Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience.

BACKGROUND: This retrospective study evaluates patient-reported outcomes in patients with multiple sclerosis (MS) spasticity who were treated with a cannabinoid oromucosal spray (Sativex®, USAN name: nabiximols) after not sufficiently responding to previous anti-spasticity medications. METHODS: Of 276 patients from eight centers in Belgium who began treatment prior to 31 December 2017, effectiveness assessment data were available for 238 patients during the test period of 4 to 8/12 weeks, and for smaller patient cohorts with continued treatment for 6/12 months. RESULTS: Mean 0-10 spasticity Numerical Rating Scale (NRS) scores improved from 8.1 at baseline to 5.2 (week 4), 4.6 (week 8) and 4.1 (week 12). Mean EuroQoL Visual Analogue Scale (EQ VAS) scores increased from 39 at baseline to 52 (week 4), 57 (week 8) and 59 (week 12). Mean NRS and EQ VAS scores remained in the same 12 weeks' range in patients with longer-term data. The average dose of cannabinoid oromucosal spray was 6 sprays/day. Most of the 93 out of 276 patients, with initial prescription (33.7%), who discontinued treatment by week 12 did so within the first 8 weeks, mainly due to lack of effectiveness. By week 12, 171 (74%) of the 230 effectiveness evaluable patients reported a clinically meaningful response, corresponding to ≥30% NRS improvement. The tolerability of cannabinoid oromucosal spray was consistent with its known safety profile. CONCLUSIONS: More than 60% of the patients with MS who started add-on treatment with cannabinoid oromucosal spray reported a clinically relevant symptomatic effect and continued treatment after 12 weeks.

Thyroid disorders in alemtuzumab-treated multiple sclerosis patients: a Belgian consensus on diagnosis and management.

This paper deals with thyroid disease that can occur after treatment with alemtuzumab (humanized monoclonal anti-CD52) for relapsing-remitting multiple sclerosis (MS). The 5-year incidence of thyroid adverse events in phase 3 clinical trials is up to 40.7%. In most cases, the thyroid dysfunction is mild and easily manageable and only few serious thyroid adverse events have been reported. The need for patient education on the risk of thyroid dysfunction, as well as regular clinical and biochemical thyroid function screening is well described. However, practical clinical guidance in case of abnormal thyroid-related findings prior to or after alemtuzumab treatment is currently lacking. Therefore, a Belgian taskforce consisting of MS and thyroid experts was created in 2016, with the objective of issuing a clinical thyroid management algorithm based on available scientific evidence and personal experience with regard to alemtuzumab treatment-related thyroid adverse events.

Natalizumab-PML survivors with subsequent MS treatment: Clinico-radiologic outcome.

OBJECTIVE: To describe the clinico-radiologic outcome of MS patients with natalizumab-related progressive multifocal leukoencephalopathy (Nz-PML) surviving and receiving disease-modifying therapy (DMT). METHODS: We describe clinical and radiologic evolution of Nz-PML survivors in an observational retrospective multicenter cohort to clarify the effect of different subsequent MS DMT strategies. Twenty-three patients from 11 centers were analyzed. Outcomes were (1) clinical efficacy of post-PML MS DMT, (2) radiologic efficacy of post-PML MS DMT, (3) radiologic evolution of PML lesion, and (4) disability progression. RESULTS: There was no clinical worsening of PML symptoms with a stability of Expanded Disability Status Scale at the last follow-up. No relapse was reported with fingolimod and dimethyl fumarate. No radiologic worsening of Nz-PML lesion was observed at the end of the follow-up. CONCLUSION: In this large cohort of patients with Nz-PML, MS therapies given after Nz discontinuation were not associated with PML worsening. A larger cohort with longer follow-up will be necessary to confirm this therapeutic strategy.

Fatigue evaluation in fingolimod treated patients: An observational study.

BACKGROUND: Fatigue is one of the most disabling symptoms in Multiple Sclerosis (MS) patients and is associated with a low quality of life. Fingolimod (Fg), a sphingosine 1-phosphate receptor modulator, is the first oral MS disease modifying treatment. Little is known about its effect on fatigue. To assess the impact of Fg on fatigue within the first 6 months of treatment in MS patients, we conducted a prospective, open label study, in real life setting. METHODS: Change of Modified Fatigue Impact Scale (MFIS) between Fg treatment start and at 6 months was used as a first outcome. Secondary outcomes were changes of MFIS subscales, Fatigue severity scale (FSS) and Visual Analogic Scale of Fatigue (VAS-F) scores, RESULTS: 54 completed the study at M6. No significant change was noted in global MFIS (and neither in sub analysis of MFIS), FSS or VAS-F at M6. Patients with high level of fatigue (MFIS or ≥38) had a higher EDSS score than patients with lower level of fatigue (MFIS <38), (mean 3.3, [SD 1.6] versus 1.6 [SD1.1], p=0.0002) but showed no significant difference in MFIS evolution at M6. There was no significant statistical difference in fatigue parameters evolution at M6 within patients Nz+ or Nz-. CONCLUSION: There is no significant impact of Fg on fatigue after 6 months of treatment.

