sclerosis (MS). However, patients with a minimal MRI lesion burden (a low T2-hyperintense [low T2] lesion count) may have borderline formal diagnostic criteria, presenting a clinical management challenge. OBJECTIVE: Compare the 10-year disease progression of patients with low and higher T2 lesion counts treated over most intervals. METHODS: CIS patients from the original CHAMPS MS trial were retrospectively assigned to low-T2 (first quartile; 2-8 lesions) or higher-T2 (second through fourth quartiles; ≥ 9 lesions) groups using baseline T2 lesion counts. The 5- and 10-year open-label extension of CHAMPS (CHAMPIONS) evaluated conversion to clinically definite MS (CDMS), MRI activity, relapses, and disability. RESULTS: The vast majority of patients showed new disease activity by MRI and/or clinical criteria at 10 years (low-T2 86%; higher-T2 98%). Fewer low-T2 than higher-T2 patients developed CDMS (40% vs. 63%; p = 0.013); low-T2 patients also had fewer new brain lesions, less brain volume loss, and less disability progression. CONCLUSION: CIS patients with low T2 lesion counts show continued disease activity. However, all assessments of disease progression over 10 years indicated a significantly less severe disease course for low-T2 patients.

Quantitative oxygen extraction fraction from 7-Tesla MRI phase: reproducibility and application in multiple sclerosis.

Quantitative oxygen extraction fraction (OEF) in cortical veins was studied in patients with multiple sclerosis (MS) and healthy subjects via magnetic resonance imaging (MRI) phase images at 7 Tesla (7 T). Flow-compensated, three-dimensional gradient-echo scans were acquired for absolute OEF quantification in 23 patients with MS and 14 age-matched controls. In patients, we collected T2*-weighted images for characterization of white matter, deep gray matter, and cortical lesions, and also assessed cognitive function. Variability of OEF across readers and scan sessions was evaluated in a subset of volunteers. OEF was averaged from 2 to 3 pial veins in the sensorimotor, parietal, and prefrontal cortical regions for each subject (total of ~10 vessels). We observed good reproducibility of mean OEF, with intraobserver coefficient of variation (COV)=2.1%, interobserver COV=5.2%, and scan-rescan COV=5.9%. Patients exhibited a 3.4% reduction in cortical OEF relative to controls (P=0.0025), which was not different across brain regions. Although oxygenation did not relate with measures of structural tissue damage, mean OEF correlated with a global measure of information processing speed. These findings suggest that cortical OEF from 7-T MRI phase is a reproducible metabolic biomarker that may be sensitive to different pathologic processes than structural MRI in patients with MS.

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis.

OBJECTIVE: To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). METHODS: We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon ß-1a monotherapy >36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. RESULTS: JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging-detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34(+) cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4(+) and CD8(+) T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4(+) T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34(+) (p = 0.05) and B cells (p = 0.03). INTERPRETATION: Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34(+) cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.

Early MRI activity predicts treatment nonresponse with intramuscular interferon beta-1a in clinically isolated syndrome.

OBJECTIVE: Determine whether MRI activity 6 months after treatment initiation in the Controlled High-Risk Subjects Avonex® Multiple Sclerosis Prevention Study (CHAMPS) predicted progression to clinically definite multiple sclerosis (CDMS) over the subsequent 30 months in intramuscular interferon beta-1a (IM IFNß-1a)-treated patients vs placebo-treated patients. METHODS: CHAMPS patients were randomized to once-weekly IM IFNß-1a 30 µg or placebo for up to 36 months. MRI was performed every 6 months until CDMS confirmation. Patient groups were defined based on new T2 and/or Gd+ lesions at 6 months. RESULTS: Thirteen IM IFNß-1a patients (6.7%) and 24 placebo patients (12.6%) developed CDMS prior to month 6 and did not undergo the 6-month MRI. At 6 months, 29.7% of IM IFNß-1a-treated patients vs 40.9% of placebo-treated patients were defined as having high MRI activity levels (≥2 new T2 and/or ≥2 Gd+ lesions). In this subgroup, estimated cumulative probabilities of CDMS were similar between groups (HR=0.88 [0.44-1.77], p=0.7227). A significant treatment response was seen for patients with <2 new T2 and <2 Gd+ lesions at 6 months (HR=0.39 [0.19-0.82], p=0.0120). CONCLUSION: MRI scans 6 months after IM IFNß-1a initiation in CIS patients predict early treatment non-response. Standardized scanning and monitoring may facilitate early disease management.

Multiple sclerosis susceptibility genes: associations with relapse severity and recovery.

