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Background: Sleep is a central component of brain development. Preterm neonates follow an exclusive sleep-wake rhythm in a way that they can sleep up to 22 hours per day, 70% of which is spent during active sleep. Sleep can create a period of time for the production of active neurotransmitters, which can enhance brain development flexibility. Objectives: It is a matter of controversy whether the widespread use of nonsynchronized nasal intermittent positive pressure ventilation (NIPPV) in neonatal intensive care units and the concerns over the use of nonrespiratory support can affect the quantity and quality of the sleep-wake cycle (SWC). Therefore, the current study aimed to compare two types of intervention, nasal continuous positive airway pressure (nCPAP) and NIPPV, during the SWC. Methods: The present randomized controlled trial crossover study was conducted on neonates with 28 - 32 weeks of gestation receiving nCPAP who had been administered surfactant after being diagnosed with respiratory distress syndrome in Shahid Beheshti hospital in Isfahan, Iran, within March 2018 to August 2020. The SWC was monitored using cerebral function monitoring for all study participants. Results: The present study showed no significant difference between the number of SWCs during nCPAP and NIPPV. The duration of SWCs when participants received nCPAP was significantly higher than when they received NIPPV intervention. Rapid eye movement (REM) sleep duration was significantly longer during nCPAP respiratory support. Furthermore, NonREM sleep duration was significantly longer in nCPAP respiratory support. Conclusions: Noninvasive respiratory support modes can affect the SWC, with nCPAP being the favored in the present study. Nonetheless, further studies are required to be performed in this regard.

For the past four decades, multiple sclerosis (MS) has been a focus for clinical trial development and execution. Advances in translational neuroimmunology have led to the development of effective disease-modifying therapies (DMTs) that greatly benefit patients with MS and mitigate their burden of disease. These achievements also stem from continued progress made in the definition and discovery of sensitive disease diagnostic criteria, objective disability assessment scales, precise imaging techniques, and disease-specific biomarkers. As a result, our knowledge of MS pathophysiology is more mature; the established clinical practice for the diagnosis and management of MS could serve as a roadmap to guide the development of more disease-specific interventions. In this article we briefly review the main achievements in the evolution of clinical trials for MS, and discuss opportunities for improvements.

A 48-year-old Caucasian woman with history of multiple sclerosis (MS) presented with erythematous papulonodular lesions in her extremities and trunk. She was being treated with glatiramer acetate (GA) for the past 10 years and the glatiramoid, Glatopa, for 2 years prior to this presentation. A skin biopsy showed CD30+ lymphoproliferative disorder consistent with lymphomatoid papulosis (LyP). Three weeks after stopping Glatopa, her skin lesions were improved. It remains unclear whether GA’s or Glatopa’s capability to alter T-cell differentiation, may have a link with LyP. This case report is a reminder to be vigilant for skin lesions in patients with MS.

Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal‐appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and nonrestricted isotropic fraction (representing edema). This study provides preliminary evidence supporting the ability of DBSI as a potential noninvasive biomarker of MS neuropathology.

Background:Rituximab and ocrelizumab are anti-CD20 monoclonal antibodies that have shown a marked reduction in multiple sclerosis (MS) inflammatory activity. However, their real-world safety profile has not been adequately compared.Objective:To investigate the adverse event (AE) profile of rituximab and ocrelizumab reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database.Methods:The FAERS database was filtered by indication (MS) and drug (rituximab or ocrelizumab). Disproportionality analyses including but not limited to reporting odds ratio (ROR) were conducted to identify drug–AE associations. A signal was detected if the lower limit of the 95% confidence interval of ROR (ROR025) exceeded 1.Results:There were 623 and 7948 reports for rituximab and ocrelizumab, respectively. The most frequent AEs with rituximab and ocrelizumab were infusion-related reaction (4.82%) and urinary tract infection (10.52%), respectively. The strongest drug–AE association for rituximab and ocrelizumab were ear pruritus (ROR025: 47.53) and oral herpes (ROR025: 38.99), respectively. Ocrelizumab was associated with an almost two times higher frequency of infections than rituximab (21.93% vs 11.05%, respectively).Conclusion:This study revealed differences in reporting AEs between rituximab and ocrelizumab. Infections were reported more frequently with ocrelizumab. Although speculative, a potentially different or more extensive B-cell depletion by ocrelizumab might explain these findings. Additional pharmacovigilance studies need to be performed to better characterize differences in the AE profile in B-cell-depleting therapies.

