An algorithm using clinical data to predict the optimal individual glucocorticoid dosage to treat multiple sclerosis relapses

Background: Glucocorticoid (GC) pulse therapy is used for multiple sclerosis (MS) relapse treatment; however, GC resistance is a common problem. Considering that GC dosing is individual with several response-influencing factors, establishing a predictive model, which supports clinicians to estimate the maximum GC dose above which no additional therapeutic value can be expected presents a huge clinical need. Method: We established two, independent retrospective cohorts of MS patients. The first was an explorative cohort for model generation, while the second was established for its validation. Using the explorative cohort, a multivariate regression analysis with the GC dose used as the dependent variable and serum vitamin D (25D) concentration, sex, age, EDSS, contrast enhancement on cranial magnetic resonance imaging (MRI), immune therapy, and the involvement of the optic nerve as independent variables was established. Results: In the explorative cohort, 113 MS patients were included. 25-hydroxyvitamin D (25D) serum concentration and the presence of optic neuritis were independent predictors of the GC dose needed to treat MS relapses [(25D): −25.95 (95% confidence interval (CI)): −47.40 to −4.49; p = 0.018; optic neuritis: 2040.51 (95% CI: 584.64–3496.36), p = 0.006]. Validation of the multivariate linear regression model was performed within a second cohort. Here, the predicted GC dose did not differ significantly from the dose administered in clinical routine (mean difference: −843.54; 95% CI: −2078.08–391.00; n = 30, p = 0.173). Conclusion: Our model could predict the GC dose given in clinical, routine MS relapse care, above which clinicians estimate no further benefit. Further studies should validate and improve our algorithm to help the implementation of predictive models in GC dosing.

Acute reperfusion therapies for acute ischemic stroke patients with unknown time of symptom onset or in extended time windows: an individualized approach

Recent randomized controlled clinical trials (RCTs) have revolutionized acute ischemic stroke care by extending the use of intravenous thrombolysis and endovascular reperfusion therapies in time windows that have been originally considered futile or even unsafe. Both systemic and endovascular reperfusion therapies have been shown to improve outcome in patients with wake-up strokes or symptom onset beyond 4.5 h for intravenous thrombolysis and beyond 6 h for endovascular treatment; however, they require advanced neuroimaging to select stroke patients safely. Experts have proposed simpler imaging algorithms but high-quality data on safety and efficacy are currently missing. RCTs used diverse imaging and clinical inclusion criteria for patient selection during the dawn of this novel stroke treatment paradigm. After taking into consideration the dismal prognosis of nonrecanalized ischemic stroke patients and the substantial clinical benefit of reperfusion therapies in selected late presenters, we propose rescue reperfusion therapies for acute ischemic stroke patients not fulfilling all clinical and imaging inclusion criteria as an option in a subgroup of patients with clinical and radiological profiles suggesting low risk for complications, notably hemorrhagic transformation as well as local or remote parenchymal hemorrhage. Incorporating new data to treatment algorithms may seem perplexing to stroke physicians, since treatment and imaging capabilities of each stroke center may dictate diverse treatment pathways. This narrative review will summarize current data that will assist clinicians in the selection of those late presenters that will most likely benefit from acute reperfusion therapies. Different treatment algorithms are provided according to available neuroimaging and endovascular treatment capabilities.

Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study

Background and aims: Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard. Methods: In this case–control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART). Results: Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70%) and neurological examination (53/86, 62%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16%) index patients. QST, QSART, and proximal IENFD were of lower impact. Conclusion: We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial

Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing–remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN–alemtuzumab), followed by additional, as-needed, alemtuzumab. Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN–alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN–alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. ClinicalTrials.gov identifiers: NCT00530348; NCT00548405; NCT00930553

Endovascular therapy in patients with large vessel occlusion due to cardioembolism versus large-artery atherosclerosis

Background and aims: To investigate whether stroke aetiology affects outcome in patients with acute ischaemic stroke who undergo endovascular therapy. Methods: We retrospectively analysed patients from the Bernese Stroke Centre Registry (January 2010–September 2018), with acute large vessel occlusion in the anterior circulation due to cardioembolism or large-artery atherosclerosis, treated with endovascular therapy (±intravenous thrombolysis). Results: The study included 850 patients (median age 77.4 years, 49.3% female, 80.1% with cardioembolism). Compared with those with large-artery atherosclerosis, patients with cardioembolism were older, more often female, and more likely to have a history of hypercholesterolaemia, atrial fibrillation, current smoking (each p < 0.0001) and higher median National Institutes of Health Stroke Scale (NIHSS) scores on admission ( p = 0.030). They were more frequently treated with stent retrievers ( p = 0.007), but the median number of stent retriever attempts was lower ( p = 0.016) and fewer had permanent stent placements ( p ⩽ 0.004). Univariable analysis showed that patients with cardioembolism had worse 3-month survival [72.7% versus 84%, odds ratio (OR) = 0.51; p = 0.004] and modified Rankin scale (mRS) score shift ( p = 0.043) and higher rates of post-interventional heart failure (33.5% versus 18.5%, OR = 2.22; p < 0.0001), but better modified thrombolysis in cerebral infarction (mTICI) score shift ( p = 0.025). Excellent (mRS = 0–1) 3-month outcome, successful reperfusion (mTICI = 2b–3), symptomatic intracranial haemorrhage and Updated Charlson Comorbidity Index were similar between groups. Propensity-matched analysis found no statistically significant difference in outcome between stroke aetiology groups. Stroke aetiology was not an independent predictor of favourable mRS score shift, but lower admission NIHSS score, younger age and independence pre-stroke were (each p < 0.0001). Stroke aetiology was not an independent predictor of heart failure, but older age, admission antithrombotics and dependence pre-stroke were (each ⩽0.027). Stroke aetiology was not an independent predictor of favourable mTICI score shift, but application of stent retriever and no permanent intracranial stent placement were (each ⩽0.044). Conclusion: We suggest prospective studies to further elucidate differences in reperfusion and outcome between patients with cardioembolism and large-artery atherosclerosis.

