When to hold and when to fold: Early prediction of nonresponse to transcranial magnetic stimulation in major depressive disorder.

BACKGROUND: Determining when to recommend a change in treatment regimen due to insufficient improvement is a common challenge in therapeutics. METHODS: In a sample of 7215 patients with major depressive disorder treated with transcranial magnetic stimulation (TMS) and with PHQ-9 scores before, during and after the course, 3 groups were identified based on number of acute course sessions: exactly 36 sessions (N = 3591), more than 36 sessions (N = 975), and less than 36 sessions (N = 2649). Two techniques were used to determine thresholds for percentage change in PHQ-9 scores at assessments after 10, 20, and 30 sessions that optimized prediction of endpoint response status: the Youden index and fixing the false positive rate at 10%. Positive and negative predictive values were calculated to assess the accuracy of identifying final nonresponders and responders, respectively. RESULTS: There was greater accuracy in predicting final response than nonresponse, especially in the groups that had at least 36 sessions. Substantial proportions of patients with low levels of early improvement were classified as responders at the end of treatment. LIMITATIONS: The findings should be validated with clinician ratings using a more comprehensive depression severity scale. CONCLUSIONS: Manifesting clinical improvement early in the TMS course is strongly predictive of final status as a responder, while lack of early improvement is a relatively poor indicator of final nonresponse status. The predictive value of lack of early symptomatic improvement is too low to make reliable recommendations regarding changes in treatment regimen.

Dosing transcranial magnetic stimulation in major depressive disorder: Relations between number of treatment sessions and effectiveness in a large patient registry.

BACKGROUND: The number of sessions in an acute TMS course for major depressive disorder (MDD) is greater than in the earlier randomized controlled trials. OBJECTIVE: To compare clinical outcomes in groups that received differing numbers of TMS sessions. METHODS: From a registry sample (N = 13,732), data were extracted for 7215 patients treated for MDD with PHQ-9 assessments before and after their TMS course. Groups were defined by number of acute course treatment sessions: 1-19 (N = 658), 20-29 (N = 616), 30-35 (N = 1375), 36 (N = 3591), 37-41 (N = 626), or >41 (N = 349) and compared in clinical outcomes at endpoint and at fixed intervals (after 10, 20, 30, and 36 sessions). The impact of additional treatments beyond 36 sessions was also examined. RESULTS: Groups that received fewer than 30 sessions had inferior endpoint outcomes than all other groups. PHQ-9 symptom reduction was greatest in the group that ended treatment at 36 sessions. The extended treatment groups (>36 sessions) differed from all other groups by manifesting less antidepressant response early in the course and had a slower but steady rate of improvement over time. Extending treatment beyond 36 sessions was associated with further improvement without evidence of a plateau. CONCLUSIONS: In real-world practice, there are strong relations between the number of TMS sessions in a course and the magnitude of symptom reduction. Courses with less than 30 sessions are associated with diminished benefit. Patients with longer than standard courses typically show less initial improvement and a more gradual trajectory, but meaningful benefit accrues with treatment beyond 36 sessions.

Postapproval Study of a Subcutaneous Implantable Cardioverter-Defibrillator System.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) was developed to avoid complications related to transvenous implantable cardioverter-defibrillator (TV-ICD) leads. Device safety and efficacy were demonstrated previously with atypical clinical patients or limited follow-up. OBJECTIVES: The S-ICD PAS (Subcutaneous Implantable Cardioverter-Defibrillator System Post Approval Study) is a real-world, multicenter, registry of U.S. centers that was designed to assess long-term S-ICD safety and efficacy in a diverse group of patients and implantation centers. METHODS: Patients were enrolled in 86 U.S. centers with standard S-ICD indications and were observed for up to 5 years. Efficacy endpoints were first and final shock efficacy. Safety endpoints were complications directly related to the S-ICD system or implantation procedure. Endpoints were assessed using prespecified performance goals. RESULTS: A total of 1,643 patients were prospectively enrolled, with a median follow-up of 4.2 years. All prespecified safety and efficacy endpoint goals were met. Shock efficacy rates for discrete episodes of ventricular tachycardia or ventricular fibrillation were 98.4%, and they did not differ significantly across follow-up years (P = 0.68). S-ICD-related and electrode-related complication-free rates were 93.4% and 99.3%, respectively. Only 1.6% of patients had their devices replaced by a TV-ICD for a pacing need. Cumulative all-cause mortality was 21.7%. CONCLUSIONS: In the largest prospective study of the S-ICD to date, all study endpoints were met, despite a cohort with more comorbidities than in most previous trials. Complication rates were low and shock efficacy was high. These results demonstrate the 5-year S-ICD safety and efficacy for a large, diverse cohort of S-ICD recipients. (Subcutaneous Implantable Cardioverter-Defibrillator [S-ICD] System Post Approval Study [PAS]; NCT01736618).

