Yves Lapierre

Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: Final report of the Northeast Cooperative Multiple Sclerosis Treatment Group

Previous studies reported that a 2- to 3-week course of IV cyclophosphamide plus adrenocorticotropic hormone (ACTH) induction can temporarily halt progressive MS for a period of 12 months in the majority of patients treated, after which reprogression occurs. The Northeast Cooperative Multiple Sclerosis Treatment Group was formed to determine whether outpatient pulse cyclophosphamide therapy could affect reprogression and whether there were differences between a modified induction regimen and the previously published regimen. Two hundred fifty-six progressive MS patients were randomized into four groups to receive IV cyclophosphamide/ACTH via the previously published versus a modified induction regimen, with or without outpatient IV cyclophosphamide boosters (700 mg/m2 every other month for 2 years). There were blinded evaluations performed every 6 months. Results demonstrate that (1) there were no differences between the modified and the published induction regimens either in terms of initial stabilization or subsequent progression; (2) without boosters, the majority of patients continued to progress; and (3) in patients receiving boosters, there was a statistically significant benefit at 24 months and 30 months (p = 0.04). Time to treatment failure after 1 year was also significantly prolonged in the booster versus the nonbooster group (p = 0.03). Age was the most important variable that correlated with response to therapy in that amelioration of disease progression occurred primarily in patients 40 years of age or younger. Boosters had a significant benefit on time to treatment failure in patients ages 18 to 40, p = 0.003, but not in patients ages 41 to 55, p = 0.97. In addition, patients with primary progressive MS had a poorer prognosis at 12 months than patients with secondarily progressive MS (p = 0.04). Our findings (1) support a role for immunosuppression in the treatment of MS, (2) begin to identify variables that may explain differences between studies of immunosuppression with cyclophosphamide in progressive MS, and (3) suggest that intermittent pulse therapy is an important method for the treatment of progressive MS and perhaps for earlier stages of MS as well.

Type 2 Monocyte and Microglia Differentiation Mediated by Glatiramer Acetate Therapy in Patients with Multiple Sclerosis

Glatiramer acetate (GA) therapy of patients with multiple sclerosis (MS) represents a unique setting in which in vivo Th2 deviation of T cells is consistently observed and associated with clinical benefit in a human autoimmune disease. We postulated that APCs are important targets of GA therapy and demonstrate that treatment of MS patients with GA reciprocally regulates the IL-10/IL-12 cytokine network of monocytes in vivo. We further show that Th1- or Th2-polarized GA-reactive T cells isolated from untreated or treated MS patients mediate type 1 and 2 APC differentiation of human monocytes, based on their ability to efficiently induce subsequent Th1 and Th2 deviation of naive T cells, respectively. These observations are extended to human microglia, providing the first demonstration of type 2 differentiation of CNS-derived APCs. Finally, we confirm that the fundamental capacity of polarized T cells to reciprocally modulate APC function is not restricted to GA-reactive T cells, thereby defining a novel and dynamic positive feedback loop between human T cell and APC responses. In the context of MS, we propose that GA therapy results in the generation of type 2 APCs, contributing to Th2 deviation both in the periphery and in the CNS of MS patients. In addition to extending insights into the therapeutic mode of action of GA, our findings revisit the concept of bystander suppression and underscore the potential of APCs as attractive targets for therapeutic immune modulation.

Reliability, validity, and applicability of the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST 2.0) for adults with multiple sclerosis