Diffusion basis spectrum imaging (DBSI) models diffusion-weighted magnetic resonance imaging (MRI) signals as a combination of discrete anisotropic diffusion tensors and a spectrum of isotropic diffusion tensors. Here, we report the histopathological correlates of DBSI in the biopsied brain tissue of a patient with an inflammatory demyelinating lesion typical of multiple sclerosis (MS). Increased radial diffusivity (marker of demyelination), decreased fiber fraction (apparent axonal density), elevated nonrestricted isotropic fraction (marker of vasogenic edema), but unchanged axial diffusivity (marker of integrity of residual axons) seen in the lesion appeared consistent with histopathological findings of inflammatory demyelination with relative axonal sparing. Our report supports the application of DBSI as a biomarker in human studies of MS.

Advances in translational neuroimmunology over the last two decades have revolutionized the treatment of relapsing forms of multiple sclerosis. A pathological hallmark of multiple sclerosis is the presence of leukocytes in the areas of disease activity in the CNS. Natalizumab inhibits the trafficking of lymphocytes from the blood into the brain and spinal cord by blocking the adhesion molecule α4-integrin. Representing the enormous success of a molecular targeted approach, natalizumab was the first mAb approved for the treatment of relapsing–remitting multiple sclerosis. However, only a few months after its approval, natalizumab was withdrawn from the market because of an unanticipated life threatening adverse effect: progressive multifocal leukoencephalopathy. Natalizumab was later reintroduced with required adherence to a strict monitoring program. In this article, we review the bench-to-bedside journey of natalizumab, along with the lessons learned from postmarketing studies.

Objective: To examine disease progression in ‘aggressive’ multiple sclerosis (MS), British Columbia, Canada (1980–2009). Methods: Aggressive (or ‘malignant’) MS was defined as Expanded Disability Status Scale (EDSS) ⩾6 within 5 years from onset. The first EDSS ⩾6 was termed ‘baseline’. Within 2, 3 and 5 years post-baseline, patients were categorized as follows: ‘worsened’ or ‘improved’, relative to baseline EDSS (the remainder exhibited no change or had no new scores). The associations between patient characteristics (sex, relapsing onset/primary progressive, onset age, onset symptoms, disease duration, cumulative prior relapses and baseline EDSS) and worsening in disability were examined longitudinally using logistic regression. Results: Of the 225/4341 (5.2%) aggressive/malignant MS patients, 134 (59.6%) were female, 167 (74.2%) were relapsing onset, 94 (41.8%) had received disease-modifying drugs at some point and the mean follow-up was 8.7 years. The proportion of patients who ‘worsened’ increased from 40.4% to 57.8%, while those who ‘improved’ varied little (range, 8.9%–10.2%). The odds of worsening increased with disease duration (adjusted odds ratio (AOR) = 1.36; 95% confidence interval (CI) = 1.22–1.52) and the presence of primary progressive (vs relapsing-onset) MS (AOR = 1.85; 95% CI = 1.01–3.38). Conclusion: Apart from disease duration and a primary progressive course, no clinically useful associations of subsequent disease worsening in patients with aggressive/malignant MS were identified.

Tumefactive appearing lesions on brain imaging can cause a diagnostic dilemma. We report a middle-aged man who presented with right-sided optic neuritis. A brain MRI showed enhancement of the right optic nerve, and non-enhancing white matter lesions including a 3 cm right frontal lesion with adjacent gyral expansion. Cerebrospinal fluid analysis showed five oligoclonal bands not present in serum. Glatiramer acetate was started for suspected tumefactive multiple sclerosis (MS). A follow-up brain MRI 6 months later showed persistence of the frontal gyral expansion. A brain biopsy led to the diagnosis of an oligodendroglioma, isocitrate dehydrogenase-mutant and 1 p/19q co-deleted (WHO grade II), managed with surgical resection and radiotherapy. Postoperative brain MRI showed a new enhancing periventricular lesion, making the choice of optimal disease-modifying therapy for MS challenging. This case highlights the possibility of coexistence of MS and oligodendroglioma, and emphasises the importance of a tissue diagnosis when atypical MS imaging features are present.