OBJECTIVE: Patients with early multiple sclerosis (MS) have stereotyped attack severity and recovery. We sought to determine if polymorphisms in MS susceptibility genes are associated with these attack features or with the risk of a second attack. METHODS: 503 white subjects evaluated within a year of MS onset were included in the study. The severity of and recovery from the first two attacks were determined based on published definitions. Seventeen MS susceptibility genes were genotyped at the UCSF MS Genetics laboratory. Each polymorphism was evaluated in multivariate ordinal models, adjusted for the other polymorphisms, for its association with attack severity and recovery. We also assessed if these polymorphisms were associated with increased risk of a second attack. RESULTS: The MPHOSPH9 polymorphism was associated with greater attack severity (odds ratios [OR] = 1.47, 95% CI [1.11, 1.94], p = 0.008), while the RGS1 and TNFRSF1A polymorphisms tended to be associated with reduced attack severity. The CD6 polymorphism tended to be associated with increased odds of worse attack recovery (OR = 1.25, 95% CI [0.93, 1.68], p = 0.13). In those who were HLA-DRB1-negative, the EVI5 polymorphism was associated with attacks of less severity; in HLA-DRB1 positive patients, EVI5 was associated with attacks of greater severity and worse recovery. The IL7R, TNFRSF1A, and GPC5 polymorphisms tended to be associated with having a second event within a year. CONCLUSIONS: Some MS susceptibility polymorphisms may be associated with attack severity, recovery, or frequency. Further characterization of these genes may lead to a better understanding of MS pathogenesis and to a more individualized treatment approach.

Association of multiple sclerosis susceptibility variants and early attack location in the CNS.

OBJECTIVE: The anatomic location of subsequent relapses in early multiple sclerosis (MS) appears to be predicted by the first attack location. We sought to determine if genetic polymorphisms associated with MS susceptibility are associated with attack location. METHODS: 17 genome-wide association study-identified MS susceptibility polymorphisms were genotyped in 503 white, non-Hispanic patients seen within a year of MS onset. Their association with the CNS location of the first two MS attacks was assessed in multivariate repeated measures analyses (generalized estimating equations with robust standard errors). RESULTS: The IL12A polymorphism was independently associated with increased odds of attacks involving the spinal cord (OR = 1.52, 95% CI 1.11, 2.07, p = 0.009), as was the IRF8 polymorphism (OR = 2.40, 95% CI [1.04, 5.50], p = 0.040). The IL7R polymorphism was associated with reduced odds of attacks involving the brainstem/cerebellum (OR = 0.46, 95% CI 0.22, 0.97, p = 0.041), as were the TNFRSF1A and IL12A polymorphisms. The CD6 polymorphism conferred reduced odds of optic neuritis as an attack location (OR = 0.69, 95% CI [0.49, 0.97], p = 0.034). Several other genes showed trends for association with attack location. CONCLUSIONS: Some of the MS susceptibility genes may be associated with MS attack location. The IL12A polymorphism is of particular interest given that interferon beta therapy appears to influence IL12 levels. These findings may lead to improved understanding of MS pathogenesis and treatment.

Internet portal use in an academic multiple sclerosis center.

OBJECTIVE: To evaluate the use of a secure internet portal in an academic Multiple Sclerosis (MS) Center. MATERIALS AND METHODS: Retrospective case-control chart review of 240 patients during the years 2008 and 2009. Patient demographic and clinical information was extracted from our online medical records, and portal use metrics were provided by Information Systems. Descriptive statistics were utilized to explore characteristics of portal users, how the portal is used, and what associations exist between medical resource utilization and active portal use. Logistic regression identified independent patient predictors and barriers to portal use. RESULTS: Portal users tended to be young professionals with minimal physical disability. The most frequently used portal feature was secure patient-physician messaging. Message content largely consisted of requests for medications or refills in addition to self-reported side effects. Independent predictors and barriers of portal use include the number of medications prescribed by our staff (OR 1.69, p<0.0001), Caucasian ethnicity (OR 5.04, p=0.007), arm and hand disability (OR 0.23, p=0.01), and impaired vision (OR 0.31, p=0.01). Discussion MS patients use the internet in a greater proportion than the general US population, yet physical disability limits their access. Technological adaptations such as voice-activated commands and easy font-size adjustment may help patients overcome these barriers. CONCLUSION: Future research should explore the influence of portal technology on healthcare resource utilization and cost. Additional emedicine applications could be linked to the patient portal for disease monitoring and prospective investigation.

Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: a 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance.