Effects of twelve weeks of aerobic or strength training in addition to standard care in Parkinson's disease: a controlled study.

BACKGROUND: Physical exercise in addition to standard care (SC) in patients with Parkinson's disease (PD) is now a common practice in many care units. However, exercises can cover a wide range of interventions, and the specific effects of different interventions still deserve to be further investigated. AIM: The aim of this study was to compare the effects of 12 weeks of two different types of physical exercises with SC in patients suffering from PD. DESIGN: Pseudo-randomized controlled trial. SETTING: University laboratory for outcomes, University Hospital Centre for interventions. POPULATION: Fifty-two outpatients suffering from mild to moderate PD at baseline. METHODS: Participants were allocated to three groups: the strength training (ST) group performed individualized upper and lower limbs strength training, the aerobic training (AE) group performed tailored gradual aerobic cycling, and the third group received SC. The effects of the interventions on body function were assessed by measuring isokinetic concentric peak torque for knee extension and flexion, peak oxygen consumption (VO2peak) and peak work load (PWL) during an incremental maximal cycling test. Changes in mobility were evaluated from spatial-temporal gait features measured by mean of an accelerometer system and the Six-Minute Walk Distance (6MWD) Test. We used questionnaires to estimate health-related quality of life and habitual physical activity. RESULTS: No significant changes in any outcome measures occurred in the SC group. More than 80% of the participants adequately completed the AE and the ST interventions. The ST group significantly improved all peak torque measures (P≤0.01), except knee extension in the least affected side (P=0.13). This group also improved the PWL (P=0.009) and 6mwd (P=0.03). The AE group improved the VO2peak (P=0.02) and PWL (P<0.001). CONCLUSIONS: Physical fitness in patients with PD rapidly improved in compliance with training specificities, but better fitness hardly translated into better mobility and health-related quality of life. CLINICAL REHABILITATION IMPACT: Physiotherapists can efficiently propose physical conditioning to patients with mild to moderate PD, but these interventions are insufficient to improve gait and participation. Notwithstanding, ST is an efficient intervention for improving walking capacity.

Impaired automatic and unconscious motor processes in Parkinson's disease.

While it is increasingly recognized that voluntary movements are produced by an interaction between conscious and unconscious processes, the role of the latter in Parkinson's disease has received little attention to date. Here, we administered a subliminal masked prime task to 15 Parkinson's disease patients and 15 age-matched healthy elderly subjects. Compatibility effects were examined by manipulating the direction of the arrows and the interstimuli interval. Analysis of the positive compatibility effect revealed performance differences between the most and the least affected hand in Parkinson's disease patients. Additionally, patients did not show the same tendency toward a negative compatibility effect as compared to elderly controls. These novel findings provide evidence supporting the role of basal ganglia circuits in controlling the balance between automatic motor response facilitation and inhibition.

Role of the supplementary motor area in the automatic activation of motor plans in de novo Parkinson's disease patients.

The role of the basal ganglia-cortical motor loop in automatic and unconscious motor processes is poorly understood. Here, we used event-related functional magnetic resonance imaging in 11 de novo Parkinson's disease patients as they performed a visuomotor masked priming task. The stronger subliminal priming effect for the non-dominant side of motor symptoms than for the dominant side was paralleled by stronger supplementary motor area proper activity in response to lateralized visual stimuli presented below the threshold of awareness. This novel result supports the prediction that this area is involved in the automatic activation of motor plans as a function of striatal dopamine levels.

Finger tapping clinimetric score prediction in Parkinson's disease using low-cost accelerometers.