Background and purpose Beta-interferons (IFNβ) are the most widely prescribed drugs for patients with multiple sclerosis (MS). However, whether or not treatment with IFNβ can delay secondary progressive MS (SPMS) onset remains unknown. Our aim was to examine the association between IFNβ exposure and SPMS onset in patients with relapsing−remitting MS (RRMS). Methods A retrospective cohort study using British Columbia (Canada) population-based clinical and health administrative data (1985–2008) was conducted. RRMS patients treated with IFNβ (n = 794) were compared with untreated contemporary (n = 933) and historical (n = 837) controls. Cohort entry was the first clinic visit during which patients became eligible for IFNβ treatment (baseline). The outcome was time from baseline to SPMS onset. Cox regression models with IFNβ as a time-dependent exposure were adjusted for sex, and baseline age, disease duration, disability, *socioeconomic status and *comorbidities (*available for the contemporary cohorts only). Additional analyses included propensity score adjustment. Results The median follow-up for the IFNβ-treated, untreated contemporary and historical controls were 5.7, 3.7 and 7.3 years, and the proportions of patients reaching SPMS were 9.2%, 11.8% and 32.9%, respectively. After adjustment for confounders, IFNβ exposure was not associated with the risk of reaching SPMS when either the contemporary or the historical untreated cohorts were considered (hazard ratio 1.07; 95% confidence interval 0.93–1.48, and hazard ratio 1.04; 95% confidence interval 0.74–1.46, respectively). Further adjustments and the propensity score yielded results consistent with the main analysis. Conclusions Amongst patients with RRMS, use of IFNβ was not associated with a delayed onset of SPMS.

Probably no other disease-modifying drug for multiple sclerosis has a more fascinating story than natalizumab from both the bench to bedside perspective and the postmarketing experience standpoint. Natalizumab is a monoclonal antibody that inhibits the trafficking of lymphocytes from the blood into the central nervous system by blocking the adhesion molecule α4-integrin. Natalizumab was approved as a disease-modifying drug for relapsing remitting multiple sclerosis only 12 years after the discovery of its target molecule-a time line that is rather fast for drug development. However, a few months after its U.S. Food and Drug Administration approval, natalizumab was withdrawn from the market because of an unanticipated complication-progressive multifocal leukoencephalopathy. It was later reinstated with required adherence to a strict monitoring program and incorporation of mitigation strategies.

Objective:To examine the association between interferon-β (IFN-β) and potential adverse events using population-based health administrative data in British Columbia, Canada.Methods:Patients with relapsing-remitting multiple sclerosis (RRMS) who were registered at a British Columbia Multiple Sclerosis Clinic (1995–2004) were eligible for inclusion and were followed up until death, absence from British Columbia, exposure to a non–IFN-β disease-modifying drug, or December 31, 2008. Incidence rates were estimated for each potential adverse event (selected a priori and defined with ICD-9/10 diagnosis codes from physician and hospital claims). A nested case-control study was conducted to assess the odds of previous IFN-β exposure for each potential adverse event with at least 30 cases. Cases were matched by age (±5 years), sex, and year of cohort entry, with up to 20 randomly selected (by incidence density sampling) controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated with conditional logistic regression adjusted for age at cohort entry.Results:Of the 2,485 eligible patients, 77.9% were women, and 1,031 were treated with IFN-β during follow-up. From the incidence analyses, 27 of the 47 potential adverse events had at least 30 cases. Patients with incident stroke (ORadj 1.83, 95% CI 1.16–2.89), migraine (ORadj 1.55, 95% CI 1.18–2.04), depression (ORadj 1.33, 95% CI 1.13–1.56), and hematologic abnormalities (ORadj 1.32, 95% CI 1.01–1.72) were more likely to have previous exposure to IFN-β than controls.Conclusions:Among patients with RRMS, IFN-β was associated with a 1.8- and 1.6-fold increase in the risk of stroke and migraine and 1.3-fold increases in depression and hematologic abnormalities.