OBJECTIVE: To determine whether immediate initiation of treatment at the time of a clinically isolated syndrome in patients at high risk for clinically definite multiple sclerosis alters disease course over 10 years. DESIGN: Prospective follow-up study. SETTING: Twenty-four Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) sites in the United States and Canada. PARTICIPANTS: A total of 81 patients originally randomly assigned to receive intramuscular interferon beta-1a (the immediate-treatment group) and 74 patients originally randomly assigned to receive placebo (the delayed-treatment group). All patients were from CHAMPS. INTERVENTION: For the immediate-treatment group, treatment was initiated within a month after the onset of a clinically isolated syndrome, and for the delayed-treatment group, treatment was initiated a median of 30 months (interquartile range, 24-35 months) after CHAMPS randomization. MAIN OUTCOME MEASURES: Rate of developing clinically definite multiple sclerosis, annualized relapse rate, disease course classification, disability measures, and magnetic resonance imaging measures. RESULTS: The immediate-treatment group showed a lower 10-year rate of clinically definite multiple sclerosis (unadjusted hazard ratio, 0.64 [95% CI, 0.48-0.87]; P = .004) and a lower annualized relapse rate between years 5 and 10 (P = .03). There was no differential effect on disability, magnetic resonance imaging T2-weighted lesions, or the proportion of patients developing progressive disease at 10 years. Few patients reached the Expanded Disability Status Scale milestone scores of 4.0 or greater (9% of patients) or 6.0 or greater (6% of patients). CONCLUSIONS: Immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome in high-risk patients reduces relapse rates over 10 years but does not improve disability outcomes compared with a control group that also initiated therapy relatively early in the disease course. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00179478.

Focal cortical lesion detection in multiple sclerosis: 3 Tesla DIR versus 7 Tesla FLASH-T2.

PURPOSE: To evaluate the inter-rater agreement of cortical lesion detection using 7 Tesla (T) FLASH-T2 and 3T DIR sequences. MATERIALS AND METHODS: Twenty-six patients with multiple sclerosis were scanned on a human 7T (Siemens) and 3T MRI (TIM Trio, Siemens) to acquire 3T DIR/MEMPR and 7T FLASH-T2 sequences. Four independent reviewers scored and categorized cortical lesions in the bilateral precentral gyri (motor strips) as leukocortical, intracortical, or subpial. Inter-rater agreement was assessed according to lesion category using the kappa statistic. The sensitivity of recent MAGNIMS consensus guidelines for cortical lesion detection using 3T DIR was assessed with 7T FLASH-T2 as the reference gold standard. RESULTS: Inter-rater agreement at 7T was excellent compared with 3T (k = 0.97 versus 0.12). FLASH-T2 at 7T detected subpial lesions while 3T DIR did not. The predicted sensitivity of 3T DIR sequence for cortical lesions in vivo is modest (range of 13.6 to 18.3%). CONCLUSION: The 7T FLASH-T2 detects more cortical-particularly subpial-lesions compared with 3T DIR. In the absence of DIR/postmortem data, 7T FLASH-T2 is a suitable gold-standard instrument and should be incorporated into future consensus guidelines.

In vivo evidence of disseminated subpial T2* signal changes in multiple sclerosis at 7 T: a surface-based analysis.

Cortical subpial demyelination is frequent in multiple sclerosis (MS) and is closely associated with disease progression and poor neurological outcome. Although cortical lesions have been difficult to detect using conventional MRI, preliminary data using T2*-weighted imaging at ultra-high field 7T MRI showed improved sensitivity for detecting and categorizing different histological types of cortical MS lesions. In this study we combined high-resolution 7T MRI with a surface-based analysis technique to quantify and map subpial T2*-weighted signal changes in seventeen patients with MS. We applied a robust method to register 7T data with the reconstructed cortical surface of each individual and used a general linear model to assess in vivo an increase in subpial T2*-weighted signal in patients versus age-matched controls, and to investigate the spatial distribution of cortical subpial changes across the cortical ribbon. We also assessed the relationship between subpial T2* signal changes at 7T, Expanded Disability Status Scale (EDSS) score and white matter lesion load (WMLL). Patients with MS showed significant T2*-weighted signal increase in the frontal lobes (parsopercularis, precentral gyrus, middle and superior frontal gyrus, orbitofrontal cortex), anterior cingulate, temporal (superior, middle and inferior temporal gyri), and parietal cortices (superior and inferior parietal cortex, precuneus), but also in occipital regions of the left hemisphere. We found significant correlations between subpial T2*-weighted signal and EDSS score in the precentral gyrus (ρ=0.56, P=0.02) and between T2*-weighted signal and WMLL in the lateral orbitofrontal, superior parietal, cuneus, precentral and superior frontal regions. Our data support the presence of disseminated subpial increases in T2* signal in subjects with MS, which may reflect the diffuse subpial pathology described in neuropathology.

Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy.

