The Role of the Neurological Examination in Primary Care Referrals to Neurology.

Low confidence with the neurological examination may contribute to primary care physicians' discomfort with neurology and a low threshold to refer patients. We surveyed primary care physicians in Quebec about their last three referrals to neurology to evaluate what role the neurological examination played in their decision. Twenty-six physicians answered concerning 73 patient referrals. We found that primary care physicians use the neurological examination to reinforce their decision but rarely depend on the findings. Our results suggest that improving history-taking rather than examination skills may have more impact on neurology referrals, influencing quality of referral information above quantity of referrals.

Practice Guidelines for Canadian Neurophysiology Laboratories During the COVID-19 Pandemic.

The COVID-19 pandemic has had a major impact on clinical practice. Safe standards of practice are essential to protect health care workers while still allowing them to provide good care. The Canadian Society of Clinical Neurophysiologists, the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists have combined to review current published literature about safe practices for neurophysiology laboratories. Herein, we present the results of our review and provide our expert opinion regarding the safe practice of neurophysiology during the COVID-19 pandemic in Canada.

The neurologist's role in disabling multiple sclerosis: A qualitative study of patient and care provider perspectives.

BACKGROUND: Patients with advanced, disabling multiple sclerosis (MS) have few effective treatment options. Little is known about the role that patients and their care providers want their neurologist to fill in this situation. OBJECTIVE: To better understand the role that patients with disabling MS and their care providers want their neurologist to have in their care. METHODS: In this exploratory qualitative study, we conducted semi-structured interviews with 29 participants (19 patients with severe disability due to MS and 10 care providers). Interview transcripts were analyzed using inductive thematic analysis. RESULTS: Participants identified three main roles for their neurologist: a source of hope for therapeutic advances, an educator about the disease and its management, and a source of support. CONCLUSION: Despite sustaining a level of disability that may be refractory to standard medical therapy, patients with disabling MS and care providers continue to value certain roles of their neurologist. The neurologist's role as a source of hope and support in particular has not received enough attention in the literature.

Risk of secondary progressive multiple sclerosis: A longitudinal study.

BACKGROUND: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. OBJECTIVE: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. METHODS: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. RESULTS: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. CONCLUSION: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.

A Diverse Specialty: What Students Teach Us About Neurology and "Neurophobia".

OBJECTIVE: To explore what elective students learn about the specialty of Neurology. METHODS: A prospective qualitative study using pre- and post-elective written questionnaires. RESULTS: Analysis concentrated on three main themes: What did students learn about the specialty of Neurology? What would they change about their experience? Did their opinions change? Major findings were (i) pre- and post-elective the most frequent response for "what is the best thing about Neurology?" was the "process of localization" and (ii) post-elective students were less likely to cite the challenge or problem-solving aspect of Neurology as the best thing while more emphasized the importance of the physical exam and the variety of cases. (iii) Students were most surprised by the scope of neurological practice. (iv) They would diversify the setting of their elective to include less time spent in the emergency room and more time in clinic. (v) The perception of Neurology as a specialty in which patients have a poor prognosis was the opinion that changed the most. CONCLUSIONS: Showcasing the diversity of cases and careers in Neurology may be a useful strategy to increase interest in the specialty and reduce neurophobia. Lectures or small groups early in medical school should concentrate on clear examples of common neurological conditions and emphasize the role of general neurologists and subspecialists involved in patient care. Whenever possible students should rotate through different clinics and not concentrate exclusively on emergency room and in-patient cases.

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.

Quantifying risk of early relapse in patients with first demyelinating events: Prediction in clinical practice.

BACKGROUND: Characteristics at clinically isolated syndrome (CIS) examination assist in identification of patient at highest risk of early second attack and could benefit the most from early disease-modifying drugs (DMDs). OBJECTIVE: To examine determinants of second attack and validate a prognostic nomogram for individualised risk assessment of clinical conversion. METHODS: Patients with CIS were prospectively followed up in the MSBase Incident Study. Predictors of clinical conversion were analysed using Cox proportional hazards regression. Prognostic nomograms were derived to calculate conversion probability and validated using concordance indices. RESULTS: A total of 3296 patients from 50 clinics in 22 countries were followed up for a median (inter-quartile range (IQR)) of 1.92 years (0.90, 3.71). In all, 1953 (59.3%) patients recorded a second attack. Higher Expanded Disability Status Scale (EDSS) at baseline, first symptom location, oligoclonal bands and various brain and spinal magnetic resonance imaging (MRI) metrics were all predictors of conversion. Conversely, older age and DMD exposure post-CIS were associated with reduced rates. Prognostic nomograms demonstrated high concordance between estimated and observed conversion probabilities. CONCLUSION: This multinational study shows that age at CIS onset, DMD exposure, EDSS, multiple brain and spinal MRI criteria and oligoclonal bands are associated with shorter time to relapse. Nomogram assessment may be useful in clinical practice for estimating future clinical conversion.

Contribution of different relapse phenotypes to disability in multiple sclerosis.

OBJECTIVE: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis. METHODS: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted. RESULTS: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (ß = 0.16, p < 0.001). Relapses of all phenotypes promoted disability accumulation, with the most pronounced increase associated with pyramidal (ß = 0.27 (0.25-0.29)), cerebellar (ß = 0.35 (0.30-0.39)) and bowel/bladder (ß = 0.42 (0.35-0.49)) phenotypes (mean (95% confidence interval)). Higher incidence of each relapse phenotype was associated with an increase in disability in the corresponding neurological domain, as well as anatomically related domains. CONCLUSION: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.

Defining secondary progressive multiple sclerosis.

A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

OBJECTIVE: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS). METHODS: MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence. RESULTS: A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation. CONCLUSION: Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications.

The Under-Utilization of the Head Impulse Test in the Emergency Department.

BACKGROUND: The head impulse test (HIT) is an evidenced based clinical tool to differentiate between peripheral and central causes of vertigo. Our objective was to determine the rate of utilization of the HIT in the emergency room (ER). METHODS: A retrospective chart review of patients presenting to the ER over one year who received a final diagnosis of dizziness or vertigo. Details of clinical examinations, investigations, and diagnosis were recorded. Patients were grouped into episodic, acute constant, and chronic vertigo groups. RESULTS: HIT was performed in only 31 of 642 (5%) patients with vertigo. In the acute constant group it was negative in 6 of 6 patients ultimately diagnosed with stroke and positive in 6 of 13 cases of peripheral vertigo. DISCUSSION: Despite good published evidence regarding its use the HIT is under-utilized in the ER. Physicians need to be aware of the HIT and newer video HITs and make use of them in practice.

General Practitioner Preferences in Managing Care of Multiple Sclerosis Patients.

BACKGROUND: Multiple sclerosis (MS) is a lifelong neurological disorder requiring care in a variety of settings. The purpose of this study is to describe preferences of general practitioners (GPs) with regards to providing care for MS patients. METHODS: A stratified sample of 900 GPs in the province of Quebec were sent a questionnaire, with 266 returning completed questionnaires. Respondents were surveyed about their preferences using four clinical scenarios describing hypothetical patients experiencing different stages of MS. Respondents were asked whether they would continue managing the patient themselves, formally refer the patient to a specialist, or seek specialist advice. RESULTS: In two scenarios representing stable courses, 40.9% and 61.6% of GPs, respectively, intended to manage the patient themselves. GPs who reported having experience with MS patients were more likely to report an intention to continue management. In one scenario, GPs operating in rural areas were less likely to consider management than those in the Montreal metropolitan area (odds ratio=0.422, 95% confidence interval 0.20-0.90). CONCLUSIONS: For MS patients with a stable disease course, an important proportion of GPs appear to be willing to manage long-term care for MS patients.

Seasonal variation of relapse rate in multiple sclerosis is latitude dependent.

OBJECTIVE: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude. METHODS: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. RESULTS: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028). INTERPRETATION: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere.

Comparative effectiveness of glatiramer acetate and interferon beta formulations in relapsing-remitting multiple sclerosis.

BACKGROUND: The results of head-to-head comparisons of injectable immunomodulators (interferon ß, glatiramer acetate) have been inconclusive and a comprehensive analysis of their effectiveness is needed. OBJECTIVE: We aimed to compare, in a real-world setting, relapse and disability outcomes among patients with multiple sclerosis (MS) treated with injectable immunomodulators. METHODS: Pairwise analysis of the international MSBase registry data was conducted using propensity-score matching. The four injectable immunomodulators were compared in six head-to-head analyses of relapse and disability outcomes using paired mixed models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity and power analyses were conducted. RESULTS: Of the 3326 included patients, 345-1199 patients per therapy were matched (median pairwise-censored follow-up was 3.7 years). Propensity matching eliminated >95% of the identified indication bias. Slightly lower relapse incidence was found among patients treated with glatiramer acetate or subcutaneous interferon ß-1a relative to intramuscular interferon ß-1a and interferon ß-1b (p≤0.001). No differences in 12-month confirmed progression of disability were observed. CONCLUSION: Small but statistically significant differences in relapse outcomes exist among the injectable immunomodulators. MSBase is sufficiently powered to identify these differences and reflects practice in tertiary MS centres. While the present study controlled indication, selection and attrition bias, centre-dependent variance in data quality was likely.

Two Multiple Sclerosis Quality-of-Life Measures: Comparison in a National Sample.

BACKGROUND: Multiple sclerosis (MS) has a profound impact on patients' health-related quality of life (HRQoL). It is unclear how HRQoL can be best assessed for different purposes. This study aimed to compare two HRQoL questionnaires of differing lengths for feasibility of administration, patient perceptions and psychometric properties. METHODS: This was an open-label, 24-month study in 334 patients with relapsing MS treated with subcutaneous interferon ß-1a. At baseline and months 6, 12, 18 and 24, patients completed the Multiple Sclerosis International Quality of Life (MusiQoL) and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaires and compared them using an evaluation questionnaire. HRQoL scores over time and psychometric properties (correlations with clinical disease measures, relative validity and responsiveness to change) of the questionnaires were assessed. RESULTS: A minority of patients had missing items on either HRQoL measure. Completion time was significantly shorter for MusiQoL versus MSQOL-54 (p<0.0001). Patients felt that MusiQoL was easier to use than MSQOL-54 but preferred MSQOL-54 in terms of thoroughness. Mean HRQoL scores increased significantly from baseline to 24 months; correlations of both measures were stronger with an anxiety and depression measure than with disability or recent relapse occurrence. Relative validity and responsiveness to change were similar for both instruments. CONCLUSION: The shorter MusiQoL is suitable for evaluating HRQoL in patients with MS and may be more practical to administer than the more thorough MSQOL-54.