Purpose A systematic evaluation of hospital events can be an important surrogate measure for drug effectiveness or adverse effects. The purpose of this study was to examine the association between beta-interferon use and hospital events in a large cohort of patients with multiple sclerosis (MS). Methods Retrospective cohort study comparing beta-interferon exposed and unexposed patients using clinical data from the British Columbia MS (BCMS) database linked with health administrative databases, 1996–2008. For each patient, the primary outcome was the number of hospital events in each month, analyzed by quasi Poisson regression. Beta-interferon exposure was examined two ways: current and cumulative exposure. Secondary outcomes included whether a hospital event occurred in each month for each specific primary diagnoses, grouped by International Classification of Diseases categories. Results Current exposure to beta-interferon was not associated with an altered rate of hospital events (adjusted incident rate ratio 1.018; 95% CI 0.803–1.290). Similarly, there was no association with cumulative exposure. Cumulative beta-interferon exposure was associated with a lower odds of respiratory disease-related hospital events compared to those never exposed to beta-interferon. Conclusions Exposure to beta-interferon for MS was not associated with a change in overall hospital event rates. Preliminary evidence suggests that the beta-interferons may have a protective effect against respiratory diseases requiring hospitalization in MS patients. Copyright © 2014 John Wiley & Sons, Ltd.

Longitudinal observational data are required to assess the association between exposure to β-interferon medications and disease progression among relapsing-remitting multiple sclerosis (MS) patients in the “real-world” clinical practice setting. Marginal structural Cox models (MSCMs) can provide distinct advantages over traditional approaches by allowing adjustment for time-varying confounders such as MS relapses, as well as baseline characteristics, through the use of inverse probability weighting. We assessed the suitability of MSCMs to analyze data from a large cohort of 1,697 relapsing-remitting MS patients in British Columbia, Canada (1995–2008). In the context of this observational study, which spanned more than a decade and involved patients with a chronic yet fluctuating disease, the recently proposed “normalized stabilized” weights were found to be the most appropriate choice of weights. Using this model, no association between β-interferon exposure and the hazard of disability progression was found (hazard ratio = 1.36, 95% confidence interval: 0.95, 1.94). For sensitivity analyses, truncated normalized unstabilized weights were used in additional MSCMs and to construct inverse probability weight-adjusted survival curves; the findings did not change. Additionally, qualitatively similar conclusions from approximation approaches to the weighted Cox model (i.e., MSCM) extend confidence in the findings.

Background Identifying highly sensitive and reliable neurological exam components are crucial in recognizing clinical deficiencies. This study aimed to investigate finger tapping performance differences between patients with CNS demyelinating lesions and healthy control subjects. Methods Twenty-three patients with multiple sclerosis or clinically isolated syndrome with infratentorial and/or cervical cord lesions on MRI, and 12 healthy controls were videotaped while tapping the tip of the index finger against the tip and distal crease of the thumb using both the dominant and non-dominant hand. Videos were assessed independently by 10 evaluators (three MS neurologists, four neurology residents, three advanced practice providers). Sensitivity and inter-evaluator reliability of finger tapping interpretations were calculated. Results A total of 1400 evaluations (four videos per each of the 35 subjects evaluated by 10 independent providers) were obtained. Impairments in finger tapping against the distal thumb crease of the non-dominant hand, identified by neurologists, had the greatest sensitivity (84%, p

