Individual and Joint Effects of Influenza-Like Illness and Vaccinations on Stroke in the Young: A Case-Control Study.

BACKGROUND: Influenza-like illness (ILI) is an acute trigger for stroke, although joint effects of vaccinations and ILI have not yet been explored. METHODS: Data for our case-control study was obtained from MarketScan Commercial Claims and Encounters between 2008 and 2014. Patients 18 to 65 years old who experienced a stroke were matched on age and admission date to a control, defined as patients with head trauma or ankle sprain at an inpatient or emergency department visit. Exposures were ILI in the prior 30 days, and any type of vaccination during the year prior. Our outcome was ischemic and intracerebral hemorrhagic strokes identified using International Classification of Diseases, Ninth Revision (ICD-9) codes. Logistic regression models estimated adjusted odds ratios (aORs) controlling for preventive care visits, diabetes, valvular heart disease, smoking, alcohol abuse, obesity, and hypertension. RESULTS: We identified and matched 24 103 cases 18 to 44 years old and 141 811 45 to 65 years old. Those aged 18 to 44 years had increased stroke risk 30 days after ILI (aOR, 1.68 [95% CI, 1.51-1.86]) and reduced risk with any vaccination in the year prior (aOR, 0.92 [95% CI, 0.87-0.99]). Joint effects indicate that ILI was associated with increased stroke risk among those with (aOR, 1.41 [95% CI, 1.08-1.85]) and without (aOR, 1.73 [95% CI, 1.55-1.94]) vaccinations in the prior year (Pinteraction=0.16). Among those aged 45 to 65 years, adjusted analyses indicate increased stroke risk for those with ILI (aOR, 1.32 [95% CI, 1.26-1.38]), although there was no effect of vaccinations (aOR, 1.00 [95% CI, 0.97-1.02]). Joint effects indicate that ILI was not associated with stroke among those with any vaccination (aOR, 1.07 [95% CI, 0.96-1.18]) but was associated with increased risk among those without vaccinations ([aOR, 1.39 [95% CI, 1.32-1.47]; Pinteraction<0.001). CONCLUSIONS: ILI was associated with increased stroke risk in the young and middle-aged, while vaccinations of any type were associated with decreased risk among the young. Joint effects of ILI and vaccinations indicate vaccinations can reduce the effect of ILI on stroke.

Differences in healthcare visit frequency and type one year prior to stroke among young versus middle-aged adults.

BACKGROUND: The incidence and prevalence of stroke among the young are increasing in the US. Data on healthcare utilization prior to stroke is limited. We hypothesized those < 45 years were less likely than those 45-65 years old to utilize healthcare in the 1 year prior to stroke. METHODS: Patients 18-65 years old who had a stroke between 2008 and 2013 in MarketScan Commercial Claims and Encounters Databases were included. We used descriptive statistics and logistic regression to examine healthcare utilization and risk factors between age groups 18-44 and 45-65 years. Healthcare utilization was categorized by visit type (no visits, inpatient visits only, emergency department visits only, outpatient patient visits only, or a combination of inpatient, outpatient or emergency department visits) during the year prior to stroke hospitalization. RESULTS: Of those 18-44 years old, 14.1% had no visits in the year prior to stroke compared to 11.2% of individuals aged 45-65 [OR = 1.30 (95% CI 1.25,1.35)]. Patients 18-44 years old had higher odds of having preventive care procedures associated with an outpatient visit and lower odds of having cardiovascular procedures compared to patients aged 45-65 years. Of stroke patients aged 18-45 and 45-65 years, 16.8 and 13.2% respectively had no known risk for stroke. CONCLUSIONS: Patients aged 45-65 were less commonly seeking preventive care and appeared to be seeking care to manage existing conditions more than patients aged 18-44 years. However, as greater than 10% of both age groups had no prior risk, further exploration of potential risk factors is needed.

Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis.

BACKGROUND: Strategies for sequencing disease modifying therapies (DMTs) in multiple sclerosis (MS) patients include escalation, high efficacy early, induction, and de-escalation. OBJECTIVE: To provide a perspective on de-escalation, which aims to match the ratio of DMT benefit/risk in aging patients. METHODS: We reanalyzed data from a retrospective, real-world cohort of MS patients to model disease activity for oral (dimethyl fumarate and fingolimod) and higher efficacy infusible (natalizumab and rituximab) DMTs by age. For patients with relapsing MS, we conducted a controlled, stratified analysis examining odds of disease activity for oral vs. infusible DMTs in patients <45 or ≥45 years. We reviewed the literature to identify DMT risks and predictors of safe discontinuation. RESULTS: Younger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration. Additionally, we identified factors predictive of disease reactivation including age, clinical stability, and MRI activity. CONCLUSION: In a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks. This cohort helps overcome some limitations of trials where older patients were excluded. To better balance benefits/risks, we propose a DMT de-escalation approach for aging MS patients.

Serious safety events in rituximab-treated multiple sclerosis and related disorders.

INTRODUCTION: Studies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited. METHODS: Rituximab-treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow-up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician-reported and laboratory data were retrospectively collected from electronic medical records. RESULTS: One-thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow-up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person-years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair-bound patients had 8.56-fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY. INTERPRETATION: Rates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B-cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections.

Rituximab versus natalizumab, fingolimod, and dimethyl fumarate in multiple sclerosis treatment.

INTRODUCTION: Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist. METHODS: Clinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator. RESULTS: A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX. INTERPRETATION: RTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort.

Natalizumab versus fingolimod and dimethyl fumarate in multiple sclerosis treatment.

Objective: To compare 2-year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). Methods: Patients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified. Clinician-reported data were retrospectively collected. Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years. Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator. Results: A total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively. Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11-12 years for all groups. At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively. Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41-2.85], P < 0.001) and 2.38 [95% CI: 1.68-3.37], P < 0.001) respectively, for experiencing a new T2 lesion, gadolinium enhancing lesion, and/or clinical relapse. At ≤24 months, 32.6%, 34.3%, and 47.1% discontinued NTZ, FTY, and DMF, respectively. The majority of discontinuations were due to becoming JCV positive(12.6%) for NTZ and due to adverse events for both FTY(17%) and DMF(24.0%). Interpretation: NTZ appears to be more effective and tolerable than FTY and DMF.

Assessing the Clinical Utility of the Question, "Is Your Child/Are You Back to Normal?" in Pediatric Concussion Symptom Resolution.

This study investigates the relationship between the general question, "Is your child/are you back to normal?" and a validated postconcussive symptom scale when assessing symptom resolution following concussion. Children with acute concussion were enrolled during an emergency department visit. Sensitivity and specificity analyses compared the true/false question, "My child is/I am back to normal" at 3 days postinjury with the Concussion Symptom Inventory (CSI; gold standard). A total of 201 participants were enrolled in the study with complete data. The true/false questions of "My child is/I am back to normal" had sensitivities of 78.4% and 59.3% and specificities of 75.0% and 86.4% for caregiver and child responses, respectively, when compared with their corresponding CSI. This study demonstrates that asking a parent or child if the child is back to normal has poor sensitivity and modest specificity in determining if a child's symptoms have resolved within 3 days of sustaining a concussion relative to a standardized symptom scale.