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.

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.

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.

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.

Health-related quality of life assessment in multiple sclerosis.

The goal of evidence-based medicine in the treatment of conditions that produce morbidity but have a minimal impact on mortality is arguably to reduce disease impact on patients' lives and to assure that interventions result in more good than harm. Achieving these goals can be demonstrated only with patient input. There is clear evidence that multiple sclerosis has a significant negative impact on health-related quality of life (HRQL). The purpose of incorporating routine HRQL data in clinical practice is to provide a comprehensive assessment of the patient's health status from that person's perspective. This article discusses the types of HRQL measures available for patient assessment and how those data can be routinely collected.

Acute paraplegia with vanishing white matter lesions.

Young adults presenting with an acute myelopathy often represent a diagnostic challenge. We present the case of a 20-year-old man who demonstrated many of the diagnostic issues involved in the evaluation of this syndrome.

Anti-tumor necrosis factor alpha-associated multiple sclerosis.

A case of multiple sclerosis presenting during anti-tumor necrosis factor treatment for rheumatoid arthritis is discussed. This association has been reported in the nonradiological literature, but is an important association for radiologists to be aware of, as they may be in a position to first suggest the diagnosis.

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.

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.

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.

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.

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.

Patterns of mobility aid use among working-age persons with multiple sclerosis living in the community in the United States.

BACKGROUND: Difficulty walking is the most visible sign of disability among persons with multiple sclerosis (MS). However, little is known about mobility aid use by persons with MS living in the community. OBJECTIVES: To explore perceptions of mobility problems related to MS and patterns of mobility aid use by persons with MS residing in communities across the United States. METHODS: We conducted a 30-minute telephone survey in mid-2007 with 703 community-dwelling, working-age adults who self-reported having MS. We identified potential survey respondents using membership lists of the National Multiple Sclerosis Society, oversampling individuals living in zip codes with relatively high poverty rates. All analyses, including calculation of simple percentages, used sampling weights to produce population estimates. The overall response rate was 73.4%. Survey questions asked basic information about all mobility aids used by respondents and details about up to two different aids. We used multivariable polychotomous logistic regression to predict use of various mobility aids accounting for demographic and disease characteristics. RESULTS: In questions about the previous 2 weeks, needing to concentrate on walking because of MS was the most common problem cited (weighted percent = 79.3%), followed by MS making standing more difficult (69.9%), increased effort needed to walk (59.0%), and needing to hold onto furniture, walls, or someone's arm when walking indoors every day (40.0%). Among the 703 respondents, 434 (weighted percent = 60.5%) reported using at least one mobility aid; the majority of these individuals reported using more than one type of aid. Manual wheelchairs were the most common mobility aid (63.4%), followed by canes (56.7%), power wheelchairs (36.7%), and scooters (32.2%). Among those using three or more different types of mobility aids, the large majority used manual wheelchairs (88.2%), followed by canes (65.4%). Persons who are married or living with partners were much less likely to use powered equipment than those who were never married (adjusted odds ratio [AOR] = 0.32; 95% CI: 0.13-0.82). Women were much less likely than men to use powered equipment (AOR = 0.40; 95% CI: 0.21-0.75). CONCLUSION: The vast majority of persons with MS who use at least one mobility aid own more than one type and about half own three or more different types of mobility aids. Persons with MS appear to "mix and match" different devices to suit their specific mobility needs. Given restrictive health insurance coverage policies for mobility aids, these findings raise questions about how persons acquire and pay for higher-technology mobility aids.

Interferon-beta1a: a once-weekly immunomodulatory treatment for patients with multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. The most common form of MS at onset, relapsing-remitting disease, is defined not by pathological features but by unpredictable periods of acute or subacute neurological worsening, followed by gradual improvement over weeks to months, often with residual neurological deficits. Evidence from serial magnetic resonance imaging studies in relapsing-remitting disease reveals significant inflammation, demyelination and axonal loss occurring both during and between relapses. Disease-modifying agents, such as interferon (IFN)-beta(1a), reduce the frequency of relapse by 30% in well established relapsing patients, reduce the risk of a second attack by 50% in high-risk patients, following a first attack, and reduce the number and volume of magnetic resonance imaging lesions. Intramuscular IFN-beta(1a) is effective in delaying disability progression and brain atrophy. The relationship between response to therapy and pathological subtype of MS is unknown. This review summarizes key findings of Phase III clinical trials, extension studies and postmarketing trials, demonstrating the efficacy and safety of intramuscular IFN-beta(1a). Results demonstrating the negative impact of anti-IFN-beta neutralizing antibodies on clinical efficacy are also addressed. Finally, expert commentary regarding the treatment of MS with IFN-beta therapy and future strategies to augment intramuscular IFN-beta(1a) efficacy by combination treatment with other agents is presented.

IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event.

BACKGROUND: The Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) showed that IM interferon beta-1a (IFNbeta-1a) significantly slows the rate of development of clinically definite multiple sclerosis (CDMS) over 2 years in high-risk patients who experience a first clinical demyelinating event. This report highlights the primary results of a 5-year, open-label extension of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]). OBJECTIVE: To determine if the benefits of IFNbeta-1a observed in CHAMPS are sustained for up to 5 years. METHODS: CHAMPS patients at participating CHAMPIONS sites were enrolled in the study. All patients were offered, but not required to take, IFNbeta-1a 30 microg IM once weekly for up to 5 years (from CHAMPS randomization). Patients who received placebo in CHAMPS were considered the delayed treatment (DT) group, and patients who received IFNbeta-1a in CHAMPS were considered the immediate treatment (IT) group. The primary outcome measure was the rate of development of CDMS. Additional outcomes included disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years. RESULTS: Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS. The median time to initiation of IFNbeta-1a therapy in the DT group was 29 months. The cumulative probability of development of CDMS was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs 49 +/- 10%; p = 0.03). Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of neurologic symptoms. Few patients in either group developed major disability within 5 years. CONCLUSIONS: These results support the use of IM interferon beta-1a after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses.

The objective of this work was to assess the effect of interferon beta-1a (Avonex) on the rate of development of clinically definite multiple sclerosis and brain magnetic resonance imaging changes in subgroups based on type of presenting event, baseline brain magnetic resonance imaging parameters, and demographic factors in the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial. After the onset of a first demyelinating event, 383 patients with brain magnetic resonance imaging evidence of subclinical demyelination were treated with corticosteroids and randomly assigned to receive weekly intramuscular injections of 30 microg interferon beta-1a or placebo. The treatment effect within subgroups was assessed in proportional hazards models both for the development of clinically definite multiple sclerosis and for a combined outcome of development of clinically definite multiple sclerosis or >1 new or enlarging T2 lesions on brain magnetic resonance imaging. A beneficial effect of treatment was noted in all subgroups evaluated. Adjusted rate ratios for the development of clinically definite multiple sclerosis in the optic neuritis, brainstem-cerebellar, and spinal cord syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01) and for the development of the combined clinically definite multiple sclerosis/magnetic resonance imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively. A treatment benefit on both outcome measures also was seen in subgroups based on baseline brain magnetic resonance imaging parameters, gender, and age. Interferon beta-1a is beneficial when initiated at the first clinical demyelinating event in patients with brain magnetic resonance imaging evidence of subclinical demyelination. The beneficial effect is present for optic neuritis, brainstem-cerebellar syndromes, and spinal cord syndromes.