The motor clinical hallmarks of Parkinson's disease (PD) are usually quantified by physicians using validated clinimetric scales such as the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). However, clinical ratings are prone to subjectivity and inter-rater variability. The PD medical community is therefore looking for a simple, inexpensive, and objective rating method. As a first step towards this goal, a triaxial accelerometer-based system was used in a sample of 36 PD patients and 10 age-matched controls as they performed the MDS-UPDRS finger tapping (FT) task. First, raw signals were epoched to isolate the successive single FT movements. Next, eighteen FT task movement features were extracted, depicting MDS-UPDRS features and accelerometer specific features. An ordinal logistic regression model and a greedy backward algorithm were used to identify the most relevant features in the prediction of MDS-UPDRS FT scores, given by 3 specialists in movement disorders (SMDs). The Goodman-Kruskal Gamma index obtained (0.961), depicting the predictive performance of the model, is similar to those obtained between the individual scores given by the SMD (0.870 to 0.970). The automatic prediction of MDS-UPDRS scores using the proposed system may be valuable in clinical trials designed to evaluate and modify motor disability in PD patients.

Brain activation pattern related to gait disturbances in Parkinson's disease.

Gait disturbances represent a therapeutic challenge in Parkinson's disease (PD). To further investigate their underlying pathophysiological mechanisms, we compared brain activation related to mental imagery of gait between 15 PD patients and 15 age-matched controls using a block-design functional MRI experiment. On average, patients showed altered locomotion relatively to controls, as assessed with a standardized gait test that evaluated the severity of PD-related gait disturbances on a 25-m path. The experiment was conducted in the subjects as they rehearsed themselves walking on the same path with a gait pattern similar as that during locomotor evaluation. Imagined walking times were measured on a trial-by-trial basis as a control of behavioral performance. In both groups, mean imagined walking time was not significantly different from that measured during real gait on the path used for evaluation. The between-group comparison of the mental gait activation pattern with reference to mental imagery of standing showed hypoactivations within parieto-occipital regions, along with the left hippocampus, midline/lateral cerebellum, and presumed pedunculopontine nucleus/mesencephalic locomotor area, in patients. More specifically, the activation level of the right posterior parietal cortex located within the impaired gait-related cognitive network decreased proportionally with the severity of gait disturbances scored on the path used for gait evaluation and mental imagery. These novel findings suggest that the right posterior parietal cortex dysfunction is strongly related to the severity of gait disturbances in PD. This region may represent a target for the development of therapeutic interventions for PD-related gait disturbances.

Construction and validation of the Dynamic Parkinson Gait Scale (DYPAGS).

The dynamic evaluation of Parkinson's disease (PD)-related episodic gait disturbances in routine is challenging. Therefore, the aim of our study was to assess the reliability/validity of the Dynamic Parkinson Gait Scale (DYPAGS) composed of eight relevant items for the objective quantification of PD gait features: walking forwards/backwards/with dual-task, turning to both sides, imaginary obstacle avoidance with both legs and passing through narrow spaces. The scale was validated on thirty-five patients with mild to severe parkinsonism in their habitual "on-state". A shorter 6 item-version was designed on the basis of a principal component analysis. No significant floor/ceiling effect was detected. The internal consistency was excellent. The levels of interrater agreement, precision and minimal detectable change were adequate. The criterion-related validity was demonstrated by strong correlations with the DYPAGS scores and those at the gait subscales of the Tinetti Mobility Test and MDS-UPDRS. The construct validity was assessed by moderate-strong correlations with the Freezing of Gait Questionnaire, mobility index of the PD Questionnaire (PDQ-39), disease duration and levodopa equivalent daily doses. Statistical analyses using the coefficient of determination showed that both DYPGAS versions were superior to the other instruments to identify patients with gait disturbances with poorer response to dopaminergic treatment. Full and short DYPAGS are reliable instruments for the quantification of "on" PD-related episodic gait disturbances. The full version is sensitive to detect subtle disturbances in mild parkinsonism. The shorter one is easily administered and reliably quantifies gait disturbances in moderate to severe parkinsonism. We recommend their use for research and clinical practice.

Motor fatigue measurement by distance-induced slow down of walking speed in multiple sclerosis.

BACKGROUND AND RATIONALE: Motor fatigue and ambulation impairment are prominent clinical features of people with multiple sclerosis (pMS). We hypothesized that a multimodal and comparative assessment of walking speed on short and long distance would allow a better delineation and quantification of gait fatigability in pMS. Our objectives were to compare 4 walking paradigms: the timed 25-foot walk (T25FW), a corrected version of the T25FW with dynamic start (T25FW(+)), the timed 100-meter walk (T100MW) and the timed 500-meter walk (T500MW). METHODS: Thirty controls and 81 pMS performed the 4 walking tests in a single study visit. RESULTS: The 4 walking tests were performed with a slower WS in pMS compared to controls even in subgroups with minimal disability. The finishing speed of the last 100-meter of the T500MW was the slowest measurable WS whereas the T25FW(+) provided the fastest measurable WS. The ratio between such slowest and fastest WS (Deceleration Index, DI) was significantly lower only in pMS with EDSS 4.0-6.0, a pyramidal or cerebellar functional system score reaching 3 or a maximum reported walking distance ≤ 4000 m. CONCLUSION: The motor fatigue which triggers gait deceleration over a sustained effort in pMS can be measured by the WS ratio between performances on a very short distance and the finishing pace on a longer more demanding task. The absolute walking speed is abnormal early in MS whatever the distance of effort when patients are unaware of ambulation impairment. In contrast, the DI-measured ambulation fatigability appears to take place later in the disease course.

