Faculty Bibliography
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person:kistei01
Total Results:
290
Protean Neurologic Manifestations of Two Rare Dermatologic Disorders: Sweet Disease and Localized Craniofacial Scleroderma
PURPOSE OF REVIEW/OBJECTIVE:To describe diverse neurologic and neuroradiologic presentations of two rare, immunologically mediated skin conditions: Sweet disease and localized scleroderma (morphea). RECENT FINDINGS/RESULTS:Core syndromes of neuro-Sweet disease (NSD) are steroid responsiveness, recurrent meningitis, and encephalitis. Focal neurologic, neuro-vascular, and neuro-ophthalmologic syndromes have been reported recently in NSD. A variety of steroid-sparing treatments and biologics have been used for relapsing NSD. Localized craniofacial scleroderma is associated with seizures, headaches, and, less commonly, focal deficits and cognitive decline. Immunosuppressive therapy may be required in patients with disease progression; some refractory cases have responded to IL-6 inhibition. Our review provides an up-to-date reference for neurologists faced with a patient with a history or skin findings consistent with Sweet disease or localized scleroderma. We hope that it will stimulate collaborative studies aimed at unraveling the pathogenesis of these disorders, better characterization of their neurologic manifestations, and discovery of optimal therapeutic solutions.
PMID: 30747288
ISSN: 1534-6293
CID: 3656202
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study
BACKGROUND:modulator, on disability progression in patients with SPMS. METHODS:This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3·0-6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. FINDINGS:1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65-0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. INTERPRETATION:Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. FUNDING:Novartis Pharma AG.
PMID: 29576505
ISSN: 1474-547x
CID: 5348122
NATALIZUMAB EXTENDED INTERVAL DOSING (EID) IS ASSOCIATED WITH A SIGNIFICANT REDUCTION IN PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) RISK COMPARED WITH STANDARD INTERVAL DOSING (SID) IN THE TOUCH (R) PRESCRIBING PROGRAM [Meeting Abstract]
ISI:000438056200071
ISSN: 0022-3050
CID: 5191992
Early start of high-efficacy therapies improves disability outcomes over 10 years [Meeting Abstract]
Introduction: The availability of numerous highly efficacious therapies for multiple sclerosis (MS) has ignited debate about whether early aggressive treatment is more favourable than the traditional approach of escalation after failure of first line therapies.
Aim(s): To compare patients' long-term disability outcomes following high efficacy therapy commenced either early or late in their disease course.
Method(s): Data were extracted from MSBase, an international observational MS registry, as well as two local databases (Cambridge and Dublin). We identified patients with relapsing remitting MS who commenced high-efficacy disease modifying therapies (Rituximab, Ocrelizumab, Mitoxantrone, Alemtuzumab, Natalizumab) either 0-2 years (early) or >4 years (late) after clinical disease onset. Indication bias was minimised by propensity score matching on demographic and clinical variables in the first two years of disease. Outcomes were assessed at years 6 to 10 after disease onset. The primary outcome was difference in disability in each year of disease, as measured by the Expanded Disability Status Score (EDSS). Secondary outcomes were cumulative hazard of confirmed disability progression and hazard of treatment discontinuation.
Result(s): There were 170 patients who commenced high-efficacy therapy at 0-2 years (early) and 578 patients who commenced at >4 years (late). During years 0-2, the early group had a higher cumulative hazard of confirmed disability progression; the inverse was true after year 2. For the year 6 outcomes analysis, 117 patients in the early group were propensity score matched to 181 patients in the late group. At baseline, the mean(SD) EDSS was 2.3(1.3) vs 2.3(1.2) in the early vs late groups. At six years, the mean(SD) EDSS was 2.5(1.8) in the early group, compared to 3.4(1.7) in the late group (p< .001). This difference remained clinically (>=.5 EDSS steps) and statistically (p<= .05) significant up to 10 years post disease onset.
Conclusion(s): Patients with MS commencing high-efficacy immunotherapy early after disease onset accumulate less long-term disability compared to those exposed later in their disease. Those treated earlier had a more aggressive disease course initially, which was then mitigated by their early active management strategy. In patients with highly active MS, early high efficacy therapy is recommended
Aim(s): To compare patients' long-term disability outcomes following high efficacy therapy commenced either early or late in their disease course.
Method(s): Data were extracted from MSBase, an international observational MS registry, as well as two local databases (Cambridge and Dublin). We identified patients with relapsing remitting MS who commenced high-efficacy disease modifying therapies (Rituximab, Ocrelizumab, Mitoxantrone, Alemtuzumab, Natalizumab) either 0-2 years (early) or >4 years (late) after clinical disease onset. Indication bias was minimised by propensity score matching on demographic and clinical variables in the first two years of disease. Outcomes were assessed at years 6 to 10 after disease onset. The primary outcome was difference in disability in each year of disease, as measured by the Expanded Disability Status Score (EDSS). Secondary outcomes were cumulative hazard of confirmed disability progression and hazard of treatment discontinuation.
Result(s): There were 170 patients who commenced high-efficacy therapy at 0-2 years (early) and 578 patients who commenced at >4 years (late). During years 0-2, the early group had a higher cumulative hazard of confirmed disability progression; the inverse was true after year 2. For the year 6 outcomes analysis, 117 patients in the early group were propensity score matched to 181 patients in the late group. At baseline, the mean(SD) EDSS was 2.3(1.3) vs 2.3(1.2) in the early vs late groups. At six years, the mean(SD) EDSS was 2.5(1.8) in the early group, compared to 3.4(1.7) in the late group (p< .001). This difference remained clinically (>=.5 EDSS steps) and statistically (p<= .05) significant up to 10 years post disease onset.
Conclusion(s): Patients with MS commencing high-efficacy immunotherapy early after disease onset accumulate less long-term disability compared to those exposed later in their disease. Those treated earlier had a more aggressive disease course initially, which was then mitigated by their early active management strategy. In patients with highly active MS, early high efficacy therapy is recommended
EMBASE:629482122
ISSN: 1477-0970
CID: 4131482
Clinical and therapeutic predictors of relapse and disability outcomes in neuromyelitis optica spectrum disorder [Meeting Abstract]
Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system autoimmune inflammatory condition associated with aquaporin-4-immunglobulin antibodies which results in demyelination. Understanding clinical and therapeutic predictors of relapses can aid management and prognostication of this disease Aim: To evaluate the effect of clinical and therapeutic predictors on risk of relapse and change in disability in NMOSD Methods: This MSBase cohort study of NMOSD patients (n=399) examined predictors of relapse in a Anderson-Gill survival model and change in expanded disability status score (EDSS) in a mixed effects model. A secondary analysis was conducted in the NMOantibody positive subgroup (>=1 core region affected: spinal cord, optic nerve or brainstem, n=202).
Result(s): Age (HR=0.82 per decade, p=0.003), disease duration (HR=0.95 per year, p=0.02), spinal cord onset (HR=0.6, p=0.007), brainstem onset (p=0.53, p=0.009) and treatment with azathioprine (HR=0.51, p< 0.001), mycophenolate mofetil (HR=0.24, p=0.016) were associated with a reduced risk of relapse in NMOSD. Treatment with glatiramer acetate (HR=1.82, p=0.028), interferon-beta (HR=1.57, p=0.013) and acute therapies-corticosteroids (HR=1.87, p < 0.001), intravenous immunoglobulin (HR=3.49, p=0.001) were associated with an increased risk of relapse. In the NMO-antibody positive subgroup, similar treatment effects on the risk of relapse were seen for azathioprine, mycophenolate mofetil, glatiramer acetate, corticosteroids and intravenous immunoglobulin. Age (p< 0.001), disease duration (p< 0.001), glatiramer acetate (p=0.001), and therapies used in acute relapses-cyclophosphamide (p=0.01), intravenous immunoglobulin (p=0.001) and plasma exchange (p< 0.001) were associated with a more pronounced increase in EDSS in the NMOSD cohort. Optic nerve onset (p=0.048), proportion of time pregnant (p=0.021) and treatment with azathioprine (p< 0.001), mycophenolate mofetil (p=0.043) and rituximab (p=0.029)-were associated with a slower increase in EDSS in the NMOSD cohort. The immunotherapies and age and disease duration showed similar associations in the NMO-antibody positive subgroup.
Conclusion(s): Treatment with azathioprine, rituximab and mycophenolate mofteil are associated with a slower increase in EDSS in NMOSD and a lower risk of relapses. The risk of relapses declines and accumulation of disability increases with age and disease duration in NMOSD
Result(s): Age (HR=0.82 per decade, p=0.003), disease duration (HR=0.95 per year, p=0.02), spinal cord onset (HR=0.6, p=0.007), brainstem onset (p=0.53, p=0.009) and treatment with azathioprine (HR=0.51, p< 0.001), mycophenolate mofetil (HR=0.24, p=0.016) were associated with a reduced risk of relapse in NMOSD. Treatment with glatiramer acetate (HR=1.82, p=0.028), interferon-beta (HR=1.57, p=0.013) and acute therapies-corticosteroids (HR=1.87, p < 0.001), intravenous immunoglobulin (HR=3.49, p=0.001) were associated with an increased risk of relapse. In the NMO-antibody positive subgroup, similar treatment effects on the risk of relapse were seen for azathioprine, mycophenolate mofetil, glatiramer acetate, corticosteroids and intravenous immunoglobulin. Age (p< 0.001), disease duration (p< 0.001), glatiramer acetate (p=0.001), and therapies used in acute relapses-cyclophosphamide (p=0.01), intravenous immunoglobulin (p=0.001) and plasma exchange (p< 0.001) were associated with a more pronounced increase in EDSS in the NMOSD cohort. Optic nerve onset (p=0.048), proportion of time pregnant (p=0.021) and treatment with azathioprine (p< 0.001), mycophenolate mofetil (p=0.043) and rituximab (p=0.029)-were associated with a slower increase in EDSS in the NMOSD cohort. The immunotherapies and age and disease duration showed similar associations in the NMO-antibody positive subgroup.
Conclusion(s): Treatment with azathioprine, rituximab and mycophenolate mofteil are associated with a slower increase in EDSS in NMOSD and a lower risk of relapses. The risk of relapses declines and accumulation of disability increases with age and disease duration in NMOSD
EMBASE:629483303
ISSN: 1477-0970
CID: 4131382
The CROCTINO project: an international retrospective multi-center study of retinal optical coherence tomography in 501 patients with neuromyelitis optica spectrum disorders [Meeting Abstract]
Introduction: Optical coherence tomography (OCT) is a valuable tool for quantifying retinal neuro-axonal damage in Neuromyelitis Optica Spectrum Disorders (NMOSD). However, existing OCT studies in NMOSD reveal inconsistencies due to non-standardised methods and limited sample sizes.
Objective(s): To collect and uniformly analyze a large international OCT dataset with corresponding clinical data for correlates of retinal damage in NMOSD in a multicenter approach (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica, CROCTINO).
Aim(s): To facilitate optimization of international OCT standards, reveal potential correlates of NMOSD disease and retinal pathology, and generate hypotheses for prospective studies.
Method(s): Centers were mainly recruited from the GJCF-ICC network including experts in NMOSD clinical care and research. OCT images were collected as source data to allow for standardised quality control and analysis. Demographic and clinical metadata were obtained with electronic record forms, adhering to institutional review board approval. We included subjects with a) NMOSD per the 2015 International Panel criteria; b) longitudinal extensive transverse myelitis; c) recurrent optic neuritis; and d) healthy controls. Only subjects with available OCT source data and a complete information on age, sex, disease subtype and attack history were included.
Result(s): Data from 501 cases from 20 international centers were collected (148 Asia, 249 Europe, 36 North America, 68 South America). Age was 44+/-15 years (range, 10-85 years), with 84% female. A total of 470 patients fulfilled the 2015 NMOSD criteria, with 345 (73.4%) seropositive for aquaporin4 antibodies (AQP4- IgG) using a validated method. Of the AQP4-IgG-negative patients, 47 (37.6%; 9.4% of all patients) were MOG antibody seropositive, and 78 (62.4%, 15.6% of all patients) were double negative or had unknown antibody status. OCT was performed in 344 patients using Spectralis SD-OCT, in 102 using Cirrus HD-OCT and 55 using Topcon 3D OCT instruments. Healthy control data were available from 90 subjects from 4 centers (all Spectralis)
Conclusion(s): CROCTINO has collected the largest OCT dataset from NMOSD patients to date. Results from this international collaborative study should facilitate improved OCT practices in NMOSD, highlight clinical correlates of disease and retinal status, and prioritize hypothesis-testing to advance clinical care and research goals in the future
Objective(s): To collect and uniformly analyze a large international OCT dataset with corresponding clinical data for correlates of retinal damage in NMOSD in a multicenter approach (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica, CROCTINO).
Aim(s): To facilitate optimization of international OCT standards, reveal potential correlates of NMOSD disease and retinal pathology, and generate hypotheses for prospective studies.
Method(s): Centers were mainly recruited from the GJCF-ICC network including experts in NMOSD clinical care and research. OCT images were collected as source data to allow for standardised quality control and analysis. Demographic and clinical metadata were obtained with electronic record forms, adhering to institutional review board approval. We included subjects with a) NMOSD per the 2015 International Panel criteria; b) longitudinal extensive transverse myelitis; c) recurrent optic neuritis; and d) healthy controls. Only subjects with available OCT source data and a complete information on age, sex, disease subtype and attack history were included.
Result(s): Data from 501 cases from 20 international centers were collected (148 Asia, 249 Europe, 36 North America, 68 South America). Age was 44+/-15 years (range, 10-85 years), with 84% female. A total of 470 patients fulfilled the 2015 NMOSD criteria, with 345 (73.4%) seropositive for aquaporin4 antibodies (AQP4- IgG) using a validated method. Of the AQP4-IgG-negative patients, 47 (37.6%; 9.4% of all patients) were MOG antibody seropositive, and 78 (62.4%, 15.6% of all patients) were double negative or had unknown antibody status. OCT was performed in 344 patients using Spectralis SD-OCT, in 102 using Cirrus HD-OCT and 55 using Topcon 3D OCT instruments. Healthy control data were available from 90 subjects from 4 centers (all Spectralis)
Conclusion(s): CROCTINO has collected the largest OCT dataset from NMOSD patients to date. Results from this international collaborative study should facilitate improved OCT practices in NMOSD, highlight clinical correlates of disease and retinal status, and prioritize hypothesis-testing to advance clinical care and research goals in the future
EMBASE:629485094
ISSN: 1477-0970
CID: 4131522
Tracking symptom impact in MS patients: Longitudinal study of symptoMScreen scores in patients attending two large tertiary MS centers [Meeting Abstract]
Background: Natural history studies in MS largely focused on determining time-to-disability benchmarks. Little is known about changes in MS symptom burden from patient's point of view. SymptoMScreen is an in-house developed and validated patientreported outcome (PRO) tool for assessing symptom severity in 12 domains commonly affected by
EMBASE:629481771
ISSN: 1477-0970
CID: 4131412
Patient-reported SymptoMScreen baseline scores in patients with relapsing-remitting multiple sclerosis enrolled in Phase IIIb studies of ocrelizumab (ENSEMBLE and CASTING) [Meeting Abstract]
Background: SymptoMScreen is a new patient-reported outcome (PRO) tool for the rapid assessment of multiple sclerosis (MS) symptom severity in 12 domains (walking, hand function/dexterity, spasticity, bodily pain, sensory, bladder, fatigue, vision, dizziness, cognitive, depression and anxiety) on 7-point Likert scales (0 [not affected] to 6 [total limitation]). SymptoMScreen is used for the first time as an outcome measure in two ongoing, openlabel, single-arm Phase IIIb clinical trials of ocrelizumab (OCR) in treatment naive patients with early-stage relapsing-remitting MS (RRMS; ENSEMBLE [NCT03085810]) and patients with RRMS who had a prior suboptimal response to disease-modifying treatment (DMT; CASTING [NCT02861014]).
Objective(s): To report ENSEMBLE and CASTING baseline SymptoMScreen results.
Method(s): Patients in ENSEMBLE (Expanded Disability Status Scale [EDSS] score <=3.5 at screening) had a disease duration of <=3 years and >=1 clinically reported relapse or >=1 sign of MRI activity within 12 months of enrolment; patients in CASTING (EDSS <=4.0 at screening) had a disease duration <=10 years and discontinued a prior DMT of >=6 months' duration for reasons of suboptimal disease control. SymptoMScreen was performed in all study patients at baseline. OCR 600mg/24 weeks (first dose, 2x300mg, 14 days apart) was administered intravenously in both ENSEMBLE (192 weeks; maximum 8 doses) and CASTING (96 weeks; maximum 4 doses).
Result(s): ENSEMBLE patient (N=676) baseline characteristics were: female=65%, mean (SD) baseline EDSS score=1.7 (1.0), disease duration=1.1 (0.9) years; and in CASTING (N=681): female=64%, baseline EDSS score=2.1 (1.1), disease duration= 5.0 (2.7) years. In CASTING, 61% of patients had received one DMT prior to enrolment (most frequently dimethyl fumarate [25%]). Total mean (SD) baseline SymptoMScreen scores were 12.2 (10.9) in ENSEMBLE and 15.3 (12.6) in CASTING; individual domain scores ranged from 0.8 (1.1) to 1.8 (1.5) and 1.0 (1.2) to 2.1 (1.6), respectively, with numerically higher scores in ENSEMBLE (all domains) and fatigue having the highest score in both studies. Moderate to severe fatigue (domain score >=3) was reported in 31% (ENSEMBLE) to 41% (CASTING) of patients.
Conclusion(s): SymptoMScreen scores were generally low, though expectedly higher in CASTING than ENSEMBLE, consistent with greater disability in the patients who experienced suboptimal control; differences were consistent in all domains, but were most pronounced in fatigue and ambulation
Objective(s): To report ENSEMBLE and CASTING baseline SymptoMScreen results.
Method(s): Patients in ENSEMBLE (Expanded Disability Status Scale [EDSS] score <=3.5 at screening) had a disease duration of <=3 years and >=1 clinically reported relapse or >=1 sign of MRI activity within 12 months of enrolment; patients in CASTING (EDSS <=4.0 at screening) had a disease duration <=10 years and discontinued a prior DMT of >=6 months' duration for reasons of suboptimal disease control. SymptoMScreen was performed in all study patients at baseline. OCR 600mg/24 weeks (first dose, 2x300mg, 14 days apart) was administered intravenously in both ENSEMBLE (192 weeks; maximum 8 doses) and CASTING (96 weeks; maximum 4 doses).
Result(s): ENSEMBLE patient (N=676) baseline characteristics were: female=65%, mean (SD) baseline EDSS score=1.7 (1.0), disease duration=1.1 (0.9) years; and in CASTING (N=681): female=64%, baseline EDSS score=2.1 (1.1), disease duration= 5.0 (2.7) years. In CASTING, 61% of patients had received one DMT prior to enrolment (most frequently dimethyl fumarate [25%]). Total mean (SD) baseline SymptoMScreen scores were 12.2 (10.9) in ENSEMBLE and 15.3 (12.6) in CASTING; individual domain scores ranged from 0.8 (1.1) to 1.8 (1.5) and 1.0 (1.2) to 2.1 (1.6), respectively, with numerically higher scores in ENSEMBLE (all domains) and fatigue having the highest score in both studies. Moderate to severe fatigue (domain score >=3) was reported in 31% (ENSEMBLE) to 41% (CASTING) of patients.
Conclusion(s): SymptoMScreen scores were generally low, though expectedly higher in CASTING than ENSEMBLE, consistent with greater disability in the patients who experienced suboptimal control; differences were consistent in all domains, but were most pronounced in fatigue and ambulation
EMBASE:629484997
ISSN: 1477-0970
CID: 4131442
Multiple sclerosis and Sarcoidosis: a case for co-existence [Meeting Abstract]
ISI:000446861400188
ISSN: 1352-4585
CID: 3885212
Anti-Myelin Oligodendrocyte Glycoprotein (MOG) Antibodies in a Patient with Ataxia, Diplopia, and an Enhancing Cerebellar Lesion [Meeting Abstract]
ISI:000453090805156
ISSN: 0028-3878
CID: 3732432