Feasibility of redo-TAVI in self-expanding Evolut valves: a CT analysis from the Evolut Low Risk Trial substudy.

BACKGROUND: Transcatheter aortic valve implantation in an existing transcatheter valve (redo-TAVI) pins the index valve leaflets in the open position (neoskirt), which can cause coronary flow compromise and limit access. Whether anatomy may preclude redo-TAVI in self-expanding Evolut valves is unknown. AIMS: We aimed to evaluate the anatomical feasibility of redo-TAVI by simulating implantation of a balloon-expandable SAPIEN 3 (S3) within an Evolut or an Evolut within an Evolut. METHODS: A total of 204 post-TAVI computed tomography (CT) scans from the Evolut Low Risk CT substudy were analysed. Five redo-TAVI positions were evaluated: S3-in-Evolut inflow-to-inflow, S3 outflow at Evolut nodes 4, 5, and 6, and Evolut-in-Evolut inflow-to-inflow. Univariable modelling identified pre-TAVI clinical characteristics, CT anatomical parameters, and procedural variables associated with coronary flow compromise using the neoskirt height and post-TAVI aortic root dimensions. RESULTS: The risk of coronary flow compromise was lowest when the S3 outflow was at Evolut node 4 (20%) and highest when at Evolut node 6 (75%). The highest likelihood of preserving coronary accessibility occurred with the S3 outflow at Evolut node 4. Female sex and higher body mass index were associated with a higher risk of coronary flow compromise, as were a smaller annulus diameter, lower sinus of Valsalva height and width, shorter coronary height, smaller sinotubular junction diameter, and shallower Evolut implant depth. CONCLUSIONS: The feasibility of redo-TAVI after Evolut failure is multifactorial and relates to the native annular anatomy, as well as the implantation depth of the index and second bioprostheses. Placement of an S3 at a lower Evolut position may reduce the risk of coronary flow compromise while preserving coronary access. CLINICALTRIALS: gov: NCT02701283.

Clinical outcomes of patients with multiple sclerosis treated with ocrelizumab in a US community MS center: an observational study.

BACKGROUND: To monitor long-term outcomes of ocrelizumab treatment. OBJECTIVE: To evaluate safety and treatment outcomes of ocrelizumab in a community-based multiple sclerosis (MS) population. METHODS: Adult patients with MS prescribed ocrelizumab were eligible. Chart reviews were conducted at the start of ocrelizumab treatment and every 6 months thereafter. RESULTS: Of the 355 patients enrolled, 71.9% were female; mean (SD) age was 51.8 (12.5) years; 78.3% had relapsing MS (RMS). Median baseline Expanded Disability Status Scale (EDSS) (IQR) was 3.0 (2.0-4.0) for RMS, 6.5 (6.0-7.5) for secondary progressive MS, and 6.5 (6.0-7.0) for primary progressive MS. Respiratory infections occurred in 40.1% and urinary tract infections in 33.1% of patients. There was no difference in the percentage of infections among patients <55 (68.5%, n=122), and those ≥55 of age (67.5%, n=104) (p=0.94). Twenty-five hospitalisations were due to infections; 69.2% of these patients were ≥55 with a mean EDSS of 5.7 (±1.86). Four patients have died. Serum IgM and IgG levels did not predict infection risk. Annualised relapse rate was 0.34 for the patients with RMS in the preceding 2 years and 0.09 in patients who received ≥2 ocrelizumab 600 mg courses. The first on-treatment MRI was stable in 262 (90.0%) patients, 6.9% had new T2 lesions, 2.7% had enlarging T2 lesions and 1.4% had gadolinium-enhancing lesions. Median EDSS at 12 months was unchanged. CONCLUSION: Ocrelizumab effectively controlled relapse risk and disability worsening. Although only 12.1% of patients have discontinued ocrelizumab, infections resulting in hospitalisation are a concern, especially in older and disabled patients.

Healthcare utilization and cost outcomes for a multicenter first seizure and new onset epilepsy clinic.