Comparison of the timed 25-foot and the 100-meter walk as performance measures in multiple sclerosis.

BACKGROUND: Ambulation impairment is a major component of physical disability in multiple sclerosis (MS) and a major target of rehabilitation programs. Outcome measures commonly used to evaluate walking capacities suffer from several limitations. OBJECTIVES: To define and validate a new test that would overcome the limitations of current gait evaluations in MS and ultimately better correlate with the maximum walking distance (MWD). METHODS: The authors developed the Timed 100-Meter Walk Test (T100MW), which was compared with the Timed 25-Foot Walk Test (T25FW). For the T100MW, the subject is invited to walk 100 m as fast as he/she can. In MS patients and healthy control volunteers, the authors measured the test-retest and interrater intraclass correlation coefficient. Spearman rank correlations were obtained between the T25FW, the T100MW, the Expanded Disability Status Scale (EDSS), and the MWD. The coefficient of variation, Bland-Altman plots, the coefficient of determination, and the area under the receiver operator characteristic curve were measured. The mean walking speed (MWS) was compared between the 2 tests. RESULTS: A total of 141 MS patients and 104 healthy control volunteers were assessed. Minor differences favoring the T100MW over the T25FW were observed. Interestingly, the authors demonstrated a paradoxically higher MWS on a long (T100MW) rather than on a short distance walk test (T25FW). CONCLUSION: The T25FW and T100MW displayed subtle differences of reproducibility, variability, and correlation with MWD favoring the T100MW. The maximum walking speed of MS patients may be poorly estimated by the T25FW since MS patients were shown to walk faster over a longer distance.

Transcranial magnetic stimulation in disorders of consciousness.

We have reviewed the literature on transcranial magnetic stimulation studies in patients with brain death, coma, vegetative, minimally conscious, and locked-in states. Transcranial magnetic stimulation permits non-invasive study of brain excitability and may extend our understanding of the underlying mechanisms of these disorders. However, use of this technique in severe brain damage remains methodologically ill-defined and must be further validated prior to clinical application in these challenging patients.

Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation.

OBJECTIVE: Focal transcranial magnetic stimulation was used to test prospectively corticospinal excitability changes and reorganization of first dorsal interosseous (FDI) motor cortical representation in 31 patients who experienced a first ischemic stroke in the middle cerebral artery territory. All had severe hand palsy at onset. METHODS: Patients were assessed clinically with the Medical Research Council, Rankin, the National Institutes of Health stroke scales and Barthel Index at days 1, 8, 30, 90, 180 and 360 after stroke. The following parameters of FDI motor evoked potential (MEPS) to focal transcranial magnetic stimulation were measured at the same delays: motor threshold, MEP amplitude, excitable cortical area, hot spot and center of gravity of FDI motor maps on affected and unaffected hemispheres. Correlations were sought between clinical and electrophysiological parameters. RESULTS: In patients whose affected motor cortex remained excitable at day 1, motor thresholds were not significantly different between sides and were similar to those of controls. Persistence of MEP on the affected side at day 1 was a strong predictor of good recovery. If present at day 1, MEPs recorded in affected FDI were significantly smaller than of the opposite side or in normals and progressively recovered up to day 360. In these patients, area of excitable cortex remained stable throughout the entire study. At day 1, amplitudes of MEPs obtained in unaffected FDI were significantly larger than later. Between days 1 and 360, we observed a significant displacement of center of gravity of motor maps towards more frontal regions on the affected side while no change was noted on the unaffected side. CONCLUSIONS: Our data confirm the early prognosis value of transcranial magnetic stimulation in stroke. They indicate that the brain insult induces a transient hyperexcitability of the unaffected motor cortex. The evolution of FDI motor maps along the course of recovery mostly reflect corticospinal excitability changes but might also reveal some degree of brain plasticity. Most modifications observed occurred within 3 months of stroke onset.