Developing a Digital Solution for Remote Assessment in Multiple Sclerosis: From Concept to Software as a Medical Device

Validación clínica; Salud digital; Salud participativaValidació clínica; Salut digital; Salut participativaClinical validation; Digital health; Participatory healthThere is increasing interest in the development and deployment of digital solutions to improve patient care and facilitate monitoring in medical practice, e.g., by remote observation of disease symptoms in the patients’ home environment. Digital health solutions today range from non-regulated wellness applications and research-grade exploratory instruments to regulated software as a medical device (SaMD). This paper discusses the considerations and complexities in developing innovative, effective, and validated SaMD for multiple sclerosis (MS). The development of SaMD requires a formalised approach (design control), inclusive of technical verification and analytical validation to ensure reliability. SaMD must be clinically evaluated, characterised for benefit and risk, and must conform to regulatory requirements associated with device classification. Cybersecurity and data privacy are also critical. Careful consideration of patient and provider needs throughout the design and testing process help developers overcome challenges of adoption in medical practice. Here, we explore the development pathway for SaMD in MS, leveraging experiences from the development of Floodlight™ MS, a continually evolving bundled solution of SaMD for remote functional assessment of MS. The development process will be charted while reflecting on common challenges in the digital space, with a view to providing insights for future developers.The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: F. Hoffmann-La Roche Ltd., Basel, Switzerland provided financial support for the publication of this manuscript

Serial Diffusion Tensor Imaging of the Optic Radiations after Acute Optic Neuritis

Previous studies have reported diffusion tensor imaging (DTI) changes within the optic radiations of patients after optic neuritis (ON). We aimed to study optic radiation DTI changes over 12 months following acute ON and to study correlations between DTI parameters and damage to the optic nerve and primary visual cortex (V1). We measured DTI parameters [fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD)] from the optic radiations of 38 acute ON patients at presentation and 6 and 12 months after acute ON. In addition, we measured retinal nerve fibre layer thickness, visual evoked potential amplitude, optic radiation lesion load, and V1 thickness. At baseline, FA was reduced and RD and MD were increased compared to control. Over 12 months, FA reduced in patients at an average rate of −2.6% per annum (control = −0.51%; = 0.006). Change in FA, RD, and MD correlated with V1 thinning over 12 months (FA: = 0.450, = 0.006; RD: = −0.428, = 0.009; MD: = −0.365, = 0.029). In patients with no optic radiation lesions, AD significantly correlated with RNFL thinning at 12 months ( = 0.489, = 0.039). In conclusion, DTI can detect optic radiation changes over 12 months following acute ON that correlate with optic nerve and V1 damage

Multiple Sclerosis Susceptibility-Associated SNPs Do Not Influence Disease Severity Measures in a Cohort of Australian MS Patients

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13–14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity

The OSCAR-MP Consensus Criteria for Quality Assessment of Retinal Optical Coherence Tomography Angiography

BACKGROUND AND OBJECTIVES: Optical coherence tomography angiography (OCTA) is a noninvasive high-resolution imaging technique for assessing the retinal vasculature and is increasingly used in various ophthalmologic, neuro-ophthalmologic, and neurologic diseases. To date, there are no validated consensus criteria for quality control (QC) of OCTA. Our study aimed to develop criteria for OCTA quality assessment. METHODS: To establish criteria through (1) extensive literature review on OCTA artifacts and image quality to generate standardized and easy-to-apply OCTA QC criteria, (2) application of OCTA QC criteria to evaluate interrater agreement, (3) identification of reasons for interrater disagreement, revision of OCTA QC criteria, development of OCTA QC scoring guide and training set, and (4) validation of QC criteria in an international, interdisciplinary multicenter study. RESULTS: We identified 7 major aspects that affect OCTA quality: (O) obvious problems, (S) signal strength, (C) centration, (A) algorithm failure, (R) retinal pathology, (M) motion artifacts, and (P) projection artifacts. Seven independent raters applied the OSCAR-MP criteria to a set of 40 OCTA scans from people with MS, Sjogren syndrome, and uveitis and healthy individuals. The interrater kappa was substantial (κ 0.67). Projection artifacts were the main reason for interrater disagreement. Because artifacts can affect only parts of OCTA images, we agreed that prior definition of a specific region of interest (ROI) is crucial for subsequent OCTA quality assessment. To enhance artifact recognition and interrater agreement on reduced image quality, we designed a scoring guide and OCTA training set. Using these educational tools, 23 raters from 14 different centers reached an almost perfect agreement (κ 0.92) for the rejection of poor-quality OCTA images using the OSCAR-MP criteria. DISCUSSION: We propose a 3-step approach for standardized quality control: (1) To define a specific ROI, (2) to assess the occurrence of OCTA artifacts according to the OSCAR-MP criteria, and (3) to evaluate OCTA quality based on the occurrence of different artifacts within the ROI. OSCAR-MP OCTA QC criteria achieved high interrater agreement in an international multicenter study and is a promising QC protocol for application in the context of future clinical trials and studies