RATIONALE: A First Seizure/New Onset Epilepsy (FS/NOE) protocol was implemented to ensure proper evaluation by an epileptologist and improve overall care for patients. We compared healthcare utilization and cost incurred by patients pre and post protocol implementation. METHODS: Clinical data were retrospectively collected from the EMR and cost data from the financial database. Patients were identified by FS event and grouped into either the pre-implementation (pre-FSC) or post-implementation cohort (post-FSC). Pre-FSC patients were seen between January 2014-December 2015 and post-FSC between March 2016-January 2018. Utilization outcomes include time from FS to neurology appointment, MRI, and electroencephalogram (EEG). Cost outcomes included the annualized median difference in pre versus post costs for ER, inpatient, outpatient or ambulatory, and total hospital services. Cost and utilization outcomes were collected within 90 days or 6 months post first-seizure event. Pre and post cohorts were compared using Kaplan-Meier analysis and Cox proportional hazard models for time-to-event outcomes, multivariable median regression models for cost differences and negative binomial regression models for utilization analyses. Models were adjusted for age, sex, health insurance, and comorbidities. RESULTS: One-hundred and fifty six patients were included with 84 (53.8%) pre- and 72 (46.2%) post-FSC patients. Kaplan-Meier and Cox regression results indicated post-FSC patients had significantly faster time-to-first neurology appointment (5.0 vs. 20.9 days, p < .001; Adjusted Hazard Ratio (HR) = 5.98, p < .001), time-to-MRI (9.0 vs. 27.0 days; p = 0.005; HR = 1.88, p = .021) and EEG (3.6 vs. 48.6 days, p < .001; HR = 9.01, p < .001). A total of 138 patients had at least one cost in the financial database. For 6-month follow-up period, post-FSC patients had higher adjusted all-cause total median costs (+$830, p = 0.009) and outpatient costs (+$1203, p < .001) but lower ED costs (-245, p = 0.073), not significant. Results were similar for seizure-related costs. Similarly, Post-FSC patients had a significantly higher likelihood of all-cause (Adjusted Rate Ratio (ARR) = 1.41, p = .029) and outpatient utilization (ARR = 1.72, p = .008) but lower ED utilization (ARR = 0.54, p < .001). CONCLUSIONS: Implementation of the FSC decreased time to evaluation by a neurologist and time to diagnostic workup. Ultimately, total healthcare costs and ambulatory costs increased but ED costs and utilization were reduced. It is our hypothesis that faster access to initial care and diagnosis would result in better control of seizures and reduce long-term costs and utilization. Further research over a longer duration of time across a broader population is needed to evaluate the full implications of an epilepsy specialist-populated FSC.

Quality of life among injectable and oral disease-modifying therapy users in the Pacific Northwest Multiple Sclerosis Registry.

BACKGROUND: Nine oral disease-modifying therapies (DMTs) have been approved for the treatment of multiple sclerosis (MS) in the United States. Few studies have examined self-reported quality of life (QoL) and functional status outcomes among patients who switch to oral medications from injectable MS therapies. This study compares self-reported QoL and disability status between participants switching from injectable to oral DMTs, to those who stay on injectable DMTs continuously for the same time period. METHODS: Longitudinal data were assessed from relapsing MS participants in the Pacific Northwest MS Registry completing a minimum of two surveys between 2012 and 2018 with a maximum of 36 months between surveys. Stayers were defined as those who remained on injectable DMTs continuously from Time 1 to Time 2; switchers were those who switched from injectable to either fingolimod, teriflunomide or dimethyl fumarate during the same time interval. Outcomes of interest were physical and psychological QoL, measured by the Multiple Sclerosis Impact Scale (MSIS-29), and disability, measured by the Patient Determined Disease Steps (PDDS). To analyze the effect of switching to oral DMT on outcomes at Time 2, a one-to-two propensity score matching (PSM) was used to match switchers to stayers. Outcomes at Time 2 were analyzed using paired t-test for QoL scores, and Stuart Maxwell test for PDDS as a categorical variable. RESULTS: Among 2385 participants who returned consecutive yearly surveys, 413 met the inclusion criteria for stayers and 66 for switchers. After one-to-two PSM, 124 stayers were matched to 62 switchers. Paired t-test showed no differences between switchers and stayers for physical (mean difference: - 0.41; [95% confidence interval CI: - 3.3-2.4]; p = 0.78) or psychological (mean difference: - 0.23; [95% CI, - 1.6- 1.1]; p = 0.74) QoL. Additionally, no differences were seen between switchers and stayers in self-reported disability status. CONCLUSIONS: MS registry participants who switched to an oral DMT from injectable showed no significant differences in QoL or self-reported disability status compared to those remaining on injectable DMT continuously in the same time period.

Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy.

BACKGROUND: Natalizumab is an effective treatment for relapsing multiple sclerosis. Return of disease activity upon natalizumab discontinuance creates the need for follow-up therapeutic strategies. OBJECTIVE: To assess the efficacy of teriflunomide following natalizumab discontinuance in relapsing multiple sclerosis patients. METHODS: Clinically stable relapsing multiple sclerosis patients completing 12 or more consecutive months of natalizumab, testing positive for anti-John Cunningham virus antibody, started teriflunomide 14 mg/day, 28 ± 7 days after their final natalizumab infusion. Physical examination, Expanded Disability Status Scale, laboratory assessments, and brain magnetic resonance imaging were performed at screening and multiple follow-up visits. RESULTS: Fifty-five patients were enrolled in the study. The proportion of patients relapse-free was 0.94, restricted mean time to first gadolinium-enhancing lesion was 10.9 months and time to 3-month sustained disability worsening was 11.8 months. The mean number of new or enlarging T2 lesions per patient at 12 months was 0.42. Exploratory analyses revealed an annualized relapse rate of 0.08, and a proportion of patients with no evidence of disease activity of 0.68. Forty-seven patients (85.5%) reported adverse events, 95% of which were mild to moderate. CONCLUSIONS: Teriflunomide therapy initiated without natalizumab washout resulted in a low rate of return of disease activity. Clinicians may consider this a worthwhile strategy when transitioning clinically stable patients off natalizumab to another therapy.ClinicalTrials.gov Identifier: NCT01970410.

Three-year clinical outcomes of relapsing multiple sclerosis patients treated with dimethyl fumarate in a United States community health center.

BACKGROUND: Following approval of dimethyl fumarate (DMF), we established a registry of relapsing multiple sclerosis (RMS) patients taking DMF at our community MS center. OBJECTIVE: To track DMF patients' tolerability, disease progression, and lymphopenia. METHODS: Patients prescribed DMF for RMS from March 2013 to March 2016 were prospectively enrolled ( N = 412). Baseline data, clinical relapses, magnetic resonance imaging (MRI) activity, discontinuation, and lymphocyte counts were captured through chart review. RESULTS: The mean age of patients starting DMF was 49.4 ± 12.0 years and 70% transitioned from a previous disease-modifying therapy (DMT). Of the patients, 38% discontinued DMF, 76% of whom discontinued due to side effects. Clinical relapse and MRI activity were low. Comparing patients who transitioned from interferon-ß (IFN), glatiramer acetate (GA), or natalizumab (NTZ), patients previously on NTZ had higher rates of relapse than those previously on GA (annualized relapse rate p = 0.039, percent relapse p = 0.021). Grade III lymphopenia developed in 11% of patients. Lymphopenia was associated with older age ( p < 0.001) and longer disease duration ( p < 0.001). CONCLUSION: Given the high rates of lymphopenia and discontinuation, it has become our clinical practice to more closely scrutinize older patients and those with a longer disease duration who are potential candidates for initiating DMF therapy.

Telehealth Stroke Dysphagia Evaluation Is Safe and Effective.

BACKGROUND: Rapid evaluation of dysphagia poststroke significantly lowers rates of aspiration pneumonia. Logistical barriers often significantly delay in-person dysphagia evaluation by speech language pathologists (SLPs) in remote and rural hospitals. Clinical swallow evaluations delivered via telehealth have been validated in a number of clinical contexts, yet no one has specifically validated a teleswallow evaluation for in-hospital post-stroke dysphagia assessment. METHODS: A team of 6 SLPs experienced in stroke care and a telestroke neurologist designed, implemented, and tested a teleswallow evaluation for acute stroke patients, in which 100 patients across 2 affiliated, urban certified stroke centers were sequentially evaluated by a bedside and telehealth SLP. Inter-rater reliability was analyzed using percent agreement, Cohen's kappa, Kendall's tau-b, and Wilcoxon matched-pairs signed rank tests. Logistic regression models accounting for age and gender were used to test the impact of stroke severity and stroke location on agreement. RESULTS: We found excellent agreement for both liquid (91% agreement; kappa = 0.808; Kendall's tau-b = 0.813, p < 0.001; Wilcoxon signed rank = -0.818, p = 0.417) and solid (87% agreement; kappa = 0.792; Kendall's tau-b = 0.844, p < 0.001; Wilcoxon signed rank = 0.243, p = 0.808) dietary textures. From regression modeling, there is suggestive but inconclusive evidence that higher National Institute of Health Stroke Scale (NIHSS) scores correlate with lower levels of agreement for liquid diet recommendations (OR [95% CI] 0.895 [0.793-1.01]; p = 0.07). There was no impact of NIHSS score for solid diet recommendations and no impact of stroke location on solid or liquid diet recommendations. Qualitatively, we identified professional, logistical, technical, and patient barriers to implementation, many of which resolved with experience over time. CONCLUSIONS: Dysphagia evaluation by a remote SLP via telehealth is safe and effective following stroke. We plan to implement teleswallow across our multistate telestroke network as standard practice for poststroke dysphagia evaluation.

