Magnetic Resonance-Guided Focused Ultrasound for Treatment of Essential Tremor: Ventral Intermediate Nucleus Ablation Alone or Additional Posterior Subthalamic Area Lesioning?

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) for treatment of essential tremor (ET) traditionally targets the ventral intermediate (Vim) nucleus. Recent strategies include a secondary lesion to the posterior subthalamic area (PSA). OBJECTIVE: The aim was to compare lesion characteristics, tremor improvement, and adverse events (AE) between patients in whom satisfactory tremor suppression was achieved with lesioning of the Vim alone and patients who required additional lesioning of the PSA. METHODS: Retrospective analysis of data collected from ET patients treated with MRgFUS at St Vincent's Hospital Sydney was performed. Clinical Rating Scale for Tremor (CRST), hand tremor score (HTS), and Quality of Life in Essential Tremor Questionnaire (QUEST) were collected pre- and posttreatment in addition to the prevalence of AEs. The lesion coordinates and overlap with the dentatorubrothalamic tract (DRTT) were evaluated using magnetic resonance imaging. RESULTS: Twenty-one patients were treated in Vim only, and 14 were treated with dual Vim-PSA lesions. Clinical data were available for 29 of the 35 patients (19 single target and 10 dual target). At follow-up (mean: 18.80 months) HTS, CRST, and QUEST in single-target patients improved by 57.97% (P < 0.001), 36.71% (P < 0.001), and 58.26% (P < 0.001), whereas dual-target patients improved by 68.34% (P < 0.001), 35.37% (P < 0.003), and 46.97% (P < 0.005), respectively. The Vim lesion of dual-target patients was further anterior relative to the posterior commissure (PC) (7.84 mm), compared with single-target patients (6.92 mm), with less DRTT involvement (14.85% vs. 23.21%). Dual-target patients exhibited a greater proportion of patients with acute motor AEs (100% vs. 58%); however, motor AE prevalence was similar in both groups at long-term follow-up (33% vs. 38%). CONCLUSION: Posterior placement of lesions targeting the Vim may confer greater tremor suppression. The addition of a PSA lesion, in patients with inadequate tremor control despite Vim lesioning, had a trend toward better long-term tremor suppression; however, this approach was associated with greater prevalence of gait disturbance in the short term.

The effects of hybrid functional electrical stimulation interval training on aerobic fitness and fatigue in people with advanced multiple sclerosis: An exploratory pilot training study.

BACKGROUND: Improving aerobic fitness in people with advanced multiple sclerosis (MS) may reduce fatigue, and lower the risk of cardiovascular disease, as has been found for people with mild to moderate MS. Training targeting aerobic fitness can be challenging due to paresis, access to suitable equipment and fatigue. The aim of this study was to investigate whether people with advanced multiple sclerosis could perform functional electrical stimulation (FES) cycling combined with arm crank interval exercise (hybrid FES interval training) training, and its effects on aerobic fitness and fatigue. METHODS: Hybrid FES interval training was performed 2 d/wk for 12 weeks. Each session consisted of 40 min of continuous FES cycling with arm crank intervals of 30 s work/30 s rest added concurrently for 20 min. The intensity target was a minimum of 60 % of arm crank power and 'hard' measured by rate of perceived exertion (RPE). Attendance, compliance to intensity and time targets, adverse events, and drop outs were measured. Aerobic fitness was assessed by an arm crank maximal test. Fatigue was measured via the Modified Fatigue Impact Scale (MFIS). RESULTS: Seven participants (6 female; age 57.1 ± 7.8y; Expanded Disability Status Scale 7.1 ± 0.8) with advanced MS attended 80 ± 10.4 % of the scheduled exercise sessions and there were no adverse events or drop outs. Average RPE at the end of each training session was 15.1 ± 2.1, representing vigorous intensity exercise. Aerobic fitness did not change pre- to post-intervention (14.2 ± 5.7 to 14.8 ± 6.0 mL/kg/min [p = 0.43]), and resulted in a small effect size (ES) (0.30). The reduction in fatigue during the intervention (31.0 ± 10.4 to 21.7 ± 11.4 [p = 0.10]), resulted in a moderate to large ES (-0.77). CONCLUSION: Hybrid FES interval training could be performed 2 days per week for 12 weeks and represented vigorous intensity exercise, but there was no change in aerobic fitness. The reduction in participants' perceptions of fatigue represented a moderate to large ES, indicating hybrid FES interval training might be suitable for people with advanced MS who need exercise equipment appropriate for their condition. CLINICAL TRIAL REGISTRATION: This study was registered with Australian and New Zealand Clinical Trials Register (U1111-1194-2040).