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

To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort

Testing paraclinical outcome markers in optic neuritis and a study of the phenomenology and treatment of tremor in multiple sclerosis

© 2012 Dr. Anneke van der WaltMultiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterised by multi-focal inflammatory demyelinating plaques and significant neuroaxonal degeneration. The clinical presentation and disease course of MS is heterogeneous and ranges from clinically isolated syndromes such as optic neuritis (ON), to disabling progressive disease at which stage tremor can be a feature. This heterogeneity reflects the multi-focal nature of the CNS injuries and suggests that the relationships between neuronal injury and clinical presentations are complex. Focused clinical and paraclinical assessments of defined neural pathways associated with discrete clinical presentations can help improve our understanding of complex clinico-pathological relationships. This thesis examined clinical manifestations and outcomes in two models at the opposite ends of the MS clinical spectrum namely acute isolated ON and MS-related tremor. The aims of section one was to comprehensively study changes in clinical and paraclinical markers after ON and more specifically to evaluate the ability of these markers to serve as predictive biomarkers of clinical and axonal outcomes after ON. The second part of this thesis aimed to perform a detailed clinical phenomenology study in MS tremor patients to help define possible underlying neuroanatomical networks and broaden understanding of injury in secondary progressive MS in general. In addition, the efficacy and safety of onabotulinumtoxin-a in the treatment of MS tremor was evaluated. In Section one, forty patients with acute, idiopathic, unilateral optic neuritis with early MS or at high risk of MS were recruited. Patients were studied prospectively over 12 months at multiple time-points. Ten healthy age and sex-matched controls were tested twice to inspect inter-scan and inter-subject variability. All participants had a detailed neurological assessment, visual acuity testing (high and low-contrast and colour vision), optic nerve diffusion tensor imaging (DTI), multi-focal visual evoked potential (mfVEP), and optical coherence tomography (OCT). The main outcome measures were 2.5% low contrast visual acuity, mfVEP amplitude and retinal nerve fibre layer thickness (RNFL) at 12 months after ON. Significant changes in clinical and paraclinical measures after ON, particularly in the first 3 months were demonstrated. Despite some initial recovery, persistent visual, functional and neuroaxonal deficits persisted at 12 months. Multivariate models identified decreased high contrast visual acuity (logMAR notation) at 1 month after ON to be the earliest predictor of persistent visual loss at 12 months. Decreased 3-month colour vision and RNFL thickness also both significantly predicted poor visual recovery. The earliest predictors of axonal outcomes at 12 months after ON were decreased 1-month mfVEP amplitude, low contrast acuity and optic nerve axial diffusivity. Decreased optic nerve axial diffusivity was the best predictor of severe combined (persistent mfVEP amplitude loss and/or RNFL thinning of greater than 30%) axonal loss. Both mfVEP amplitude and clinical assessments are limited in the hyper- acute setting due to inflammatory oedema, conduction block and variable patient performance. Therefore, the finding of an early structural marker, optic nerve axial diffusivity, that is able to predict axonal outcome after ON is important as this measure could serve as a biomarker in future studies of putative neuroprotective therapies by identifying those patients at most risk of permanent axonal loss. In Section 2 of the thesis, a cross-sectional study of 54 MS patients with and without tremor was undertaken. Of the 27 tremor cases, 25 were included in a double-blind randomized placebo-controlled crossover trial (RCT) to evaluate the efficacy of onabotulinumtoxin-a. A detailed comparison between MS patients with and without tremor was completed. Patients underwent a detailed history and neurological assessment that included the Expanded Disability Severity Scale (EDSS) as well assessments of cerebellar ataxia, dystonia and tremor-related quality of life. All patients were assessed for the presence of tremor and tremor severity was rated using the Bain score, a validated MS tremor severity score to rate tremor severity, writing and drawing an Archimedes spiral. Functional tasks such as writing, drawing, drinking from a cup and pouring water from one cup to another were completed. A blinded, independent observer, rated standardized video assessments. In the RCT, patients were assessed 6 weekly for 6 months with baseline and 3 months injections of either onabotulinumtoxin- a or placebo. MS tremor was found to be predominantly an action tremor of the upper limb with prominent cerebellar and dystonic features. Dystonic features (including geste antagonistes, mirror movements, dystonic posturing and writer’s cramp) were more prominent and more severe in patients with tremor than those without. A further novel finding was the impact of dystonia severity in the affected limb on tremor severity. This result highlights the complexity of MS tremor as a movement disorder with injury that is not localized to the cerebellum alone, but rather to the wider cerebello-thalamo-cortical, pallido-thalamic as well as cortico-cerebellar network. In a RCT of the efficacy of onabotulinumtoxin-a in MS tremor, the drug was found to reduce MS tremor severity by an average of 40%, with writing and drawing severity improving by an average of 30%. Injections were well tolerated with transient focal weakness being the predominant side effect. The efficacy of onabotulinumtoxin-a likely reflects modulation of the central tremor-generating networks by modification of peripheral stretch reflexes and muscle- spindle excitability. In addition, the efficacy of a drug used predominantly for focal dystonia underscores the importance of recognizing dystonia as a feature of MS tremor

