A new era in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.

Randomized comparison trial of density and context of upper limb intensive group versus individualized occupational therapy for children with unilateral cerebral palsy.

AIM: To determine whether short-term intensive group-based therapy combining modified constraint-induced movement therapy and bimanual therapy (hybrid-CIMT) is more effective than an equal total dose of distributed individualized occupational therapy (standard care) on upper limb motor and individualized outcomes. METHOD: Fifty-three children with unilateral cerebral palsy (69% males; mean age 7y 10mo, SD 2y 4mo; Manual Ability Classification System level I, n=24; level II, n=23) were randomly allocated, and 44 received either hybrid-CIMT (n=25) or standard care (n=19). Standard care comprised six weekly occupational therapy sessions and a 12-week home programme. Outcomes were assessed at baseline, 13 weeks, and 26 weeks after treatment. RESULTS: Groups were equivalent at baseline. Standard care achieved greater gains on satisfaction with occupational performance after intervention (estimated mean difference -1.2, 95% CI -2.2 to -0.1; p=0.04) and Assisting Hand Assessment at 26 weeks (estimated mean difference 3.1, 95% CI 0.2-6.0; p=0.04). Both groups demonstrated significant improvements in dexterity of the impaired upper limb, and bimanual and occupational performance over time. The differences between groups were not clinically meaningful. INTERPRETATION: There were no differences between the two models of therapy delivery. Group-based intensive camps may not be readily available; however, individualized standard care augmented with a home programme may offer an effective alternative but needs to be provided at a sufficient dose.

Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee.

The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity.

Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation.

Importance: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. Objectives: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. Design, Setting, and Participants: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. Exposures: Dimethyl fumarate, fingolimod, and ocrelizumab. Main Outcomes and Measures: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. Results: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. Conclusion and Relevance: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

Baseline smoking status and the long-term risk of death or nonfatal vascular event in people with stroke: a 10-year survival analysis.

BACKGROUND AND PURPOSE: Smoking may exacerbate the risk of death or further vascular events in those with stroke, but data are limited. METHODS: 1589 cases of first-ever and recurrent stroke were recruited between 1996 and 1999 from a defined geographical region in North East Melbourne. Both hospital and nonhospital cases were included. Over a 10-year period, all deaths, recurrent stroke events, and acute myocardial infarctions that were reported at follow-up interviews were validated using medical records. Cox proportional hazards regression was used to assess the association between baseline smoking status (never, ex, and current) and outcome (death, acute myocardial infarction, or recurrent stroke). RESULTS: Patients who were current smokers (Hazard Ratio [HR], 1.30; 95% Confidence Interval [CI], 1.06-1.60; P=0.012) at the time of their stroke had poorer outcome when compared with those who had never smoked. Among those who survived the first 28 days of stroke, current smokers (HR, 1.42; 95% CI, 1.13-1.78; P<0.003) and ex-smokers (HR, 1.18; 95% CI, 1.01-1.39; P=0.039) at baseline had poorer outcome than those who had never smoked. Current smokers also had a greater risk of recurrent events than past smokers (HR, 1.23; 95% CI, 1.00-1.50; P=0.050). CONCLUSIONS: Patients who smoked at the time of their stroke or had smoked before their stroke had greater risk of death or recurrent vascular events when compared with patients who were never smokers. There are benefits of smoking cessation, with ex-smokers appearing to have a lesser risk of recurrent vascular events than current smokers.

Cortical excitability decreases in Lennox-Gastaut syndrome.