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation.

Importance: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. Objectives: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. Design, Setting, and Participants: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. Exposures: Dimethyl fumarate, fingolimod, and ocrelizumab. Main Outcomes and Measures: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. Results: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. Conclusion and Relevance: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

Patient experience and satisfaction with symptomatic faecal immunochemical testing: an explanatory sequential mixed-methods evaluation.

BACKGROUND: Recent evidence suggests that faecal immunochemical testing (FIT) can rule out colorectal cancer (CRC) in symptomatic adults. To date, there has been little research exploring experiences of FIT for this population. AIM: To explore patient experience and satisfaction with FIT in an 'early adopter' site in England. DESIGN: Explanatory sequential mixed-methods approach combining mailed quantitative surveys with semi-structured telephone interviews. METHOD: Multivariate logistic regression was used to analyse quantitative data. Thematic analysis was used to assess qualitative transcripts. RESULTS: The survey had 260 responders, and it found that satisfaction with FIT was high (88.7%). Compared with test satisfaction, the proportion of responders satisfied with their GP consultation and how they received their results was lower (74.4% and 76.2%, respectively). Multivariate analysis showed that increased area-level deprivation and not receiving an explanation of the purpose of the test were associated with lower satisfaction with the GP consultation (both P-values <0.05), while increased area-level deprivation and not receiving results from the GP were associated with lower satisfaction with receiving results (both P-values <0.05). Interviews with responders (n = 20) helped explain the quantitative results. They revealed that 'not knowing the purpose of the test' caused 'anxiety' and 'confusion', which led to dissatisfaction. 'Not receiving results from GP' was considered 'unacceptable', as this left patients with a 'niggling doubt' and lack of diagnosis or assurance that they did not have cancer. CONCLUSION: Patient satisfaction with symptomatic FIT is high. Efforts to improve satisfaction should focus on ensuring that patients understand the purpose of the test and always receive their test results.

Progressive loss of hearing and balance in superficial siderosis due to occult spinal dural defects.

PURPOSE: Superficial siderosis, a progressive, debilitating, neurological disease, often presents with bilateral impairment of auditory and vestibular function. We highlight that superficial siderosis is often due to a repairable spinal dural defect of the type that can also cause spontaneous intracranial hypotension. METHODS: Retrospective chart review of five patients presenting with moderate to severe, progressive bilateral sensorineural hearing loss as well as vestibular loss. All patients had developed superficial siderosis from spinal dural defects: three after trauma, one after spinal surgery and one from a thoracic discogenic microspur. RESULTS: The diagnosis was made late in all five patients; despite surgical repair in four, hearing and vestibular loss failed to improve. CONCLUSIONS: In patients presenting with progressive bilateral sensorineural hearing loss, superficial siderosis should be considered as a possible cause. If these patients also have bilateral vestibular loss, cerebellar impairment and anosmia, then the diagnosis is likely and the inevitable disease progress might be halted by finding and repairing the spinal dural defect.

Presumptive isolated neurosarcoidosis involving eloquent structures: An argument for empirical TNF-α inhibition.

There are clinical and radiological phenotypes characteristic of neurosarcoidosis. Histopathologic confirmation is preferred, however, biopsy is associated with a significant risk of morbidity when only eloquent neural structures are involved and where there is no systemic disease. We present a series of patients with isolated neurosarcoidosis and suggest circumstances where an empirical, closely monitored, trial of tumour-necrosis-factor-alpha inhibitor therapy can improve outcome and diagnostic confidence.

Changes in Cancer Screening Rates Following a New Cancer Diagnosis in a Primary Care Patient Panel.

