No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: Real-world evidence from MS PATHS

BACKGROUND: Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy. METHODS: Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EID + SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons. RESULTS: The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; p = 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; p = 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; p = 0.566) and -0.11% (-0.25%, -0.10%; p = 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p\u3c0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p\u3c0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; p = 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p\u3c0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison. CONCLUSIONS: The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics

Adverse Childhood Experiences Are Linked to Age of Onset and Reading Recognition in Multiple Sclerosis

BackgroundAdverse childhood experiences (ACEs) exert a psychological and physiological toll that increases risk of chronic conditions, poorer social functioning, and cognitive impairment in adulthood.ObjectiveTo investigate the relationship between childhood adversity and clinical disease features in multiple sclerosis (MS).MethodsSixty-seven participants with MS completed the ACE assessment and neuropsychological assessments as part of a larger clinical trial of cognitive remediation.ResultsAdverse childhood experience scores, a measure of exposure to adverse events in childhood, significantly predicted age of MS onset (r = –0.30, p = 0.04). ACEs were also linked to reading recognition (a proxy for premorbid IQ) (r = –0.25, p = 0.04). ACE scores were not related to age, current disability, or current level of cognitive impairment measured by the Symbol Digit Modalities Test (SDMT).ConclusionChildhood adversity may increase the likelihood of earlier age of onset and poorer estimated premorbid IQ in MS

Update on the Use of Transcranial Electrical Brain Stimulation to Manage Acute and Chronic COVID-19 Symptoms

The coronavirus disease 19 (COVID-19) pandemic has resulted in the urgent need to develop and deploy treatment approaches that can minimize mortality and morbidity. As infection, resulting illness, and the often prolonged recovery period continue to be characterized, therapeutic roles for transcranial electrical stimulation (tES) have emerged as promising non-pharmacological interventions. tES techniques have established therapeutic potential for managing a range of conditions relevant to COVID-19 illness and recovery, and may further be relevant for the general management of increased mental health problems during this time. Furthermore, these tES techniques can be inexpensive, portable, and allow for trained self-administration. Here, we summarize the rationale for using tES techniques, specifically transcranial Direct Current Stimulation (tDCS), across the COVID-19 clinical course, and index ongoing efforts to evaluate the inclusion of tES optimal clinical care

Long term at-home treatment with transcranial direct current stimulation (tDCS) improves symptoms of cerebellar ataxia: a case report

Abstract Background Progressive cerebellar ataxia is a neurodegenerative disorder without effective treatment options that seriously hinders quality of life. Previously, transcranial direct current stimulation (tDCS) has been demonstrated to benefit cerebellar functions (including improved motor control, learning and emotional processing) in healthy individuals and patients with neurological disorders. While tDCS is an emerging therapy, multiple daily sessions are needed for optimal clinical benefit. This case study tests the symptomatic benefit of remotely supervised tDCS (RS-tDCS) for a patient with cerebellar ataxia. Methods We report a case of a 71-year-old female patient with progressive cerebellar ataxia, who presented with unsteady gait and balance impairment, treated with tDCS. tDCS was administered using our RS-tDCS protocol and was completed daily in the patient’s home (Monday – Friday) with the help of a trained study technician. tDCS was paired with 20 min of simultaneous cognitive training, followed by 20 min of physical exercises directed by a physical therapist. Stimulation consisted of 20 min of 2.5 mA direct current targeting the cerebellum via an anodal electrode and a cathodal electrode placed over the right shoulder. The patient completed baseline and treatment end visits with neurological, cognitive, and motor (Lafayette Grooved Pegboard Test, 25 ft walk test and Timed Up and Go Test) assessments. Results The patient successfully completed sixty tDCS sessions, 59 of which were administered remotely at the patient’s home with the use of real time supervision as enabled by video conferencing. Mild improvement was observed in the patient’s gait with a 7% improvement in walking speed, which she completed without a walking-aid at treatment end, which was in stark contrast to her baseline assessment. Improvements were also achieved in manual dexterity, with an increase in pegboard scores bilaterally compared to baseline. Conclusions Results from this case report suggest that consecutively administered tDCS treatments paired with cognitive and physical exercise hold promise for improving balance, gait, and manual dexterity in patients with progressive ataxia. Remotely supervised tDCS provides home access to enable the administration over an extended period. Further controlled study in a large group of those with cerebellar ataxia is needed to replicate these findings. Trial registration ClinicalTrials.gov Identifier: NCT03049969. Registered 10 February 2017- Retrospectively registered

Gait and Functional Mobility in Multiple Sclerosis: Immediate Effects of Transcranial Direct Current Stimulation (tDCS) Paired With Aerobic Exercise