PURPOSE: We used transcranial magnetic stimulation (TMS) to investigate cortical excitability changes in Lennox-Gastaut syndrome (LGS), anticipating we would find a marked increase in excitability compared to other patients with refractory epilepsies. METHODS: Eighteen patients with LGS were studied. Motor threshold (MT), short intracortical inhibition (paired pulse TMS at 2 and 5 msec interstimulus intervals [ISIs]), intracortical facilitation (10 and 15 msec ISIs), and long intracortical inhibition (100-300 msec ISIs) were measured. Results were compared to those of 20 patients with chronic refractory idiopathic generalized epilepsy (IGE), 20 patients with chronic refractory focal epilepsy, and 20 healthy nonepilepsy controls. KEY FINDINGS: A significant decrease in cortical excitability was observed in LGS compared to the other two groups with refractory epilepsy as evidenced by increased MT and intracortical inhibition at both short (2, 5 msec ISIs), and long (100-300 msec ISIs) as well as decreased intracortical facilitation (10, 15 msec ISIs), (p < 0.01; effect sizes ranging from 0.3 to 1.8). Cortical excitability was also lower in LGS compared to nonepilepsy controls (increased MT and decreased intracortical facilitation; p < 0.05; effect sizes ranging from 0.5 to 0.9). SIGNIFICANCE: Interictal cortical excitability is decreased in LGS; a feature that distinguishes it from other refractory epilepsy syndromes. This decrease may be an important mechanism for the neurobehavioral comorbidities associated with LGS.

Cortical excitability and neurology: insights into the pathophysiology.

Transcranial magnetic stimulation (TMS) is a technique developed to non-invasively investigate the integrity of human motor corticospinal tracts. Over the last three decades, the use of stimulation paradigms including single-pulse TMS, paired-pulse TMS, repetitive TMS, and integration with EEG and functional imaging have been developed to facilitate measurement of cortical excitability.Through the use of these protocols, TMS has evolved in-to an excellent tool for measuring cortical excitability.TMS has high sensitivity in detecting subtle changes in cortical excitability, and therefore it is also a good measure of disturbances associated with brain disorders. In this review, we appraise the current literature on cortical excitability studies using TMS in neurological disorders.We begin with a brief overview of current TMS measures and then show how these have added to our understand-ing of the underlying mechanisms of brain disorders.

Response to treatment in NMOSD: the Australasian experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis.

Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.

Predicting seizure control: cortical excitability and antiepileptic medication.

OBJECTIVE: Approximately 30% of patients with newly diagnosed epilepsy do not respond to antiepileptic drugs (AEDs), but this is not predictable. We used transcranial magnetic stimulation to determine the effect of AEDs on cortical excitability in patients with epilepsy and correlated this with a successful response to treatment. METHODS: Ninety-nine drug-naïve patients with newly diagnosed epilepsy (55 idiopathic generalized epilepsy, 44 focal epilepsy) were evaluated. Motor threshold and cortical excitability on recovery curve analysis were measured before and 4 to 16 weeks after starting medication. After 1 year of treatment, 43 of 55 idiopathic generalized epilepsy and 26 of 44 focal epilepsy patients were seizure free. RESULTS: A decrease in cortical excitability occurred in the seizure-free group as indicated by an increase in motor threshold (p < 0.05) and intracortical inhibition on recovery curve analysis, maximum at the 250-millisecond interstimulus interval (p < 0.01) compared with pretreatment values. These changes were not present in the group with ongoing seizures. INTERPRETATION: Seizure freedom is marked by a reduction in transcranial magnetic stimulation measures of cortical excitability, evident shortly after beginning therapy. This virtual normalization of cortical excitability occurred regardless of the seizure characteristics or AED used. Failure to show this response to AED treatment may be valuable as an early predictor of pharmacoresistance in individual patients.

Factors associated with quality of life in 7-year survivors of stroke.

BACKGROUND: Little is known about health-related quality of life (HRQoL) in the long term after stroke. AIM: The aim of this study was to assess the level of, and factors associated with, HRQoL at 7 years post-stroke. METHODS: All stroke cases from a prospective community-based stroke incidence study (excluding subarachnoid haemorrhage) were assessed 7 years after stroke. HRQoL was measured with the Assessment of Quality of Life instrument. Proportional odds ordinal logistic regression was used to determine factors associated with HRQoL at 7 years post-stroke. RESULTS: Overall, 1321 stroke cases were recruited. Seven years after stroke, 413 (31.2%) were alive and 328 (79.4%) were assessed. Those assessed were less often current smokers pre-stroke than those not assessed (p<0.01). Seventy-six survivors (23%) had very poor HRQoL (range: -0.038 to 0.100). Factors present at 7 years that were associated with better 7-year HRQoL were independence in instrumental activities of daily living (IADL) (estimated OR=11.2, 95% CI 4.87 to 25.6, p<0.001), independence in basic activities of daily living (BADL) (OR=4.53, 95% CI 2.03 to 10.1, p<0.001), independence in IADL and BADL (OR=9.90, 95% CI 4.51 to 21.7, p<0.001), male gender (OR=1.89, 95% CI 1.21 to 2.96, p=0.005) and lesser handicap (trend: OR=3.47, 95% CI 2.51 to 4.79, p<0.001). Participants' HRQoL scores tended to be lower when HRQoL assessments were completed by proxy (OR=0.13, 95% CI 0.06 to 0.31, p<0.001). CONCLUSION: At 7 years post-stroke, 68.8% had died and a substantial proportion of survivors had poor HRQoL. Factors such as handicap, BADL and IADL could be targeted to improve HRQoL in long-term survivors of stroke.