Importance: Although screenings for breast and colorectal cancer are widely recommended, patient screening rates vary greatly and remain below public health targets, and primary care physicians' (PCPs') counseling and referrals play critical roles in patients' use of cancer screenings. Recent adverse events may influence PCPs' decision-making, but it remains unknown whether cancer screening rates of PCPs' patients change after PCPs are exposed to new cancer diagnoses. Objective: To investigate whether PCPs' exposures to patients with new diagnoses of breast or colorectal cancer were associated with changes in screening rates for other patients subsequently visiting the affected PCPs. Design, Setting, and Participants: This cohort study used stacked difference-in-differences analyses of all-payer claims data for New Hampshire and Maine in 2009 to 2015. Participants were PCPs caring for patients. Data analysis was performed from June 2020 to May 2022. Exposures: New diagnosis of a PCP's patient with breast cancer or colorectal cancer. Main Outcomes and Measures: Patients' breast and colorectal cancer screening rates within 1 year of a PCP visit. Results: The sample included 3158 PCPs (1819 male PCPs [57.6%]) caring for 1 920 189 patients (1 073 408 female patients [55.9%]; mean [SD] age, 41.0 [21.9] years) aged 18 to 64 years. During the study period, 898 PCPs had a patient with a new diagnosis of breast cancer and 370 PCPs had a patient with a new diagnosis of colorectal cancer. In the preexposure period, 68 837 female patients (37.3% of those visiting a PCP) underwent breast cancer screening within 1 year of the visit, and 13 137 patients (10.1% of those visiting a PCP) underwent colorectal cancer screening within 1 year of the visit. For both cancer types, after exposure to a new cancer diagnosis, PCPs' cancer screening rates displayed a rapid, sustained increase. Breast cancer screening rates increased by 4.5 percentage points (95% CI, 3.0-6.1 percentage points; P < .001). Colorectal cancer screening rates increased by 1.3 percentage points (95% CI, 0.3-2.2 percentage points; P = .01). Observed breast cancer screening increases were higher for male PCPs than for female PCPs (3.1 percentage points; 95% CI, 0.4-5.8 percentage points; P = .03). Conclusions and Relevance: This study found significant, sustained increases in cancer screening rates for patients visiting PCPs recently exposed to new breast and colorectal cancer diagnoses. These findings suggest that PCPs may update practice patterns on the basis of recent patient diagnoses. Future work should assess whether salient cues to PCPs about patient diagnoses when clinically appropriate can improve screening practices.

New drugs for multiple sclerosis: new treatment algorithms.

PURPOSE OF REVIEW: To discuss recent changes in the multiple sclerosis (MS) treatment algorithm and to present therapies currently in MS clinical trials. RECENT FINDINGS: High efficacy disease modifying therapies are optimally beneficial when used in the early, inflammatory phase of MS. Bruton's tyrosine kinase has emerged as an important therapeutic target for both relapsing and progressive forms of MS. Multiple therapies targeting remyelination failed to provide conclusive evidence of broad therapeutic benefit; however, more targeted approaches offer hope that myelin repair might be achieved resulting in specific clinical improvements. Strategies targeting chronic Epstein-Barr virus infection and dysbiosis of the gut microbiome are the first to link microbial risk factors for MS and therapeutic interventions. SUMMARY: A striking number of diverse treatments under investigation bodes well for development of better and more effective therapies in MS.

Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study.

BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. METHODS: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. RESULTS: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (ß = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (ß = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (ß = - 0.5, 95% CI -0.6 to 0.4) and 18 years (ß = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (ß = -1.0, 95% CI -1.1 to 0.9). DISCUSSION: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.

Brain atrophy and lesion burden are associated with disability progression in a multiple sclerosis real-world dataset using only T2-FLAIR: The NeuroSTREAM MSBase study.

BACKGROUND: Methodological challenges limit the use of brain atrophy and lesion burden measures in the follow-up of multiple sclerosis (MS) patients on clinical routine datasets. OBJECTIVE: To determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. METHODS: A total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. RESULTS: Longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner-related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). CONCLUSIONS: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term.

Clinical Knowledge and Trends in Physicians' Prescribing of Opioids for New Onset Back Pain, 2009-2017.

