Lauren B. Krupp

Consensus definitions proposed for pediatric multiple sclerosis and related disorders

Background: The CNS inflammatory demyelinating disorders of childhood include both self-limited and lifelong conditions, which can be indistinguishable at the time of initial presentation. Clinical, biologic, and radiographic delineation of the various monophasic and chronic childhood demyelinating disorders requires an operational classification system to facilitate prospective research studies. Methods: The National Multiple Sclerosis Society (NMSS) organized an International Pediatric MS Study Group (Study Group) composed of adult and pediatric neurologists and experts in genetics, epidemiology, neuropsychology, nursing, and immunology. The group met several times to develop consensus definitions regarding the major CNS inflammatory demyelinating disorders of children and adolescents. Results: Clinical definitions are proposed for pediatric multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), recurrent ADEM, multiphasic ADEM, neuromyelitis optica, and clinically isolated syndrome. These definitions are considered operational and need to be tested in future research and modified accordingly. Conclusion: CNS inflammatory demyelinating disorders presenting in children and adolescents can be defined and distinguished. However, prospective research is necessary to determine the validity and utility of the proposed diagnostic categories.

THE MEASUREMENT OF FATIGUE: A NEW INSTRUMENT

Fatigue is a frequent medical symptom which has not been routinely measured. We present a 29-item fatigue assessment instrument, describe its psychometric properties, and use it to differentiate normal fatigue from fatigue related medical disorders. Differences in fatigue across a variety of medical disorders, the reproducibility of the fatigue instrument, and its convergent validity with other fatigue measures are also described.

Treatment of neuromyelitis optica with rituximab: Retrospective analysis of 25 patients

BACKGROUND Neuromyelitis optica (NMO) is an uncommon, life-threatening inflammatory demyelinating disorder. Recently, much has become known about its immunopathogenesis. However, optimal treatments, with expected outcomes, have not been established. OBJECTIVE To evaluate the use and efficacy of rituximab for treating NMO. DESIGN Retrospective multicenter case series of NMO patients treated with rituximab. SETTING Seven tertiary medical centers in the United States and England. PATIENTS Twenty-five patients (including 2 children), 23 of whom experienced relapses despite use of other drugs before rituximab. Extended follow-up of 7 previously reported patients is included. INTERVENTIONS Infusions of rituximab at median intervals of 8 months. MAIN OUTCOME MEASURES Annualized relapse rate and disability (expressed as Expanded Disability Status Scale score). RESULTS At a median follow-up of 19 months, the median annualized posttreatment relapse rate was lower than the pretreatment rate (0 [range 0-3.2] vs 1.7 [range, 0.5-5] relapses, P < .001). Disability improved or stabilized in 20 of 25 patients (80%, P = .02). Two patients died during the follow-up period, 1 owing to a brainstem relapse and 1 owing to suspected septicemia. Infections were reported in 20% of patients. CONCLUSIONS In NMO, treatment with rituximab appears to reduce the frequency of attacks, with subsequent stabilization or improvement in disability.

International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.

Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. Objective: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. Methods: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. Results: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. Conclusions: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

Psychiatric Disorders in Patients With Fibromyalgia: A Multicenter Investigation

The authors conducted an investigation in four tertiary-care centers to determine if psychiatric comorbidity and psychological variables were predictive of functional impairment in patients with fibromyalgia syndrome (FMS). Seventy-three individuals were administered the Structured Clinical Interview for DSM-III-R, the Rand 36-item Health Survey (SF-36), and multiple self-report measures. The patients with FMS were found to have a high lifetime and current prevalence of major depression and panic disorder. The most common disorders were major depression (lifetime [L] = 68%, current [C] = 22%); dysthymia (10% [C only]); panic disorder (L = 16%, C = 7%); and simple phobia (L = 16%, C = 12%). The self-report scales revealed significant elevations in depression, anxiety, neuroticism, and hypochondriasis. Functional impairment on all measures of the SF-36 was severe (e.g., physical functioning = 45.5 and role limitations due to physical problems = 20.0). Stepwise multiple-regression analysis revealed that current anxiety was the only variable that predicted a significant proportion of the variance (29%) in SF-36 physical functioning. Thus, in this multicenter study, the persons with FMS exhibited marked functional impairment, high levels of some lifetime and current psychiatric disorders, and significant current psychological distress. Current anxiety level appears to be an important correlate of functional impairment in individuals with FMS.

