Psychometric Properties of a Core Set of Measures of Balance for People With Cerebellar Ataxia Secondary to Multiple Sclerosis.

OBJECTIVE: To examine the reliability, validity, and interpretability of 4 clinical measures in assessing the severity of balance dysfunction among people with cerebellar ataxia (CA) secondary to multiple sclerosis (MS). DESIGN: Cross-sectional observation study. SETTING: Outpatient clinics. PARTICIPANTS: Consecutive participants with CA secondary to MS (N=60). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Balance was assessed and video recorded using the Berg Balance Scale (BBS), timed Up and Go (TUG) test, posture and gait subcomponent of the International Co-operative Ataxia Rating Scale (ICARS), and gait, stance, and sit subcomponents of the Scale for the Assessment and Rating of Ataxia (SARA). The videos were later used to estimate reliability. The Barthel Index, Expanded Disability Status Scale (EDSS), ICARS, and SARA were assessed, and disease duration was recorded. RESULTS: Reliability was good for all 4 measures (intraclass correlation coefficient range, .95-.99). Internal consistency was moderate to good for all 4 measures (α range, .72-.94), with a moderate to good correlation between the measures of balance (Spearman ρ range, .72-.85) and poor to moderate correlation with disease severity (EDSS), functional independence (Barthel Index), and disease duration (Spearman ρ range, -.37 to .76). Minimal detectable change was derived for the BBS (3), posture and gait subcomponent of the ICARS (2), and gait, stance, and sit subcomponents of the SARA (2). Measures were able to discriminate between assistive walking device users and nonusers. CONCLUSIONS: All 4 measures showed good reliability and acceptable validity; however, because of the item repetition in scoring of the posture and gait subcomponent of the ICARS and moderate construct, criterion, and convergent validity of the TUG, the BBS and gait, stance, and sit subcomponents of the SARA are recommended for balance assessment in clinical practice for people with CA secondary to MS.

Patterns of Utilization and Expenditure Across Multiple Sclerosis Disease-Modifying Therapies: A Retrospective Cohort Study Using Claims Data from a Commercially Insured Population in the United States, 2010-2019.

INTRODUCTION: Comparisons of healthcare utilization and expenditure among multiple sclerosis (MS) disease-modifying therapies (DMTs) are limited. METHODS: In this retrospective cohort study using commercial insurance claims data of a US population (2010-2019), we compared healthcare utilization and costs in MS across different DMTs. We assigned patients to different treatment arms: no DMT (ND), high-efficacy (HE) DMT (alemtuzumab, B cell depletion, cladribine, and natalizumab), and standard-efficacy (SE) DMT (dimethyl fumarate, glatiramer acetate, interferon beta, sphingosine-1-phosphate receptor modulator, and teriflunomide). We obtained healthcare costs and occurrences of healthcare services: outpatient visits, emergency room visits, hospitalizations, MS-related magnetic resonance imaging (MRI). We quantified relapses (based on MS-related hospitalizations, as well as outpatient visits with prescription of high-dose steroids) and medical complexity (based on unique drug classes of prescriptions). We calculated covariate-adjusted incidence rate ratio of healthcare services using negative binomial regression with ND as reference and covariate-adjusted mean cumulative healthcare costs using a generalized linear model with log-link function and gamma distribution. RESULTS: Among the 25,932 patients with MS (mean age 52.8 years, 75.2% women), both HE (mean age 54.0 years, 76.2% women) and SE (mean age 43.9 years, 75.6% women) groups had more non-pharmacy healthcare utilization than ND (mean age 57.6 years, 75.4% women), including overall outpatient doctor visits, neurology visits, and MS-related MRIs as well as relapses and medical complexities. Relative to ND, both HE and SE groups had higher pharmacy costs and overall healthcare costs 12 months after treatment initiation, despite having lower or equivalent non-pharmacy medical costs. In patients on DMT, pharmacy costs accounted for up to 65% of overall healthcare costs with over 85% of pharmacy costs attributable to DMT costs. CONCLUSION: DMT cost is a key driver of the overall healthcare expenditure in MS. Future comparative and cost-effectiveness studies integrating claims and electronic health records data with better balancing of patient characteristics are warranted.

Association of personality traits with physical function, cognition, and mood in multiple sclerosis.

BACKGROUND: Growing literature supports the hypothesis that personality influences health outcomes. Few studies have examined the association between personality traits and key clinical manifestations in persons with multiple sclerosis (pwMS). OBJECTIVE: To investigate whether personality traits are associated with physical function, cognition, and depression in persons with MS. METHODS: In this cross-sectional study, we analyzed data from two cohorts (UPMC, n = 365 and CUIMC, n = 129). Participants completed a personality scale (assessing neuroticism, extraversion, openness, agreeableness, and conscientiousness) and validated surveys measuring physical function, cognition, and depression. Stepwise linear regressions were used to evaluate associations between personality traits and outcome measures. RESULTS: Consistently across cohorts, higher extraversion was associated with better physical function, whereas higher neuroticism was associated with worse depression. In the first cohort, higher extraversion was associated with better cognition, while higher neuroticism was associated with greater risk for memory impairment in the second cohort. Relationships were independent of age and disease duration. CONCLUSION: Findings suggest a potentially protective role of extraversion, and a harmful role of neuroticism, in MS-specific patient-reported clinical outcomes. Increased understanding of the interplay between personality and health outcomes may inform risk models for physical decline, cognitive impairment, and depression in pwMS.

Infection incidence and management in multiple sclerosis patients after initiating disease-modifying therapy.

Disease-modifying therapies for multiple sclerosis (MS) are effective, but frequently cost $70,000+/year and can predispose patients to serious infections. This retrospective cohort analysis (N = 3,204) compared rates of infections over a 24-month period by MS medication route of administration and antimicrobial use. Infection rates were: 38.7% (oral), 37.3% (infused), and 36.8% (injectable). Of those infections, antimicrobials were prescribed in 86.5% (oral), 84.3% (infused), and 85.5% (injectable) cases. We found differences within bacterial and herpes zoster infection rates (and antimicrobial use) among new users by medication route of administration. Our findings suggest that pharmacovigilance may inform the shared-decision processes when choosing MS medications.

Ultrasound measurement of optic nerve sheath diameter pre- and post-lumbar puncture.

BACKGROUND: To test the hypothesis that optic nerve sheath diameter (ONSD) correlates with real-time changes in intracranial pressure, we performed ultrasound measurements of the ONSD in ambulatory patients undergoing elective lumbar puncture (LP). We conducted a prospective cohort study, including adult patients undergoing LP in a non-emergent setting. We measured ONSD perpendicular to the optic nerve at 3 mm behind the globe in both eyes in the traverse and sagittal planes, with the patient supine. The primary outcome was change in ONSD from pre-LP to post-LP. We calculated association of opening and closing LP pressures with changes in the pre- and post-LP ONSD measurements. RESULTS: The mean patient age was 49.0 years (SD = 37-61, range 19-67) with 21 females (72.4%) and 26 (89.7%) white American (not Hispanic or Latino). The average opening pressure and closing pressures were 20.4 cm and 13.5 cm with a difference of 6.9 cm, (95% CI 3.9-10.0 cm). Pressures between the participants with baseline ONSD measurement > 5 mm (average opening pressure = 21.3 cm) to those < 5 mm (20.2 cm) differed by 1.1 cm (95% CI - 5.7 to 8.0). Linear regression revealed no association between the sagittal, transverse, average, and change in ONSD measurements with the observed LP opening pressure, change in LP pressure, or volume of cerebral spinal fluid (CSF) drained. CONCLUSIONS: In this study of ambulatory patients undergoing rapid decreases in ICP via elective LP, we detected no acute changes in ultrasonographic measurement of the ONSD.

Association of social network structure and physical function in patients with multiple sclerosis.

OBJECTIVE: To test the association between physical function and the social environment in multiple sclerosis (MS), we quantified personal social networks. METHODS: In this cross-sectional study, we analyzed data from 2 academic MS centers, with center 1 serving as a discovery group and center 2 as the extension group. We performed a meta-analysis of the centers to extend the analysis. We used responses from a questionnaire to map the structure and health habits of participants' social networks as well as the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) physical function scale (0-100, mean 50 for US general population) as the primary outcome. We applied multivariable models to test the association between network metrics and physical function. RESULTS: The discovery cohort included 263 patients with MS: 81% were women, 96% non-Hispanic European, 78% had relapsing MS, average age was 50 (12.4) years, and mean disease duration was 17 (12.3) years. The extension group included 163 patients, who were younger, more racially diverse, and less physically disabled, and had shorter disease duration. In the meta-analysis, higher network constraint, a measure of tightly bound networks, was associated with worse physical function (ß = -0.163 ± 0.047, p < 0.001), while larger network effective size, a measure of clustered groups in the network, correlated with better physical function (ß = 0.134 ± 0.046, p = 0.003). CONCLUSIONS: Our study highlights personal networks as an important environmental factor associated with physical function in MS. Patients with close-knit networks had worse function than those with more open networks. Longitudinal studies are warranted to evaluate a causal relationship between network structure and physical impairment.