Importance: Opioid musculoskeletal pain overprescribing was widespread in the mid-2000s. The degree to which prescribing changed as awareness of the danger grew among physicians with different levels of clinical knowledge remains unstudied. Objective: To compare the association of clinical knowledge with opioid prescribing from 2009 to 2011 when prescribing peaked nationally with 2015 to 2017 when guidelines shifted away from opioid prescribing. Design, Setting, and Participants: This cross-sectional study included 10 246 midcareer general internal medicine physicians in the United States who saw patients who were Medicare beneficiaries with Part D enrollment from 2009 to 2017. Main Outcomes and Measures: Any opioid prescription and high dosage or long duration (HDLD) (>7 days or >50 daily morphine milligram equivalents) opioid prescriptions filled within 7 days of applicable visits for new low back pain concerns. Associations between opioid prescribing for new low back pain concerns during outpatient visits and clinical knowledge measured by prior year American Board of Internal Medicine (ABIM) Maintenance of Certification examination performance were estimated using serial cross-sectional logit regressions. Regression covariates included yearly examination quartile (ie, knowledge quartile) interacted with 3-year group dummies (ie, early: 2009-2011; middle: 2012-2014; late: 2015-2017), state and year dummies, physician, practice, patient characteristics, and state opioid regulations. Results: Of the 55 387 low back pain visits included in this study, 37 185 (67.1%) were visits with female patients, 41 978 (75.8%) were with White patients, and the mean (SE) age of patients was 76.2 (<0.01) years. The rate of opioid prescribing was 21.6% (11 978) for any opioid prescription and 17.6% (9759) for HDLD prescriptions. From 2009 to 2011, visits with physicians in the highest and lowest knowledge quartiles had similar adjusted opioid prescribing rates with a 0.5 (95% CI, -1.9 to 3.0) percentage point difference. By 2015 to 2017, visits with physicians in the highest knowledge quartile prescribed opioids less frequently that physicians in the lowest knowledge quartile (4.6 percentage point difference; 95% CI, -7.5 to -1.8 percentage points). Visits in which HDLD opioids were prescribed showed no difference in the early period but showed a difference in the late period when comparing physicians in the highest and lowest knowledge quartiles (early period: difference -0.1; 95% CI, -2.4 to 2.2 percentage points; late period difference: 4.8; 95% CI, -7.4 to -2.1 percentage points). Conclusions and Relevance: In this cross-sectional study, when the standard of care shifted away from routine opioid prescribing, physicians who performed well on an ABIM examination were less likely to prescribe opioids for back pain than physicians who performed less well on the examination.

Multiple sclerosis: structural and functional integrity of the visual system following alemtuzumab therapy.

OBJECTIVE: To investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model. METHODS: We monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints. RESULTS: In patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both p<0.01). Mean Mars letter contrast sensitivity was improved at 24 months vs baseline (p<0.001), and driven by an early improvement, in both patients and HC. CONCLUSION: We found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a 'permissive' local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials.

Coprescription of Opioids With Other Medications and Risk of Opioid Overdose.

Polypharmacy is common among patients taking prescription opioids long-term, and the codispensing of interacting medications may further increase opioid overdose risk. To identify nonopioid medications that may increase opioid overdose risk in this population, we conducted a case-crossover-based screening of electronic claims data from IBM MarketScan and Optum Clinformatics Data Mart spanning 2003 through 2019. Eligible patients were 18 years of age or older and had at least 180 days of continuous enrollment and 90 days of prescription opioid use immediately before an opioid overdose resulting in an emergency room visit or hospitalization. The main analysis quantified the odds ratio (OR) between opioid overdose and each nonopioid medication dispensed in the 90 days immediately before the opioid overdose date after adjustment for prescription opioid dosage and benzodiazepine codispensing. Additional analyses restricted to patients without cancer diagnoses and individuals who used only oxycodone for 90 days immediately before the opioid overdose date. The false discovery rate (FDR) was used to account for multiple testing. We identified 24,866 individuals who experienced opioid overdose. Baclofen (OR 1.56; FDR < 0.01; 95% confidence interval (CI), 1.29 to 1.89), lorazepam (OR 1.53; FDR < 0.01; 95% CI, 1.25 to 1.88), and gabapentin (OR 1.16; FDR = 0.09; 95% CI, 1.04 to 1.28), among other nonopioid medications, were associated with opioid overdose. Similar patterns were observed in noncancer patients and individuals who used only oxycodone. Interventions may focus on prescribing safer alternatives when a potential for interaction exists.

Hospital Responses to Incentives in Episode-Based Payment for Joint Surgery: A Controlled Population-Based Study.