Purpose : To investigate the measurement properties of the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST 2.0) with respect to test-retest stability, alternate form reliability, construct validity and applicability. Method : Data on satisfaction and quality of life impacts of mobility devices were obtained from 81 community-based adults with Multiple Sclerosis, using the QUEST 2.0 and the Psychosocial Impact of Assistive Devices Scale (PIADS). Subjects were assigned to four groups and a second QUEST 2.0 was administered one week later. Groups differed with respect to the format and the order in which alternate forms were presented. Measures of association were calculated between QUEST 2.0 and PIADS (n = 81) and between QUEST 2.0 alternate forms (n = 48). Respondents reactions were considered. Results : The device subscale, services subscale, and total QUEST 2.0 scores achieved good test-retest stability (ICC 0.82, 0.82, 0.91). Alternate-form equivalence (ICC 0.89, 0.76, 0.91) was lower for services. The positive correlations between QUEST 2.0 and the three PIADS dimensions were fair to moderate for device and total QUEST 2.0 (r p 0.34 to 0.45) and fair with services (r p 0.27 to 0.30). The tool was positively received, with some restrictions for the services subscale. Conclusions : These findings on the psychometric properties of the QUEST 2.0 reinforce the relevance of the device subscale as an important outcome measure for assistive technology MS users. Further assessment of the services subscale is needed.

Choline is increased in pre-lesional normal appearing white matter in multiple sclerosis.

Abstract.Objective: Our aim was to determine if the resonance intensity of choline-containing compounds (Cho) measured using proton magnetic resonance spectroscopy (MRS) was increased in pre-lesional normal appearing white matter (NAWM) in patients with multiple sclerosis (MS) relative to NAWM that remained stable in subsequent scans. Background: The Cho peak in MR spectra is associated with membrane phospholipids and increases in acute MS plaques, possibly even before the appearance of MRI-visible MS lesions. Methods: Three combined proton MRI and MRS imaging examinations of the corpus callosum and adjacent periventricular white matter were performed on 12 MS patients at intervals of 6 months. Proton density (PD) images were visually matched across 3 time points and the lesion volume in each voxel of the volume of interest was determined. The voxels were subdivided into four groups based on the presence or absence of lesion at baseline and change or no change in lesion volume on the subsequent scan. Results: We found a significantly higher baseline Cho/Creatine (Cr) ratio in NAWM voxels that displayed MRI visible lesions 6 months later than NAWM voxels that remained unchanged (1.57 ± 0.30 and 1.37 ± 0.33, respectively, p < 0.001). The 12-month interval data revealed similar pre-lesional elevated Cho/Cr, (1.51 ± 0.29 versus 1.39 ± 0.32, p = 0.009). Voxels that contained lesion at baseline and increased in lesion volume at 6 months also showed a significantly higher Cho/Cr ratio than those whose lesion volume did not change (1.60 ± 0.32 and 1.49 ± 0.36, respectively, p = 0.043). Conclusions: The results of this study are consistent with focal pre-lesional myelin membrane pathology in the NAWM at least 12 months before lesions become visible on conventional MRI. This could reflect altered myelin chemistry or the presence of inflammation as seen in experimental allergic encephalomyelitis.

Treatment optimization in MS: Canadian MS Working Group updated recommendations.

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

Neuromyelitis optica with hypothalamic involvement

We describe two cases of neuromyelitis optica (NMO) with clinical and radiographically confirmed features of hypothalamic involvement, in the absence of other parenchymal brain lesions. Their course is otherwise typical of Devic’s form of NMO. A review of the literature identifies additional cases of NMO in which clinical features attributable to under-recognized dysfunction of the hypothalamic-pituitary axis were present. We propose that the currently accepted criteria for the diagnosis of NMO could be revisited to recognize the possibility of lesions developing within hypothalamic structures.

Fatigue in multiple sclerosis: association with disease-related, behavioural and psychosocial factors