OBJECTIVE: To assess clinical consequences of temporary natalizumab dosage suspension. DESIGN: Prospective cohort study. SETTING: Multiple sclerosis (MS) center at an academic medical center in the United States. PATIENTS: Thirty-two patients with MS who had received at least 12 consecutive natalizumab infusions. MAIN OUTCOMES MEASURES: Recurrent MS disease activity, defined as a clinically documented exacerbation with objective findings and/or the development of 1 or more new gadolinium-enhancing lesions on magnetic resonance imaging. RESULTS: Thirty-eight percent of patients with relapsing-remitting and secondary progressive MS experienced relapses during therapy interruption or shortly after restarting natalizumab therapy (9 of 24 and 3 of 8, respectively), but relapses were severe with unusually widespread evidence of inflammatory activity on magnetic resonance imaging in several patients with secondary progressive MS with greater inflammatory disease activity prior to starting natalizumab therapy. Imaging and cerebrospinal fluid findings in these cases were suggestive of an immune reconstitution inflammatory syndrome. Overall, relapses occurred more often in younger patients with fewer natalizumab infusions prior to therapy interruption. The number of gadolinium-enhancing lesions at the time of relapse after therapy interruption was modestly correlated with the number of gadolinium-enhancing lesions prior to starting natalizumab therapy (r = 0.51; P = .45). Prior disease control resumed after reinstitution of natalizumab therapy in all patients. CONCLUSIONS: In this cohort of patients with MS who had disease refractive to multiple therapeutics before starting natalizumab treatment, magnetic resonance imaging and clinical disease activity returned, often aggressively, following discontinuation of natalizumab therapy. These findings suggest we should consider strategies to minimize the risk of immune reconstitution inflammatory syndrome after natalizumab discontinuation.

Gender effects on intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis: analysis of 1406 patients.

BACKGROUND: We aimed to evaluate effects of gender on efficacy and safety of intramuscular (IM) interferon beta (IFNß)-1a in patients with relapsing-remitting MS (RRMS) or clinically isolated syndromes (CIS) characteristic of early MS. METHODS: Pooled data from 1406 (1027 women; 379 men) patients enrolled in five clinical studies of IM IFNß-1a were analyzed. One analysis examined data for all patients treated with IM IFNß-1a from all studies. Separate analyses were conducted of pooled IM IFNß-1a-treated groups from all studies and pooled IFNß-1a-treated and placebo-treated patients from the placebo-controlled studies. Outcome measures included time to first relapse, annualized relapse rate, time to disability progression, number of gadolinium-enhanced lesions, adverse events, laboratory evaluations, and neutralizing antibodies. RESULTS: All efficacy assessments indicated similar treatment effects of IM IFNß-1a in men and women with no significant treatment-by-gender interactions. Women reported more headaches, urinary tract infections, and depression in the analysis; however, these were also common in women who received placebo. Men reported more frequent flu-like symptoms in the placebo-controlled studies only. There were no other differences in the safety profile of IM IFNß-1a between men and women. CONCLUSIONS: We conclude that no significant gender-related differences were found in the efficacy and safety of IM IFNß-1a in patients with RRMS or CIS.

Experiences acquiring and using mobility aids among working-age persons with multiple sclerosis living in communities in the United States.

OBJECTIVE: To examine patterns of mobility aid ownership and use among working-age United States residents with multiple sclerosis. DESIGN: A 30-min telephone survey in mid-2007 with 703 community-dwelling, working-age adults who self-reported having multiple sclerosis; response rate was 73.4%. We identified potential survey respondents using membership lists of the National Multiple Sclerosis Society. All analyses and calculations used sampling weights to produce population estimates. RESULTS: Among working-age persons with multiple sclerosis living in communities nationwide, 60.5% own at least one mobility aid, most commonly manual wheelchairs (38.4%), followed by canes or crutches (35.7%). Despite owning mobility aids, many had not used this equipment in the previous 12 mos, including 4.5% of power wheelchair owners, 13.8% of those with manual wheelchairs, and 9.3% of scooter owners. Among manual wheelchair and scooter users, 25%-30% used this equipment only outside their homes. Many reported needing wheeled mobility aids inside their homes but being unable to move their equipment easily within their homes. CONCLUSIONS: Persons with multiple sclerosis own many mobility aids but can confront substantial barriers to their use, especially within homes. Consultations with physiatrists and home evaluations by physical or occupational therapists before purchasing equipment could provide practical suggestions for addressing barriers.

Asymptomatic reactivation of JC virus in patients treated with natalizumab.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus. METHODS: We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chain-reaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus-related polyomavirus, was used as a control. We determined JC virus-specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences. RESULTS: After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P=0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P=0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus-specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML. CONCLUSIONS: Subclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus-specific cellular immune response.

In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI.

OBJECTIVE: We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data. METHODS: We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 x 033 x 1 mm(3)), and a 3-dimensional magnetization-prepared rapid gradient echo. RESULTS: Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing-remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p < 0.02 by Spearman test) and older age (p < 0.04 by Spearman test). CONCLUSIONS: Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability.