Oral contraceptives do not modify the risk of a second attack and disability accrual in a prospective cohort of women with a clinically isolated syndrome and early multiple sclerosis

Objective: To evaluate whether oral contraceptive (OC) use is associated with the risk of a second attack and disability accrual in women with a clinically isolated syndrome (CIS) and early multiple sclerosis (MS). Methods: Reproductive information from women included in the Barcelona CIS prospective cohort was collected through a self-reported cross-sectional survey. We examined the relationship of OC exposure with the risk of a second attack and confirmed Expanded Disability Status Scale of 3.0 using multivariate Cox regression models, adjusted by age, topography of CIS, oligoclonal bands, baseline brain T2 lesions, body size at menarche, smoking, and disease-modifying treatment (DMT). OC and DMT exposures were considered as time-varying variables. Findings were confirmed with sensitivity analyses using propensity score models. Results: A total of 495 women were included, 389 (78.6%) referred to ever use OC and 341 (68.9%) started OC before the CIS. Exposure to OC was not associated with a second attack (adjusted hazard ratio (aHR) = 0.73, 95% confidence interval (CI) = 0.33–1.61) or disability accrual (aHR = 0.81, 95% CI = 0.17–3.76). Sensitivity analyses confirmed these results. Conclusion: OC use does not modify the risk of second attack or disability accrual in patients with CIS and early MS, once considered as a time-dependent exposure and adjusted by other potential confounders.

Pregnancy in women with MS: Impact on long-term disability accrual in a nationwide Danish Cohort

Background: Pregnancy is considered to influence the disease course in women with multiple sclerosis (MS). Objective: The aim of this study was to investigate the effect of pregnancy on long-term disability accrual in women with MS. Methods: The Danish Multiple Sclerosis Registry (DMSR) was used to identify women diagnosed with clinically isolated syndrome or relapsing-remitting MS. Cox models with pregnancy as a time-dependent exposure and propensity score (PS) models were used to evaluate time to reach confirmed Expanded Disability Status Scale (EDSS) score of 4 and 6. Results: A total of 425 women became parous and 840 remained nulliparous. When including pregnancy as a time-dependent exposure, a non-significant association with time to reach EDSS 4 (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.61–1.20) and EDSS 6 (HR 0.70, 95% CI 0.40–1.20) was found. Correspondingly, the PS model showed no association with pregnancy on time to reach EDSS 4 (HR 0.85, 95% CI 0.56–1.28). Conclusion: This study concludes that pregnancy does not affect long-term disability accumulation.

Corneal confocal microscopy demonstrates axonal loss in different courses of multiple sclerosis

Axonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing–remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm2, 95% CI − 18.24 to − 11.59, P < .0001), CNFL [for ACCMetrics: 19.75 ± 2.39 vs. 12.40 ± 3.30 mm/mm2, 95% CI − 8.94 to − 5.77, P < .0001; for deepNerve: 21.98 ± 2.76 vs. 14.40 ± 4.17 mm/mm2, 95% CI − 9.55 to − 5.6, P < .0001] and CNFrD [for ACCMetrics: 1.52 ± 0.02 vs. 1.45 ± 0.04, 95% CI − 0.09 to − 0.05, P < .0001; for deepNerve: 1.29 ± 0.03 vs. 1.19 ± 0.07, 95% − 0.13 to − 0.07, P < .0001]. Corneal nerve parameters were comparably reduced in different courses of MS. There was excellent reproducibility between the algorithms. Significant corneal axonal loss is detected in different courses of MS including patients with clinically isolated syndrome.