We determined biopsychosocial correlates of general, physical, and mental fatigue in MS patients, by evaluating the additional contribution of potentially modifiable factors after accounting for non-modifiable disease-related factors. Fifty-three ambulatory MS patients, along with 28 normal controls were recruited for a cross-sectional study. Subjects completed the Multidimensional Fatigue Inventory (MFI) and Fatigue Severity Scale. Potential correlates evaluated were: disease-related factors (disease duration and type, immunomodulating treatment, muscle strength, pain, forced vital capacity (FVC), respiratory muscle strength, body mass index, disability, fibromyalgia), behavioural factors (physical activity, sleep quality) and psychosocial factors (depression, stress, self-efficacy). Multivariate models were calculated for MFI General, Physical, and Mental Fatigue. Age-adjusted multivariate models with non-modifiable factors included the following predictors (P ≤ 0.10) of 1) MFI General and Mental Fatigue: none; and 2) MFI Physical Fatigue: FVC and disability. The following potentially modifiable predictors (P ≤ 0.10) made an additional contribution to the models 1) MFI General Fatigue: sleep quality, self-efficacy, pain; 2) MFI Physical Fatigue: self-efficacy, physical activity; and 3) MFI Mental Fatigue: stress, self-efficacy. Fatigue in MS is multidimensional. Correlates of general and physical fatigue are disease-related, behavioural and psychosocial factors. Correlates of mental fatigue are psychosocial factors. Potentially modifiable factors account for a considerable portion of fatigue. Multiple Sclerosis 2007; 13: 985—995. http://msj.sagepub.com

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

BACKGROUNDnStrong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.nnnMETHODSnWe did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.nnnFINDINGSnBetween diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.nnnINTERPRETATIONnWe describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their diseases aggressive nature.nnnFUNDINGnMultiple Sclerosis Scientific Research Foundation.

Obstructive sleep apnea is associated with fatigue in multiple sclerosis.

Background: Multiple sclerosis (MS) patients often suffer from fatigue. Objective: We evaluated the relationship of obstructive sleep apnea (OSA) to fatigue and sleepiness in MS patients. Methods: Ambulatory MS patients without known sleep disorders and healthy controls underwent diagnostic polysomnography and a multiple sleep latency test (objective sleepiness measure). Fatigue was measured with the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI), and subjective sleepiness by Epworth Sleepiness Scale. Covariates included age, sex, body mass index, Expanded Disability Status Scale (EDSS), depression, pain, nocturia, restless legs syndrome, and medication. Results: OSA (apnea–hypopnea index ≥15) was found in 36 of 62 MS subjects and 15 of 32 controls. After adjusting for confounders, severe fatigue (FSS ≥5) and MFI-mental fatigue (>group median) were associated with OSA and respiratory-related arousals in MS, but not control subjects. Subjective and objective sleepiness were not related to OSA in either group. In a multivariate model, variables independently associated with severe fatigue in MS were severe OSA [OR 17.33, 95% CI 2.53–199.84], EDSS [OR 1.88, 95% CI 1.21–3.25], and immunomodulating treatment [OR 0.14, 95% CI 0.023–0.65]. Conclusions: OSA was frequent in MS and was associated with fatigue but not sleepiness, independent of MS-related disability and other covariates.

Multiple sclerosis vs acute disseminated encephalomyelitis in childhood

The initial presenting clinical and laboratory findings of either acute disseminated encephalomyelitis or the first attack of multiple sclerosis in the pediatric population were compared and contrasted. A retrospective review of the medical records was conducted of all children younger than 17 years who presented with either the diagnosis of acute disseminated encephalomyelitis or multiple sclerosis between 1987 and 2001. Seventeen cases of clinically definite multiple sclerosis (seven female, mean age 12.4 +/- 4.5 years) and seven cases of acute disseminated encephalomyelitis (three female; mean age 8.7 +/- 3.8 years) were reviewed. Systemic and nonfocal neurologic symptoms were more commonly evident in acute disseminated encephalomyelitis than in multiple sclerosis: fever (43% vs 6%), headache (57% vs 24%), fatigue (71% vs 29%), vomiting (57% vs 0%), and encephalopathy (71% vs 6%). In multiple sclerosis patients, T(2)-weighted white matter magnetic resonance imaging lesions were more commonly located in the corpus callosum (64% vs 17%) and the periventricular area (91% vs 50%) compared with those in patients with acute disseminated encephalomyelitis. These results suggest that acute disseminated encephalomyelitis and multiple sclerosis can be differentiated to some degree according to clinical and radiologic data at initial presentation, which is important because the long-term prognosis for childhood multiple sclerosis appears to be less favorable.