Objective To examine mortality and factors associated with survival in a population based multiple sclerosis (MS) cohort. Methods Clinical and demographic data of MS patients registered with the British Columbia MS clinics (1980e2004) were linked to provincial death data, and patients were followed until death, emigration or study end (31 December 2007). Absolute survival and the influence of patient characteristics (sex, disease course (primary progressive (PPMS) vs relapsing onset (R-MS)) and onset age) were estimated by KaplaneMeier analyses (from birth and disease onset). Mortality relative to the general population was examined using standardised mortality ratios. Excess mortality associated with patient characteristics and time period of cohort entry was assessed by relative survival modelling. Results Of 6917 patients, 1025 died. Median survival age was 78.6 years (95% CI 77.5 to 79.7) for women and 74.3 years (95% CI 73.1 to 75.4) for men. Survival from onset was longer for R-MS (49.7 years; 95% CI 47.9 to 51.5) than for PPMS (32.5 years; 95% CI 29.5 to 35.7); however, survival age was similar. The overall standardised mortality ratios was 2.89 (95% CI 2.71 to 3.07), and patients survived approximately 6 years less than expected, relative to the general population. PPMS had a higher relative mortality risk compared with R-MS (relative mortality ratio (RMR) 1.52; 95% CI 1.30 to 1.80). Women with PPMS had a relative survival disadvantage compared with men with PPMS (RMR 1.55; 95% CI 1.19 to 2.01). Relative survival within 10 years of cohort entry was similar between time periods. Conclusions Some of the longest MS survival times are reported here but the risk of death was still greater than in the age, sex and calendar year matched general population. No evidence of increased survival over time was found when improved survival in the general population was taken into consideration.

A relationship between handedness and clinicodemographic profiles of people with multiple sclerosis was sought using data from the Multiple Sclerosis Partners Advancing Technology Health Solutions network of 10 multiple sclerosis centers in the USA and Europe. Handedness data were available for 8888 multiple sclerosis patients, of which 917 (10.3%) were left-handed. Clinicodemographic profiles of right versus left-handed multiple sclerosis patients were similar except for a slightly increased proportion of men who were left-handed, and slightly reduced performance on the manual dexterity test using the non-dominant hand in left-handed patients. We found no evidence to suggest a prognostic implication of handedness in multiple sclerosis.

The purpose of this study was to investigate the antimicrobial resistance pattern among common Gram-negative bacilli isolated from patients with nosocomial infection. A total of 200 samples of common Gram-negative bacilli (Klebsiella, Pseudomonas, Acinetobacter, and Escherichia coli) were collected from 2 university hospitals in Iran during a 1.5-year period from June 2004 to December 2005. All samples were examined for the antimicrobial activity of imipenem, cefepime, ciprofloxacin, ceftriaxone, and ceftazidime using E-test methods. The most frequent pathogens were Klebsiella spp. (38.5%) followed by Pseudomonas aeruginosa (28.5%), Acinetobacter spp. (20.5%), and E. coli (12.5%). The most active antibiotic was imipenem (84%). The susceptibility of the studied microorganisms was 25% for cefepime, 24% for ciprofloxacin, 20.5% for ceftazidime, and 11.8% for ceftriaxone. The susceptibility rates of Klebsiella to imipenem, cefepime, ciprofloxacin, ceftazidime, and ceftriaxone were 90.9%, 20.8%, 18.2%, 10.4%, and 5.2%, respectively. Likewise, these rates were 88%, 19%, 17%, 21%, and 21% for E. coli. Among Acinetobacter spp., the susceptibility rates were 77% for imipenem and 21% for ciprofloxacin. Among Pseudomonas, the rates were 75% for imipenem and 39% for ciprofloxacin. The antibiotics resistance among Gram-negative bacilli was widespread, so an antibiotic policy is urgently needed to delay the resistance development.

In addition to surfactant deficiency, increase of lung fluid content and secretion of fluid derived from the blood participate in the pathogenesis of RDS in newborns. We hypothesized that the administration of salbutamol (β-agonist) to increase lung fluid absorption would decrease the INSURE failure rate in newborns with respiratory distress syndrome (RDS) treated with intratracheal surfactant. Design Blinded, randomized clinical trial study. Setting/population Level III NICU, premature infants with RDS requiring intratracheal Surfactant. Forty Eight newborns with RDS treated with intratracheal Surfactant were randomized into two groups as Group A, Normal saline (as control group) and Group B (intervention group), Salbutamol were administered intratracheally in addition to Surfactant. Intubation-Surfactant administration- Rapid Extubation (INSURE) failure rate as primary outcome and secondary outcome as follow: duration of the need to NCPAP, mechanical ventilation and oxygen therapy; complications (patent ductus arteriosus, pneumothorax); mortality (respiratory or prematurity related complication) and the duration of hospitalization were assessed. Twenty Four patients in each group were studied. INSURE failure was seen in16 (66.7 %) and 10 (41.7 %) of normal saline and salbutamol groups respectively (p = 0.082). The duration of NCPAP in control group was 69.5 ± 54.9 h while in Salbutamol group was 51.6 ± 48.7 h (p = 0.316). All of deaths were related to respiratory failure. No differences in mortality or complications of RDS were observed. The duration of hospitalization was longer in control group than interventional group, 28.3 ± 18.1 and 18.6 ± 8.6 days, respectively. (p = 0.047). Salbutamol may improve the clinical course of newborns with RDS requiring Surfactant. IRCT2014072714215N1

Identifying effective therapies for the treatment of progressive forms of multiple sclerosis (MS) is a highly relevant priority and one of the greatest challenges for the global MS community. Better understanding of the mechanisms involved in progression of the disease, novel trial designs, drug repurposing strategies, and new models of collaboration may assist in identifying effective therapies. In this review, we discuss various therapies under study in phase II or III trials, including antioxidants (idebenone); tyrosine kinase inhibitors (masitinib); sphingosine receptor modulators (siponimod); monoclonal antibodies (anti-leucine-rich repeat and immunoglobulin-like domain containing neurite outgrowth inhibitor receptor-interacting protein-1, natalizumab, ocrelizumab, intrathecal rituximab); hematopoetic stem cell therapy; statins and other possible neuroprotective agents (amiloride, riluzole, fluoxetine, oxcarbazepine); lithium; phosphodiesterase inhibitors (ibudilast); hormone-based therapies (adrenocorticotrophic hormone and erythropoietin); T-cell receptor peptide vaccine (NeuroVax); autologous T-cell immunotherapy (Tcelna); MIS416 (a microparticulate immune response modifier); dopamine antagonists (domperidone); and nutritional supplements, including lipoic acid, biotin, and sunphenon epigallocatechin-3-gallate (green tea extract). Given ongoing and planned clinical trial initiatives, and the largest ever focus of the global research community on progressive MS, future prospects for developing targeted therapeutics aimed at reducing disability in progressive forms of MS appear promising.

The object of this study was to determine the relationship between outcome (assessed by Glasgow Outcome Scale) and recurrence in chronic subdural haematoma (CSDH). Eighty-two consecutive patients who underwent surgery for CSDH were included in this study. The relationship between the following variables and CSDH recurrence was studied: sex; age; history of trauma; Glasgow Coma Scale (GCS) at the time of admission (stage 1: GCS12, stage 2: GCS: 8 - 12, stage 3: GCS8); interval between head injury (when a history of trauma was present) and surgery; presence of a midline shift on CT scans; presence of intracranial air 7 days after surgery; haematoma density; haematoma width; presence of brain atrophy; and Glasgow Outcome Scale (GOS, both quantitative and non-quantitative) at the time of discharge. Throughout the analysis, p0.05 was considered statistically significant. The results showed lower GCS (p0.001), higher GOS (p0.001), presence of intracranial air 7 days after surgery (p=0.002), and a high density haematoma (p0.001) were significantly associated with recurrence of CSDH. It was concluded that GOS is related with recurrence in CSDH.

Background. We examined (1) patient characteristics and disease-modifying drug (DMD) exposure in late-onset (LOMS, ≥50 years at symptom onset) versus adult-onset (AOMS, 18–β) and disability progression in older relapsing-onset MS adults (≥50 years).Methods. This retrospective study (1980–2004, British Columbia, Canada) included 358 LOMS and 5627 AOMS patients. IFNβ-treated relapsing-onset MS patients aged ≥50 (regardless of onset age, 90) were compared with 171 contemporary and 106 historical controls. Times to EDSS 6 from onset and from IFNβeligibility were examined using survival analyses.Results. LOMS patients (6%) were more likely to be male, with motor onset and a primary-progressive course, and exhibit faster progression and were less likely to take DMDs. Nonetheless, 57% were relapsing-onset, of which 31% were prescribed DMDs, most commonly IFNβ. Among older relapsing-onset MS adults, no significant association between IFNβexposure and disability progression was found when either the contemporary (hazard ratio [HR]: 0.46; 95% CI: 0.18–1.22) or historical controls (HR: 0.54; 95% CI: 0.20–1.42) were considered.Conclusion. LOMS differed clinically from AOMS. One-third of older relapsing-onset MS patients were prescribed a DMD. IFNβexposure was not significantly associated with reduced disability in older MS patients.