Multiple sclerosis and acute disseminated encephalomyelitis diagnosed in children after long-term follow-up: comparison of presenting features.

The aim of this study was to compare the characteristics of the first demyelinating event between acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS). Children with acute demyelinating disease of the central nervous system and an abnormal brain magnetic resonance image (MRI) were studied. Patients were assigned a final diagnosis after long-term follow-up. Comparisons were made between the MS and ADEM groups. Proposed definitions by the Pediatric MS Study Group were applied to our cohort in retrospect and are discussed. Fifty-two children and adolescents with a documented abnormal brain MRI were identified (24 females, 28 males; mean age 10y 11mo [SD 5y 4mo] range 1y 10mo-19y 7mo). To date, 26 children have been diagnosed with MS, and 24 with ADEM. One child has relapsing neuromyelitis optica and one child has clinically isolated optic neuritis. Follow-up duration was 6 years 8 months in monophasic patients, and 5 years 6 months in relapsing patients. None of the patients with MS had encephalopathy while encephalopathy was present in 42% of patients with ADEM. Cerebrospinal fluid oligoclonal bands, an elevated immunoglobulin and the periventricular perpendicular ovoid lesions correlated with MS outcome. Several clinical characteristics differ between ADEM and MS at first presentation; encephalopathy, when present, strongly suggests the diagnosis of ADEM.

Trends in Prices, Market Share, and Spending on Self-administered Disease-Modifying Therapies for Multiple Sclerosis in Medicare Part D.

IMPORTANCE: Before 2009, only 4 self-administered disease-modifying therapies (DMTs) were approved for the treatment of multiple sclerosis (MS). Since then, 7 new agents have entered the market. OBJECTIVE: To assess trends in prices, market share, and spending on self-administered DMTs for MS in Medicare Part D from 2006 through 2016. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used claims data from 2006 through 2016 from a 5% random sample of Medicare beneficiaries (a mean of 2.8 million Medicare beneficiaries per year). All prescription claims for self-administered DMTs for MS (glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod hydrochloride, teriflunomide, dimethyl fumarate, and peginterferon beta-1a) were extracted throughout the study period. MAIN OUTCOMES AND MEASURES: The main outcomes were the annual cost of treatment with each medication, based on Medicare Part D prescription claims gross costs and US Food and Drug Administration-approved recommended dosing; market share of each medication, defined as the proportion of pharmaceutical spending accounted by every drug; and pharmaceutical spending per 1000 Medicare beneficiaries for all drugs. The relative contributions of Medicare Part D Plans' payments, Medicare catastrophic coverage payments, low-income cost-sharing subsidies, patients' out-of-pocket costs, manufacturers' coverage gap discounts, and other payments toward pharmaceutical spending were further quantified. RESULTS: Annual costs of treatment with self-administered DMTs for MS more than quadrupled from 2006 to 2016, from a mean (SD) of $18 660 ($1177) to $75 847 ($16 956) and at a mean rate of 12.8% every year. Brand-name glatiramers accounted for the largest market share across the study period, ranging between $25 552 of $79 411 per 1000 Medicare beneficiaries (32.2%) and $10 342 of $21 365 per 1000 Medicare beneficiaries (48.4%). Platform therapies experienced a substantial drop from 2006 to 2016 in favor of newer therapies, with decreases in the market shares of brand-name glatiramers (per 1000 Medicare beneficiaries: $2861 of $7794 [36.7%] to $25 552 of $79 411 [32.2%]), interferon beta-1a (30 µg; per 1000 Medicare beneficiaries: $2521 of $7794 [32.3%] to $11 298 of $79 411 [14.2%]), interferon beta-1b (Betaseron; per 1000 Medicare beneficiaries: $1460 of $7794 [18.7%] to $3588 of $79 411 [4.5%]), and interferon beta-1a (8.8/22/44 µg; per 1000 Medicare beneficiaries: $951 of $7794 [12.2%] to $6588 of $79 411 [8.3%]) and increases in fingolimod (to $6311 of $79 411 per 1000 Medicare beneficiaries [7.9%]), teriflunomide (to $7177 of $79 411 per 1000 Medicare beneficiaries [9.0%]), and dimethyl fumarate (to $15 262 of $79 411 per 1000 Medicare beneficiaries [19.2%]). Throughout the study period, pharmaceutical spending per 1000 beneficiaries increased 10.2-fold (from $7794 to $79 411), and out-of-pocket patient spending per 1000 beneficiaries increased 7.2-fold (from $372 to $2673). The relative contribution of federal payments toward pharmaceutical spending increased from $5335 of $7794 (68.5%) to $58 620 to $79 411 (73.8%). CONCLUSIONS AND RELEVANCE: Per this analysis, prices of self-administered DMTs for MS increased dramatically between 2006 and 2016. This resulted in a 7.2-fold increase in patient out-of-pocket costs.