The feasibility, reliability and concurrent validity of the MSReactor computerized cognitive screening tool in multiple sclerosis

Background: Multiple sclerosis (MS) cognitive tests are resource intensive and limited by practice effects that prevent frequent retesting. Brief, reliable and valid monitoring tools are urgently needed to detect subtle, subclinical cognitive changes in people with MS. Cognitive monitoring over time could contribute to a new definition of disease progression, supplementing routine clinical monitoring. Methods: MSReactor is a web-based battery that measures psychomotor (processing) speed, visual attention and working memory, using simple reaction time tasks. Clinic-based tasks were completed at baseline and 6 monthly with home testing 1-3 monthly. Acceptability, quality of life, depression and anxiety surveys were completed. We studied its correlation with the Symbol Digit Modalities Test, practice effects, test-retest reliability and the discriminative ability of MSReactor. Results: A total of 450 people with MS were recruited over 18 months, with 81% opting to complete home-based testing. Most participants (96%) would be happy (or neutral) to repeat the tasks again and just four reported the tasks made them 'very anxious'. Persistence of home testing was high and practice effects stabilized within three tests. MSReactor tasks correlated with Symbol Digit Modalities Test scores and participants with MS performed slower than healthy controls. Conclusion: MSReactor is a scalable and reliable cognitive screening tool that can be used in the clinic and remotely. MSReactor task performance correlated with another highly validated cognitive test, was sensitive to MS and baseline predictors of cognitive performance were identified

Quality of stroke care within a hospital: Effects of a mobile stroke service

Objective: An Australian stroke services study (SCOPES) has developed a framework to compare different forms of acute stroke services, the gold standard being localised stroke units. We aimed to use this framework to assess changes in the quality of stroke care over time as a sequential audit process. Design and setting: A retrospective medical record audit comparing 100 sequential stroke admissions (July 2002 to June 2003) two years after institution of a mobile stroke service (MSS) with 100 historical controls (September 1998 to October 1999) at a 260-bed hospital in Melbourne. The MSS results were also compared with stroke units in SCOPES. Main outcome measures: Adherence to quality indicators and standard measures of outcome (complications, length of stay and discharge disability) after implementing the MSS. Results: Significant improvements were seen in prophylaxis for deep-vein thrombosis, incontinence management, premorbid function documentation, frequent neurological observations and early occupational therapy. The MSS demonstrated fewer severe complications (9% versus 24%; P=0.004), reduced median length of stay (discharged patients: 12.0 days versus 18.5 days; P=0.003) and more patients were independent at discharge (32% versus 9%; P<0.001). Comparison with SCOPES stroke units showed our MSS could improve in incontinence management and appropriate use of antiplatelet therapy. Conclusion: Institution of the MSS was associated with improvements in the quality of stroke care. This study demonstrates application of an audit procedure for quality improvement in hospital stroke management and the potential to improve stroke services in smaller centres