A systematic evaluation of hospital events can be an important surrogate measure for drug effectiveness or adverse effects. The purpose of this study was to examine the association between beta-interferon use and hospital events in a large cohort of patients with multiple sclerosis (MS).Retrospective cohort study comparing beta-interferon exposed and unexposed patients using clinical data from the British Columbia MS (BCMS) database linked with health administrative databases, 1996-2008. For each patient, the primary outcome was the number of hospital events in each month, analyzed by quasi Poisson regression. Beta-interferon exposure was examined two ways: current and cumulative exposure. Secondary outcomes included whether a hospital event occurred in each month for each specific primary diagnoses, grouped by International Classification of Diseases categories.Current exposure to beta-interferon was not associated with an altered rate of hospital events (adjusted incident rate ratio 1.018; 95% CI 0.803-1.290). Similarly, there was no association with cumulative exposure. Cumulative beta-interferon exposure was associated with a lower odds of respiratory disease-related hospital events compared to those never exposed to beta-interferon.Exposure to beta-interferon for MS was not associated with a change in overall hospital event rates. Preliminary evidence suggests that the beta-interferons may have a protective effect against respiratory diseases requiring hospitalization in MS patients.

Background and purpose It was recently reported that there was no significant overall association between interferon beta exposure and disability progression in relapsing−remitting multiple sclerosis (RRMS) patients in an observational study from Canada. In the current study, the potential for heterogeneity in the association between exposure to interferon beta and disability progression across patients' baseline characteristics was investigated. Methods RRMS patients treated with interferon beta (n = 868) and two cohorts of untreated patients (829 contemporary and 959 historical controls) were included. The main outcome was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained Expanded Disability Status Scale (EDSS) score 6 using a multivariable Cox model, with treatment as a time-varying predictor, testing interaction effects for five pre-specified baseline characteristics: sex, age, disease duration, EDSS and annualized relapse rate (ARR) based on the previous 2 years. Results Significant heterogeneity was found in the association of interferon beta exposure and disability progression only across ARR, and only when treated patients were compared with historical controls (P = 0.005 at a Bonferroni-adjusted alpha of 0.01). For patients with ARR>1, treatment-exposed time was associated with a hazard ratio of 0.38 (95%CI 0.20–0.75) for disability progression compared with the unexposed time. Conclusions RRMS patients with more frequent relapses at baseline may be more likely to benefit from interferon beta treatment with respect to long-term disability progression.

Objective To explore the occurrence and characteristics of aggressive multiple sclerosis (AMS) in adult-onset multiple sclerosis (MS) patients. Methods Prospectively collected data (1980–2009) from British Columbia, Canada, were retrospectively analysed. AMS was defined in three different ways (AMS1, 2 and 3): ‘AMS1’—confirmed Expanded Disability Status Scale (EDSS) ≥6 within 5 years of MS onset; ‘AMS2’—confirmed EDSS ≥6 by age 40; and ‘AMS3’—secondary progressive MS within 3 years of a relapsing-onset course. Three respective ‘non-aggressive’ MS comparison cohorts were selected. Patients’ characteristics were compared between aggressive and non-aggressive cohorts using multivariable logistic regression, with findings expressed as adjusted OR (AOR) and 95% CI. Results Application of the three definitions to the source population of 5891 patients resulted in 235/4285 (5.5%) patients fulfilling criteria for AMS1 (59.6% were female; 74.5% had relapsing-onset MS), 388/2762 (14.0%) for AMS2 (65.2% were female; 92.8% had relapsing-onset MS) and 195/4918 (4.0%) patients for AMS3 (61.0% were female). Compared to the respective control cohorts, those with AMS were more likely to be male (AOR=1.5, 95% CI 1.1 to 2.0 (AMS1); 1.6, 95% CI 1.3 to 2.1 (AMS2); 1.8, 95% CI 1.3 to 2.4 (AMS3)), older at MS symptom onset (AOR=1.1; 95% CI 1.1 to 1.1 (AMS1 and AMS3)) and have primary progressive MS (AOR=2.3, 95% CI 1.6 to 3.3 (AMS1); 2.7, 95% CI 1.7 to 4.4 (AMS2)). Conclusions AMS was identified in 4–14% of patients, depending on the definition used. Although there was a relative preponderance of men and primary progressive MS presenting with AMS, the majority of patients were still women and those with relapsing-onset MS.