Relationship between subjective visual vertical and balance in individuals with multiple sclerosis.

BACKGROUND: Subjective visual vertical (SVV) deviations have been correlated to abnormal cerebellar function in individuals diagnosed with multiple sclerosis (MS). It has been shown that individuals with MS have increased incidence of SVV abnormalities, yet this is not routinely tested in this population during physical therapy evaluation. OBJECTIVE: This study aims to determine if there is a relationship between SVV and balance performance in people with MS who have cerebellar involvement. We hypothesize that individuals with greater SVV deviations will have worse balance performance. METHODS: Fifteen females and five males (mean age 54.5 years [±7.03 SD]) with the diagnosis of MS and cerebellar involvement participated. Computerized SVV testing included rod and rod-and-frame conditions. None of the balance outcomes were correlated with the rod-only condition. Because there was a difference in magnitude of results within the rod-and-frame condition, based on whether the frame was rotated clockwise (CW) or counterclockwise (CCW), they were analysed independently. RESULTS: For all six of the balance outcomes, there was a statistically significant moderate correlation with SVV deviations when the frame was tilted CCW: Barthel Index (r = -0.47, p = 0.018), Berg Balance Score (r = -0.59, p = 0.003), gait velocity (r = -0.52, p = 0.010), International Cooperative Ataxia Rating Scale (r = 0.56, p = 0.006), Scale for the Assessment and Rating of Ataxia (r = 0.62, p = 0.002), and Timed Up and Go (r = 0.58, p = 0.003). Interestingly, the Barthel Index was the only outcome that had statistical significance with a moderate correlation (r = -0.66, p = 0.001) when the frame was rotated CW. In this cohort, greater deviations during the rod-and-frame condition of SVV testing correlated with worse functional outcomes, especially when the frame was tilted CCW. CONCLUSION: Individuals with MS who demonstrate decreased balance performance may rely more heavily on visual backgrounds. Implementation of SVV assessment for individuals with MS may provide clinicians with valuable information to identify clinical interventions.

Adding to the burden: gastrointestinal symptoms and syndromes in multiple sclerosis.

Background. Multiple sclerosis (MS) patients often suffer from gastrointestinal (GI) symptoms. However, the full extent and prevalence of such symptoms are not clearly established. Thus, we sought to define the prevalence of GI symptoms and syndromes in those with MS. Methods. 218 MS patients completed self-reported demographic and clinical data questionnaires as well as several standardized surveys probing MS severity and GI health. Results. Nearly two thirds (65.6%) of patients endorsed at least one persistent GI symptom. Constipation (36.6%), dysphagia (21.1%), and fecal incontinence (15.1%) were common. Surprisingly, nearly 30% (28.4%) of the patients reported dyspeptic symptoms. Using validated diagnostic algorithms, patients met criteria for functional dysphagia (14.7%), functional dyspepsia (16.5%), functional constipation (31.7%), and IBS (19.3%), among others. Functional dysphagia, functional dyspepsia, and IBS were significantly more common in those with self-identified mood disorders. Conclusions. Constipation, fecal incontinence, and dysphagia are indeed frequent symptoms seen in MS patients. We also noted a ~30% prevalence of dyspepsia in this population. The mechanisms driving this association are not clear and require further study. However, due to this high prevalence, dyspeptic symptoms should be incorporated into the routine assessment of MS patients and, if found, may warrant collaborative referral with a GI specialist.