Patients with Low National Institutes of Health Stroke Scale Scores Have Longer Door-to-Needle Times: Analysis of a Telestroke Network.

BACKGROUND: The benefits of intravenous tissue-type plasminogen activator (IV-tPA) in acute ischemic stroke (AIS) are time dependent. Because emergency rooms quickly initiate a stroke alert with more severe symptoms, we hypothesized that patients with lower National Institutes of Health Stroke Scale (NIHSS) scores, indicating a less severe stroke, would have longer door-to-needle (DTN) times compared to patients with higher NIHSS scores. METHODS: Data obtained from the 19-hospital Providence Stroke Registry were used to identify AIS patients who received IV-tPA within 4.5 hours of last-known-well. NIHSS scores were obtained prior to tPA administration at the time of emergency department presentation and categorized as low-NIHSS (score = 0-5) or high-NIHSS (score = 6-42) strokes. Median DTN times were collected for both groups as the primary outcome variable. Linear mixed-effects regression models were used to assess the effect of NIHSS scores on DTN and its 2 components: door-to-CT (DCT) and CT-to-needle (CTN) times. RESULTS: We identified 692 AIS patients who received IV-tPA within 4.5 hours of last-known-well, with 198 patients presenting with low-NIHSS strokes and 494 patients with high-NIHSS strokes. In multivariable analysis, median DTN time was estimated to be 18% higher for low-NIHSS strokes than high-NIHSS strokes after adjusting for covariates (P < .001). Median DCT times were also higher for low-NIHSS (19 minutes) compared to high-NIHSS (11 minutes) strokes after adjusting for covariates (P < .001), whereas CTN times were unchanged (P = .055). CONCLUSION: In AIS patients receiving IV-tPA in a telestroke network, lower NIHSS scores were associated with longer DTN and DCT times.

Carotid-jugular fistula diagnosed by transesophageal echocardiography.

Arteriovenous fistulas (AVFs) in the neck are rare, and are most frequently caused by internal jugular catheter placement or penetrating trauma. Diagnosis can be missed when pathognomonic physical exam findings are absent, and heart failure can develop late when AVFs go unrepaired. We present what we believe to be the first reported case of common carotid-internal jugular fistula diagnosed during transesophageal echocardiography. Causes, physical exam findings, complications, diagnostic imaging, and treatment are discussed.

Treatment of statin adverse effects with supplemental Coenzyme Q10 and statin drug discontinuation.

Fifty consecutive new cardiology clinic patients who were on statin drug therapy (for an average of 28 months) on their initial visit were evaluated for possible adverse statin effects (myalgia, fatigue, dyspnea, memory loss, and peripheral neuropathy). All patients discontinued statin therapy due to side effects and began supplemental CoQ(10) at an average of 240 mg/day upon initial visit. Patients have been followed for an average of 22 months with 84% of the patients followed now for more than 12 months. The prevalence of patient symptoms on initial visit and on most recent follow-up demonstrated a decrease in fatigue from 84% to 16%, myalgia from 64% to 6%, dyspnea from 58% to 12%, memory loss from 8% to 4% and peripheral neuropathy from 10% to 2%. There were two deaths from lung cancer and one death from aortic stenosis with no strokes or myocardial infarctions. Measurements of heart function either improved or remained stable in the majority of patients. We conclude that statin-related side effects, including statin cardiomyopathy, are far more common than previously published and are reversible with the combination of statin discontinuation and supplemental CoQ(10). We saw no adverse consequences from statin discontinuation.