Importance: Medicare's Comprehensive Care for Joint Replacement (CJR) model, initiated in 2016, is a national episode-based payment model for lower-extremity joint replacement (LEJR). Metropolitan statistical areas (MSAs) were randomly assigned to participation. In the third year of the program, Medicare made hospital participation voluntary in half of the MSAs and enabled LEJRs for knees to be performed in the outpatient setting without being subject to episode-based payment. How these changes affected program savings is unclear. Objective: To estimate savings from the CJR program over time and assess how responses by hospitals to changing incentives were associated with those savings. Design, Participants, and Setting: This controlled population-based study used Medicare claims data from January 1, 2014, to December 31, 2019, to analyze the spending for beneficiaries who received LEJR in 171 MSAs randomized to CJR vs typical payment. One-quarter of beneficiaries before and after the April 1, 2016, start date were excluded as a 6-month washout period (January 1 to June 30, 2016) to allow time in the evaluation period for hospitals to respond to the program rules. Main Outcomes and Measures: The main outcomes were episode spending and, starting in year 3 of the program, the hospitals' decision to no longer participate in CJR and perform LEJRs in the outpatient setting. Results: Data from 1 087 177 patients (mean [SD] age, 74.4 [8.4] years; 692 604 women [63.7%]; 980 635 non-Hispanic White patients [90.2%]) were analyzed. Over the first 4 years of CJR, 321 038 LEJR episodes were performed at 702 CJR hospitals, and 456 792 episodes were performed at 826 control hospitals. From the second to the fourth year of the program, savings in CJR vs control MSAs diminished from -$976 per LEJR episode (95% CI, -$1340 to -$612) to -$331 (95% CI, -$792 to $130). In MSAs where hospital participation was made voluntary in the third year, more hospitals in the highest quartile of baseline spending dropped out compared with the lowest quartile (56 of 60 [93.3%] vs 29 of 56 [51.8%]). In MSAs where participation remained mandatory, CJR hospitals shifted fewer knee replacements to the outpatient setting in years 3 to 4 than controls (12 571 of 59 182 [21.2%] vs 21 650 of 68 722 [31.5%] of knee LEJRs). In these mandatory MSAs, 75% of the reduction in savings per episode from years 1 to 2 to years 3 to 4 of the program ($455; 95% CI, $137-$722) was attributable to CJR hospitals' decision on which patients would undergo surgery or whether the surgical procedure would occur in the outpatient setting. Conclusions and Relevance: This controlled population-based study found that savings observed in the second year of CJR largely dissipated by the fourth year owing to a combination of responses among hospitals to changes in the program. These results suggest a need for caution regarding the design of new alternative payment models.

Nerve biopsy: Current indications and decision tools.

After initial investigation of patients presenting with symptoms suggestive of neuropathy, a clinical decision is made for a minority of patients to undergo further assessment with nerve biopsy. Many nerve biopsies do not demonstrate a definitive pathological diagnosis and there is considerable cost and morbidity associated with the procedure. This highlights the need for appropriate selection of patients, nerves and neuropathology techniques. Additionally, concomitant muscle and skin biopsies may improve the diagnostic yield in some cases. Several advances have been made in diagnostics in recent years, particularly in genomics. The indications for nerve biopsy have consequently changed over time. This review explores the current indications for nerve biopsies and some of the issues surrounding its use. Also included are comments on alternative diagnostic modalities that may help to supplant or reduce the use of nerve biopsy as a diagnostic test. These primarily include extraneural biopsy and neuroimaging techniques such as magnetic resonance neurography and nerve ultrasound. Finally, we propose an algorithm to assist in deciding when to perform nerve biopsies.

Interferon-ß Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS.

OBJECTIVE: To investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS. METHODS: One hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography. Twenty-five healthy subjects were also included as normal controls. The rates of global peripapillary retinal nerve fiber layer (pRNFL), temporal RNFL (tRNFL), and ganglion cell inner plexiform layer (GCIPL) thinning were analyzed according to DMT type using a linear mixed-effects model. Optic radiation lesion volume was measured on brain MRI and included as a covariate to minimize the effects of retrograde transsynaptic degeneration. RESULTS: The annual rates of RNFL and GCIPL thinning were higher in patients treated with "platform" therapies (interferon-ß and glatiramer acetate) compared with DMTs of higher clinical efficacy (including fingolimod, dimethyl fumarate, natalizumab, alemtuzumab, rituximab, and ocrelizumab) (difference = -0.22 µm/y, p = 0.02 for pRNFL; difference = -0.34 µm/y, p = 0.009 for tRNFL; and difference = -0.16 µm/y, p = 0.005 for GCIPL). Based on an analysis of individual treatments (interferon-ß, glatiramer acetate, fingolimod, and natalizumab), interferon-ß was associated with inferior RGC preservation, relative to the other drugs. No effect difference was found between glatiramer acetate, fingolimod, and natalizumab. CONCLUSIONS: Progressive loss of RGCs in patients with MS is more pronounced in patients treated with interferon-ß than other DMTs. This finding may have implications for DMT selection in MS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS, treatment with interferon-ß compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss.