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.
Background:
Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses.
Objective:
To evaluate efficacy and safety of additional ...alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) studies and their extensions.
Methods:
Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course.
Results:
In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses.
Conclusion:
Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Health-related quality of life (HRQoL) data are scarce from unselected populations. The aims were to assess HRQoL at 2 years poststroke, to identify determinants of HRQoL in stroke survivors, and to ...identify predictors at stroke onset of subsequent HRQoL.
All first-ever cases of stroke in a population of 306 631 over a 1-year period were assessed. Stroke severity, comorbidity, and demographic information were recorded. Two-year poststroke HRQoL was assessed using the Assessment of Quality of Life (AQoL) instrument (deceased patients score=0). Handicap, disability, physical impairment, depression, anxiety, living arrangements, and recurrent stroke at 2 years were documented. If necessary, proxy assessments were obtained, except for mood. Linear regression analyses were performed to identify factors independently associated with HRQoL.
Of 266 incident cases alive at 2 years, 225 (85%) were assessed. The mean AQoL utility score for all survivors was 0.47 (95% CI, 0.42 to 0.52). Almost 25% of survivors had a score of < or =0.1. The independent determinants of HRQoL in survivors were handicap, physical impairment, anxiety and depression, disability, institutionalization, dementia, and age. The factors present at stroke onset that independently predicted HRQoL at 2 years poststroke were age, female sex, initial NIHSS score, neglect, and low socioeconomic status.
A substantial proportion of stroke survivors have very poor HRQoL. Interventions targeting handicap and mood have the potential to improve HRQoL independently of physical impairment and disability.
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 5–16y; 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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
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.
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.
ACTRN12609000912280.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Clinical diagnostic utility of transcranial magnetic stimulation (TMS) has been established in neurological disorders.•Paired-pulse TMS exhibits utility in neurodegenerative, movement, episodic, and ...functional disorders.•TMS-EEG provides novel parameter (cortical excitability, effective connectivity, response complexity) for neurological diseases.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Little is known about health-related quality of life (HRQoL) in the long term after stroke.
The aim of this study was to assess the level of, and factors associated with, HRQoL at 7 years ...post-stroke.
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.
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).
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.
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. ANN NEUROL 2010;67:64–73
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Smoking may exacerbate the risk of death or further vascular events in those with stroke, but data are limited.
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).
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).
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.
Abstract Epilepsy encompasses a diverse group of seizure disorders caused by a variety of structural, cellular and molecular alterations of the brain primarily affecting the cerebral cortex, leading ...to recurrent unprovoked epileptic seizures. In this two-part review we examine the mechanisms underlying normal neuronal function and those predisposing to recurrent epileptic seizures starting at the most basic cellular derangements (Part 1) and working up to the highly complex epileptic networks (Part 2). We attempt to show that multiple factors can modify the epileptic process and that different mechanisms underlie different types of epilepsy, and in most situations there is an interplay between multiple genetic and environmental factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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