Fatigue therapy in multiple sclerosis Results of a double‐blind, randomized, parallel trial of amantadine, pemoline, and placebo

Objective To determine the relative efficacy of amantadine, pemoline, and placebo in treatment of multiple sclerosis (MS)-related fatigue. Background Fatigue is a complication of MS. Both pemoline and amantadine have been used to treat MS fatigue, but their relative efficacy is not known. Methods Amantadine, pemoline, and placebo were compared in a randomized, double-blind, placebo-controlled study using a parallel-group design. Ninety-three ambulatory MS patients completed the study. Primary outcome measures were the fatigue seventy scale (FSS); the MS-specific fatigue scale (MS-FS); and subjective response determined by verbal self-report. Secondary outcome measures consisted of assessments of sleep, depression, and vitality. Repeated-measures analysis of variance with planned post-hoc contrasts and Fishers exact test were used to compare treatment response. Results Amantadine-treated patients showed a significantly greater reduction in fatigue, as measured by the MS-FS, than did patients treated with placebo (p = 0.04). By verbal report at the end of the study, 79% of patients treated with amantadine versus 52% treated with placebo and 32% treated with pemoline preferred drug therapy compared with no treatment (p = 0.03). No significant differences in any primary outcome measures were noted between pemoline and placebo. Neither amantadine nor pemoline affected sleep or depression relative to placebo. Conclusion Amantadine was significantly better than placebo in treating fatigue in MS patients, whereas pemoline was not. The benefit of amantadine was not due to changes in sleep, depression, or neurologic disability.

Study and treatment of post Lyme disease (STOP-LD): A randomized double masked clinical trial

Objective: To determine whether post Lyme syndrome (PLS) is antibiotic responsive. Methods: The authors conducted a single-center randomized double-masked placebo-controlled trial on 55 patients with Lyme disease with persistent severe fatigue at least 6 or more months after antibiotic therapy. Patients were randomly assigned to receive 28 days of IV ceftriaxone or placebo. The primary clinical outcomes were improvement in fatigue, defined by a change of 0.7 points or more on an 11-item fatigue questionnaire, and improvement in cognitive function (mental speed), defined by a change of 25% or more on a test of reaction time. The primary laboratory outcome was an experimental measure of CSF infection, outer surface protein A (OspA). Outcome data were collected at the 6-month visit. Results: Patients assigned to ceftriaxone showed improvement in disabling fatigue compared to the placebo group (rate ratio, 3.5; 95% CI, 1.50 to 8.03; p = 0.001). No beneficial treatment effect was observed for cognitive function or the laboratory measure of persistent infection. Four patients, three of whom were on placebo, had adverse events associated with treatment, which required hospitalization. Conclusions: Ceftriaxone therapy in patients with PLS with severe fatigue was associated with an improvement in fatigue but not with cognitive function or an experimental laboratory measure of infection in this study. Because fatigue (a nonspecific symptom) was the only outcome that improved and because treatment was associated with adverse events, this study does not support the use of additional antibiotic therapy with parenteral ceftriaxone in post-treatment, persistently fatigued patients with PLS.

Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis

We sought to determine if vitamin D status, a risk factor for multiple sclerosis, is associated with the rate of subsequent clinical relapses in pediatric‐onset multiple sclerosis.

A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.

A previous phase 3 study showed significant improvement in walking ability in multiple sclerosis (MS) patients treated with oral, extended‐release dalfampridine (4‐aminopyridine) 10mg twice daily. The current study was designed to confirm efficacy and further define safety and pharmacodynamics.

Donepezil improved memory in multiple sclerosis in a randomized clinical trial

Objective: To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS). Methods: This single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change. Results: Donepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010). Conclusions: Donepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.