R. Philip Kinkel

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.

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.

Interferon β‐1a for early multiple sclerosis: CHAMPS trial subgroup analyses

The objective of this work was to assess the effect of interferon β‐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 30μg interferon β‐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 β‐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.

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*

To evaluate the inter‐rater agreement of cortical lesion detection using 7 Tesla (T) FLASH‐T2* and 3T DIR sequences.

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis.

To determine the prevalence of JC virus (JCV) reactivation and JCV‐specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS).

Transcallosal bands: A sign of neuronal tract degeneration in early MS?

A pattern of injury observed in patients at high risk for MS described as transcallosal bands (TCB) is hypothesized to be the result of neuronal tract degeneration in earliest MS, extending from typical acute, focal demyelinating lesions located along the lateral borders of the corpus callosum. The TCB, a T2-hyperintense lesion traversing the corpus callosum is recognized on 3-mm thick, T2-weighted imaging, develops over months and persists over years.

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.

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.

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

Iezzoni LI, Rao SR, Kinkel RP: 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.