Walking impairments are a debilitating feature of multiple sclerosis (MS) because of the direct interference with daily activity. The management of motor symptoms in those with MS remains a therapeutic challenge. Transcranial direct current stimulation (tDCS) is a type of non-invasive brain stimulation that is emerging as a promising rehabilitative tool but requires further characterization to determine its optimal therapeutic use. In this randomized, sham-controlled proof-of-concept study, we tested the immediate effects of a single tDCS session on walking and functional mobility in those with MS. Seventeen participants with MS completed one 20-min session of aerobic exercise, randomly assigned to be paired with either active (2.5mA, n = 9) or sham (n = 8) tDCS over the primary motor cortex (M1). The groups (active vs. sham) were matched according to gender (50% vs. 60% F), age (52.1 ± 12.85 vs. 54.2 ± 8.5 years), and level of neurological disability (median Expanded Disability Status Scale score 5.5 vs. 5). Gait speed on the 10-m walk test and the Timed Up and Go (TUG) time were measured by a wearable inertial sensor immediately before and following the 20-min session, with changes compared between conditions and time. There were no significant differences in gait speed or TUG time changes following the session in the full sample or between the active vs. sham groups. These findings suggest that a single session of anodal tDCS over M1 is not sufficient to affect walking and functional mobility in those with MS. Instead, behavioral motor response of tDCS is likely to be cumulative, and the effects of multiple tDCS sessions require further study

Cognitive function in multiple sclerosis improves with telerehabilitation: Results from a randomized controlled trial.

Cognitive impairment affects more than half of all individuals living with multiple sclerosis (MS). We hypothesized that training at home with an adaptive online cognitive training program would have greater cognitive benefit than ordinary computer games in cognitively-impaired adults with MS. This was a double-blind, randomized, active-placebo-controlled trial. Participants with MS were recruited through Stony Brook Medicine and randomly assigned to either the adaptive cognitive remediation (ACR) program or active control of ordinary computer games for 60 hours over 12 weeks. Training was remotely-supervised and delivered through a study-provided laptop computer. A computer generated, blocked stratification table prepared by statistician provided the randomization schedule and condition was assigned by a study technician. The primary outcome, administered by study psychometrician, was measured by change in a neuropsychological composite measure from baseline to study end. An intent-to-treat analysis was employed and missing primary outcome values were imputed via Markov Chain Monte Carlo method. Participants in the ACR (n = 74) vs. active control (n = 61) training program had significantly greater improvement in the primary outcome of cognitive functioning (mean change in composite z score±SD: 0·25±0·45 vs. 0·09±0·37, p = 0·03, estimated difference = 0·16 with 95% CI: 0·02-0·30), despite greater training time in the active control condition (mean±SD:56·9 ± 34·6 vs. 37·7 ±23 ·8 hours played, p = 0·006). This study provides Class I evidence that adaptive, computer-based cognitive remediation accessed from home can improve cognitive functioning in MS. This telerehabilitation approach allowed for rapid recruitment and high compliance, and can be readily applied to other neurological conditions associated with cognitive dysfunction. TRIAL REGISTRATION:Clinicaltrials.gov NCT02141386

Remotely-Supervised Transcranial Direct Current Stimulation (tDCS) for Clinical Trials: Guidelines for Technology and Protocols

The effect of transcranial direct current stimulation (tDCS) is cumulative. Treatment protocols typically require multiple consecutive sessions spanning weeks or months. However, traveling to clinic for a tDCS session can present an obstacle to subjects and their caregivers. With modified devices and headgear, tDCS treatment can be administered remotely under clinical supervision, potentially enhancing recruitment, throughput, and convenience. Here we propose standards and protocols for clinical trials utilizing remotely-supervised tDCS with the goal of providing safe, reproducible and well-tolerated stimulation therapy outside of the clinic. The recommendations include: 1) training of staff in tDCS treatment and supervision, 2) assessment of the user’s capability to participate in tDCS remotely, 3) ongoing training procedures and materials including assessments of the user and/or caregiver, 4) simple and fail-safe electrode preparation techniques and tDCS headgear, 5) strict dose control for each session, 6) ongoing monitoring to quantify compliance (device preparation, electrode saturation/placement, stimulation protocol), with corresponding corrective steps as required, 7) monitoring for treatment-emergent adverse effects, 8) guidelines for discontinuation of a session and/or study participation including emergency failsafe procedures tailored to the treatment population’s level of need. These guidelines are intended to provide a minimal level of methodological rigor for clinical trials seeking to apply tDCS outside a specialized treatment center. We outline indication-specific applications (Attention Deficit Hyperactivity Disorder, Depression, Multiple Sclerosis, Palliative Care) following these recommendations that support a standardized framework for evaluating the tolerability and reproducibility of remote-supervised tDCS that, once established, will allow for translation of tDCS clinical trials to a greater size and range of patient populations

Composite score differences between conditions.

<p>Composite score differences between conditions.</p

Total time spent in program by condition.

<p>*Greater time was spent in program by the active control condition (p = 0.006).</p