New-Onset Right-Sided Numbness and Double Vision

A 40-year-old right-handed man sought care for right hand numbness, right-sided facial numbness, and diplopia progressing to maximal severity over 10 days. At his worst he was unable to write. His symptoms remained maximal for 4 weeks. He was hospitalized and treated with 5 days of intravenous methylprednisolone. He improved to approximately 95% of normal over 4 weeks. He had residual mild right-sided facial and right leg numbness. Antibodies to JC polyoma virus and varicella-zoster virus were positive, which indicated prior exposure to these viruses. Total 25-hydroxyvitamin D level was low at 8.2 ng/mL. Optical coherence tomography findings were normal. Magnetic resonance imaging of the brain performed 3 months after the onset of symptoms demonstrated a T2-hyperintense lesion in the left midbrain peduncle extending into the upper pons, without gadolinium enhancement. A small area of T2 hyperintensity was seen in the right frontal deep white matter. Follow-up brain magnetic resonance imaging showed almost complete resolution of the left midbrain peduncle lesion with persistence of the right frontal deep white matter lesion. Spinal fluid analysis showed 1 white blood cell/µL with 95% lymphocytes, protein 35 mg/dL, 0 unique oligoclonal bands, and normal immunoglobulin G index (0.54). A diagnosis of clinically isolated syndrome-first episode of multiple sclerosis was made. After detailed discussion with the patient, he elected to commence disease-modifying therapy with fingolimod. He underwent routine monitoring with magnetic resonance imaging of the brain and cervical and thoracic spine on an annual basis, without any further relapses at 5-year follow-up. Patients with typical demyelinating syndromes may not always fulfill the diagnostic criteria for multiple sclerosis. After careful exclusion of other mimicking conditions, most notably aquaporin-4-immunoglobulin G– and myelin oligodendrocyte glycoprotein-immunoglobulin G–associated disease, a diagnosis of clinically isolated syndrome may be made.

Cerebrospinal Fluid IgM and Oligoclonal IgG Bands in Multiple Sclerosis: A Meta-Analysis of Prevalence and Prognosis

The presence of intrathecal IgM synthesis (ITMS) has been associated with an aggressive multiple sclerosis (MS) clinical course. In the present systematic review, we aimed at assessing the prevalence of ITMS among different MS phenotypes. Moreover, we aimed at quantifying the risk of a second relapse in ITMS positive and oligoclonal IgG bands (OCGBs)-positive patients. We selected clinical studies reporting the ITMS prevalence assessed as oligoclonal IgM Bands (OCMBs), lipid-specific OCMBs (LS-OCMBs), and/or as an intrathecal IgM production > 0% (IgMLoc, Reiber formula). The overall prevalence of ITMS was higher in relapsing-remitting (RR) than clinically isolated syndrome (CIS) patients (40.1% versus 23.8%, p < 0.00001), while was in line with that detected in primary progressive MS (PPMS, 26.7%). Almost all patients (98%) with ITMS had also OCGBs. The risk of having a second relapse was higher in OCGBs positive patients (HR = 2.18, p = 0.007) but much higher in ITMS positive patients (HR = 3.62, p = 0.0005). This study revealed that the prevalence of ITMS is higher in RRMS patients. It suggests that the risk of having a second relapse, previously ascribed to OCGBs, may, to a certain extent, be related to the presence of intrathecal IgM.

Performance of the 2017 and 2010 Revised McDonald Criteria in Predicting MS Diagnosis After a Clinically Isolated Syndrome

Background and ObjectivesTo compare the performance of the 2017 revisions to the McDonald criteria with the 2010 McDonald criteria in establishing MS diagnosis and predicting prognosis in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS).MethodsCSF examination, brain and spinal cord MRI obtained ≤5 months from CIS onset, and a follow-up brain MRI acquired within 15 months from CIS onset were evaluated in 785 CIS patients from 9 European centers. Date of second clinical attack and of reaching Expanded Disability Status Score (EDSS) ≥ 3.0, if they occurred, were also collected. Performance of the 2017 and 2010 McDonald criteria for dissemination in space (DIS), time (DIT) (including oligoclonal bands assessment) and DIS + DIT for predicting a second clinical attack (clinically definite [CD] MS) and EDSS ≥ 3.0 at follow-up was evaluated. Time to MS diagnosis for the different criteria was also estimated.ResultsAt follow-up (median = 69.1 months), 406/785 CIS patients developed CDMS. At 36 months, the 2017 DIS + DIT criteria had higher sensitivity (0.83 vs 0.66), lower specificity (0.39 vs 0.60) and similar area under the curve values (0.61 vs 0.63). Median time to MS diagnosis was shorter with the 2017 vs the 2010 or CDMS criteria (2017 revision = 3.2; 2010 revision = 13.0; CDMS = 58.5 months). The 2 sets of criteria similarly predicted EDSS ≥ 3.0 milestone. Three periventricular lesions improved specificity in patients ≥45 years.DiscussionThe 2017 McDonald criteria showed higher sensitivity, lower specificity and similar accuracy in predicting CDMS compared to 2010 McDonald criteria, while shortening time to diagnosis of MS.Classification of EvidenceThis study provides Class II evidence that the 2017 McDonald Criteria more accurately distinguish CDMS in patients early after a CIS when compared to the 2010 McDonald criteria.