Randomized trial of constraint-induced movement therapy and bimanual training on activity outcomes for children with congenital hemiplegia.

AIM: To determine if constraint-induced movement therapy (CIMT) is more effective than bimanual training (BIM) in improving upper limb activity outcomes for children with congenital hemiplegia in a matched-pairs randomized trial. METHOD: Sixty-three children (mean age 10.2, SD 2.7, range 5-16 y; 33 males, 30 females), 16 in Manual Ability Classification System level I, 46 level II, and 1 level III and 16 in Gross Motor Function Classification level I, 47 level II) were randomly allocated to either CIMT or BIM group day camps (60 hours over 10 days). The Melbourne Assessment of Unilateral Upper Limb Function assessed unimanual capacity of the impaired limb and Assisting Hand Assessment evaluated bimanual coordination at baseline, 3 and 26 weeks, scored by blinded raters. RESULTS: After concealed random allocation, there was no baseline difference between groups. CIMT had superior outcomes compared with BIM for unimanual capacity at 26 weeks (estimated mean difference [EMD] 4.4, 95% confidence interval [CI] 2.2-6.7; p < 0.001). There was no other significant difference between groups post-intervention. Both groups demonstrated significant improvements in bimanual performance at 3 weeks, with gains maintained by BIM at 26 weeks (EMD 2.3; 95% CI 0.6-4.0; p = 0.008). Interpretation Overall, there were only small differences between the two training approaches. CIMT yielded greater changes in unimanual capacity of the impaired upper limb compared with BIM. Results generally reflect specificity of practice, with CIMT improving unimanual capacity and BIM improving bimanual performance. Considerable inter-individual variation in response to either intervention was evident. Future research should consider serial sequencing unimanual then BIM approaches to optimize upper limb outcomes for children with congenital hemiplegia.

Participation outcomes in a randomized trial of 2 models of upper-limb rehabilitation for children with congenital hemiplegia.

OBJECTIVE: To determine if constraint-induced movement therapy (CIMT) is more effective than bimanual training to improve occupational performance and participation in children with congenital hemiplegia. DESIGN: Single-blind randomized comparison trial with evaluations at baseline, 3, and 26 weeks. SETTING: Community facilities in 2 Australian states. PARTICIPANTS: Referred sample of children (N=64; mean age ± SD, 10.2±2.7y, 52% boys) were matched for age, sex, side of hemiplegia, and upper-limb function and were randomized to CIMT or bimanual training. After random allocation, 100% of CIMT and 94% of the bimanual training group completed the intervention. INTERVENTIONS: Each intervention was delivered in day camps (total 60 h over 10d) using a circus theme with goal-directed training. Children receiving CIMT wore a tailor-made glove during the camp. MAIN OUTCOME MEASURES: The primary outcome was the Canadian Occupational Performance Measure (COPM). Secondary measures included the Assessment of Life Habits (LIFE-H), Children's Assessment of Participation and Enjoyment, and School Function Assessment. RESULTS: There were no between-group differences at baseline. Both groups made significant changes for COPM performance at 3 weeks (estimated mean difference =2.9; 95% confidence interval [CI], 2.3-3.6; P<.001 for CIMT; estimated mean difference=2.8; 95% CI, 2.2-3.4; P<.001 for bimanual training) that were maintained at 26 weeks. Significant gains were made in the personal care LIFE-H domain following CIMT (estimated mean difference=0.5; 95% CI, 0.1-0.9; P=.01) and bimanual training (estimated mean difference=0.6; 95% CI, 0.2-1.1; P=.006). CONCLUSIONS: There were minimal differences between the 2 training approaches. Goal-directed, activity-based, upper-limb training, addressed through either CIMT or bimanual training achieved gains in occupational performance. Changes in participation on specific domains of participation assessments appear to correspond with identified goals.

Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies.

INTRODUCTION: In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW. METHODS: CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed. RESULTS: Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores. CONCLUSION: CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9.

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis.

OBJECTIVE: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. METHODS: Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses. RESULTS: We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum. CONCLUSION: Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications.

Can changes in cortical excitability distinguish progressive from juvenile myoclonic epilepsy?

PURPOSE: We used transcranial magnetic stimulation (TMS) to investigate whether there were any characteristic cortical excitability changes in progressive myoclonic epilepsy (PME) compared to juvenile myoclonic epilepsy (JME). METHODS: Six patients with PME were studied. Motor threshold (MT) at rest and recovery curve analysis using paired-pulse stimulation at a number of interstimulus intervals (ISIs) was determined. Results were compared to those of 9 patients with chronic refractory JME and 10 with chronic well-controlled JME. RESULTS: PME showed a marked increase in cortical excitability at all the long ISIs (p < 0.01), compared to refractory JME (effect sizes ranging from 1.4 to 1.9) and well-controlled JME (effect sizes ranging from 2.0 to 2.4). Significant differences at the short ISIs 2-5 ms were seen only on comparison with the well-controlled group (p < 0.05, effect size 0.6, 0.7). There were no significant differences in MTs of PME compared to either JME groups. CONCLUSION: Our findings demonstrate specific differences in cortical excitability using TMS between PME and those with JME, particularly at long latencies in the paired-pulse paradigm, implicating a role for γ-aminobutyric acid (GABA)(B) -mediated networks.

INCITE: A randomised trial comparing constraint induced movement therapy and bimanual training in children with congenital hemiplegia.

BACKGROUND: Congenital hemiplegia is the most common form of cerebral palsy (CP) accounting for 1 in 1300 live births. These children have limitations in capacity to use the impaired upper limb and bimanual coordination deficits which impact on daily activities and participation in home, school and community life. There are currently two diverse intensive therapy approaches. Traditional therapy has adopted a bimanual approach (BIM training) and recently, constraint induced movement therapy (CIMT) has emerged as a promising unimanual approach. Uncertainty remains about the efficacy of these interventions and characteristics of best responders. This study aims to compare the efficacy of CIMT to BIM training to improve outcomes across the ICF for school children with congenital hemiplegia. METHODS/DESIGN: A matched pairs randomised comparison design will be used with children matched by age, gender, side of hemiplegia and level of upper limb function. Based on power calculations a sample size of 52 children (26 matched pairs) will be recruited. Children will be randomised within pairs to receive either CIMT or BIM training. Both interventions will use an intensive activity based day camp model, with groups receiving the same dosage of intervention delivered in the same environment (total 60 hours over 10 days). A novel circus theme will be used to enhance motivation. Groups will be compared at baseline, then at 3, 26 and 52 weeks following intervention. Severity of congenital hemiplegia will be classified according to brain structure (MRI and white matter fibre tracking), cortical excitability using Transcranial Magnetic Stimulation (TMS), functional use of the hand in everyday tasks (Manual Ability Classification System) and Gross Motor Function Classification System (GMFCS). Outcomes will address neurovascular changes (functional MRI, functional connectivity), and brain (re)organisation (TMS), body structure and function (range of motion, spasticity, strength and sensation), activity limitations (upper limb unimanual capacity and bimanual motor coordination), participation restrictions (in home, school and recreation), environmental (barriers and facilitators to participation) and quality of life. DISCUSSION: This paper outlines the theoretical basis, study hypotheses and outcome measures for a matched pairs randomised trial comparing CIMT and BIM training to improve outcomes across the ICF. TRIAL REGISTRATION: ACTRN12609000912280.

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.