Improved gastrointestinal profile with diroximel fumarate is associated with a positive impact on quality of life compared with dimethyl fumarate: results from the randomized, double-blind, phase III EVOLVE-MS-2 study

Background: Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS). DRF demonstrated significantly improved gastrointestinal (GI) tolerability versus dimethyl fumarate (DMF) with fewer days of Individual Gastrointestinal Symptom and Impact Scale (IGISIS) scores ⩾2, GI adverse events (AEs), and treatment discontinuations due to GI AEs. Our aim was to evaluate the impact of GI tolerability events on quality of life (QoL) for patients with relapsing–remitting MS who received DRF or DMF in EVOLVE-MS-2. Methods: A post hoc analysis was conducted in patients who were enrolled in the randomized, blinded, 5-week, EVOLVE-MS-2 [ClinicalTrials.gov identifier: NCT03093324] study of DRF versus DMF. Patients completed daily IGISIS and Global GISIS (GGISIS) eDiary questionnaires to assess GI symptom intensity and interference with daily activities and work. Results: In total, 504 patients (DRF, n = 253; DMF, n = 251) received study drug and 502 (DRF, n = 253; DMF, n = 249) completed at least one post-baseline questionnaire. With DRF, GI symptoms were less likely to interfere ‘quite a bit’ or ‘extremely’ with regular daily activities [IGISIS: DRF, 9.5% (24/253) versus DMF, 28.9% (72/249)] or work productivity [GGISIS: DRF, 6.1% (10/165) versus DMF, 11.3% (18/159)]. DRF-treated patients had fewer days with ⩾1 h of missed work (DRF, 43 days, n = 20 versus DMF, 88 days, n = 26). DMF-treated patients reported highest GI symptom severity and missed work at week 2–3 shortly after completing the titration period, which coincided with the majority of GI-related treatment discontinuations [58.3% (7/12)]. GI tolerability AEs [DRF, 34.8% (88/253); DMF, 48.2% (121/251)], concomitant symptomatic medication use [DRF, 19.3% (17/88) versus DMF, 30.6% (37/121)], and GI-related discontinuations (DRF, 0.8% versus DMF, 4.8%) were lower with DRF versus DMF. Conclusions: The improved GI tolerability with DRF translated into clinically meaningful benefits to QoL, as patients experienced less impact on daily life and work and required less concomitant symptomatic medication use. Trial registration: [ClinicalTrials.gov identifier: NCT03093324]

Matching comparisons of therapeutic efficacy suggest better clinical outcomes for patients treated with peginterferon beta-1a than with glatiramer acetate

Background: Peginterferon beta-1a and glatiramer acetate (GA) are approved first-line therapies for the treatment of relapsing forms of multiple sclerosis, but their therapeutic efficacy has not been compared directly. Methods: Clinical outcomes at 2 years, including no evidence of disease activity (NEDA), for patients receiving peginterferon beta-1a 125 mcg every 2 weeks (Q2W) or GA 20 mg/ml once daily (QD) were compared by propensity score matching analysis using individual patient data from ADVANCE and CONFIRM phase III clinical trials. In addition, clinical outcomes at 1–3 years for patients receiving peginterferon beta-1a Q2W or GA 40 mg/ml three times a week (TIW) were evaluated using a matching-adjusted comparison analysis of individual patient data from ADVANCE and the ADVANCE extension study, ATTAIN, and aggregate patient data from the phase III GALA and the GALA extension studies. Results: Propensity-score-matched peginterferon beta-1a patients ( n = 336) had a significantly lower annualized relapse rate [ARR (0.204 versus 0.282); rate ratio = 0.724; p = 0.045], a significantly lower probability of 12-week confirmed disability worsening (10.0% versus 14.6%; hazard ratio = 0.625; p = 0.048), and a significantly higher rate of NEDA (20.3% versus 11.5%; p = 0.047) compared with GA 20 mg/ml QD patients after 2 years of treatment. Matching-adjusted peginterferon beta-1a patients (effective n = 276) demonstrated a similar ARR at 1 year (0.278 versus 0.318; p = 0.375) and significantly lower ARR at 2 years (0.0901 versus 0.203; p = 0.032) and 3 years (0.109 versus 0.209; p = 0.047) compared with GA 40 mg/ml TIW patients ( n = 834). Conclusion: Results from separate matching comparisons of phase III clinical trials and extension studies suggest that peginterferon beta-1a 125 mcg Q2W may provide better clinical outcomes than GA (20 mg/ml QD or 40 mg/ml TIW).

Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis

Background: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers. Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous history of optic neuritis (HON). In addition, a subgroup of patients ( n = 38) was studied longitudinally over 2 years. Support vector machine analysis was applied to test a regression model for significant changes. Results: In our cohort, HON patients had a thinner outer plexiform layer (OPL) volume compared to NHON patients ( B = −0.016, SE = 0.006, p = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients ( B = −6.734, SE = 2.514, p = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy ( B = 5.974, SE = 2.420, p = 0.019). sNfL levels were 75.7% accurate at predicting OPL volume in the supervised machine learning. Conclusions: In summary, sNfL levels were a good predictor of future outer retinal thinning in MS. Changes within the neurofilament-rich OPL could be considered as an additional retinal marker linked to MS neurodegeneration.