Multiple sclerosis: pathogenesis and treatment.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. It affects approximately 400,000 people in the United States and onset is usually during young adulthood. There are four clinical forms of MS, of which relapsing remitting type is the most common. As the etiology of MS is unknown, finding a cure will remain challenging. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. These agents for relapsing forms of MS target different parts of the immune system, with the end goal of decreasing and avoiding further inflammation. No agents are FDA approved for the primary progressive version of MS. FDA approved agents include four preparations of interferon ß (Avonex, Rebif, Betaseron and Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri) and fingolimod (Gilenya). There are several drug undergoing phase II and III trials. The heterogeneity of the MS disease process, individual patient response, and medication toxicities continue to challenge the treating physician.

A multimodal approach to managing the symptoms of multiple sclerosis.

Multiple sclerosis (MS) is a disease of the CNS with a challenging clinical course characterized by heterogeneous symptoms related to inflammation and demyelination. Disease-modifying agents (DMAs) are used to treat the related neuronal degradation. Certain symptoms occur regularly, although with variable frequency, regardless of treatment with DMAs. Because there is no cure for MS at this time, symptom management is critically important to quality of life. Symptoms commonly seen are spasticity, fatigue, sexual dysfunction, bladder dysfunction, pain, and cognitive dysfunction. Other symptoms include depression, bowel dysfunction, paroxysmal symptoms, and weakness. The symptom management model that provides optimal results for patients with MS is a multimodal approach using effective communication, patient education, physical modalities and activities, occupational and other therapies, and pharmacologic interventions. Individualizing treatment for each patient involves gaining control of symptoms as early as possible to prevent cycles of symptoms from developing.

Stressful life events precede exacerbations of multiple sclerosis.

OBJECTIVE: We longitudinally monitored life events and health changes in patients with multiple sclerosis (MS) to determine whether stressful events may trigger exacerbation of MS. METHODS: Twenty-three women with MS were followed for 1 year. Each subject completed the Psychiatric Epidemiologic Research Interview on a weekly basis. Further information on potentially stressful events was acquired using the Life Events and Difficulties Schedule. Neurologic symptoms were also monitored on a weekly basis throughout the year. Potential MS exacerbations were confirmed by a neurologist who was blind to the presence and timing of stressors. RESULTS: Eighty-five percent of MS exacerbations were associated with stressful life events in the preceding 6 weeks. Stressful life events occurred an average of 14 days before MS exacerbations, compared with 33 days before a randomly selected control date (p < .0001). Survival analysis confirmed that an increase in frequency of life events was associated with greater likelihood of MS exacerbations (hazard ratio = 13.18, p < .05). CONCLUSIONS: These results are consistent with the hypothesis that stress is a potential trigger of disease activity in patients with relapsing-remitting MS.

2002 Robert Ader New Investigator award. Relationship of cardiovascular reactivity, stressful life events, and multiple sclerosis disease activity.

Previous studies of stress in multiple sclerosis patients have suggested that life events may alter the onset and development of MS. However, results have been inconsistent because of infrequent monitoring and reporting bias. We followed fifty female MS patients for 1 year to determine characteristics of life events associated with MS exacerbations, and examine the influence of cardiovascular activity. Subjects completed weekly life-event checklists. The short- and long-term threat of each event was determined using the Life Events and Difficulties Schedule. Neurologic symptoms were also monitored weekly. MS exacerbations were confirmed by a neurologist blinded to psychosocial events. Cardiovascular reactivity to an acute psychological stressor was determined at study onset, and resting heart rate and blood pressure were monitored monthly. Forty-two percent of life events were associated with exacerbations in the subsequent 6 weeks. Logistic regression confirmed that exacerbations were more likely during at-risk periods following life events and were relatively independent of the threat level and type of stressor. Participants with higher cardiovascular reactivity to acute stress and higher baseline heart rate demonstrated a greater number of exacerbations and proportion of weeks ill. Using multiple regression, we found that disability level, medication usage, cardiovascular reactivity, baseline heart rate, and life event density explained approximately 30% of the variance in the proportion of weeks ill. These results are consistent with the hypothesis that stress is a potential trigger of MS disease activity and suggest that autonomic tone and stress reactivity may play a role in the development of stress-related exacerbations.