Background: The use of oligoclonal bands (OCBs) and cerebrospinal fluid (CSF) parameters are established in the diagnosis of MS, but poorly as markers of disease. Objective: To investigate the role of OCBs in disease course and progression. Methods: CSF data for 1120 patients with MS were analyzed for associations between OCBs and CSF parameters and clinical data (disease course [relapsing-onset MS (ROMS) vs primary-progressive MS (PPMS)]), disability progression (proportion reaching Expanded Disability Status Scale 6 within 10 years of onset and progression index) and ethnicity. Results: Of patients with MS, 72.5% had detectable OCBs. For patients with detectable OCBs, 84.6% had ROMS and 15.4% PPMS versus 89.7% and 10.3%, respectively for those without detectable OCBs ( p=0.04). Total CSF IgG and protein levels were higher in PPMS compared with ROMS ( pConclusions: OCB positivity and elevated total CSF IgG and protein were moderately associated with a PPMS disease course, but not disease progression. Patients with atypical clinical presentations were more likely to have had CSF work-up, suggesting a testing bias.

Context Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. Objective To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. Design, Setting, and Patients Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. Main Outcome Measures The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. Results The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta–treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. Conclusion Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Background: Recent natural history studies suggest that multiple sclerosis (MS) is a more slowly progressing disease than previously thought. These observations are from studies separated by time, geography and methodological approach. Objectives: We investigated whether MS disease progression has changed over time in British Columbia, Canada. Methods: The British Columbia MS database was queried for relapsing-onset MS patients with symptom onset from 1975 to Results: A total of 2236 relapsing-onset MS patients (73.4% female; mean age at onset: 32.3 ± 8.8 years) were included. No significant temporal trend was found in the proportion of patients reaching EDSS 6 within 15 years from onset (28.5%, 26.4%, 27.7%, 22.3% for intervals 1975 to Conclusions: Rates of disease progression remained relatively stable over two decades of MS onset in British Columbia, Canada. Our results suggest that differences in disease progression findings between natural history studies may be related to factors other than time period.

To propose a diagnostic work-up specifically tailored to the undiagnosed primary (UDP) tumor patients.To investigate the distribution of primary tumors and presenting symptoms in UDP versus diagnosed primary (DP) patients, 50 consecutive patients with diagnosis of brain metastasis in Shohada Hospital, Tehran, Iran from January 2001 to December 2005 were included in this study. Univariate analyses were performed to assess the difference of various variables between DP and UDP patients.The UDP patients represented 46% of all. Aphasia was significantly more common in the UDP group (p=0.0008) and ataxia in the DP group (p=0.04). The source of the metastases proved to be different between the 2 groups of interest (p=0.0006). The lung was the most frequent primary site in both groups. Among all UDP patients, a primary tumor in a location other than the lung was only found in 17% of patients. This study validated the hypothesis that the distribution of primary tumors differs between DP and UDP patients.If lung investigation fails to disclose the location of primary tumor, the patient is unlikely to benefit from extensive paraclinical investigation. In such a situation, a neurosurgical procedure should be considered the most appropriate second step to be taken.

Background – A new treatment approach to multiple sclerosis (MS) is the initiation of interferon therapy in the early phase of the disease when a patient presents with clinically isolated syndrome. Aims of the study – The goal of this study was to assess the effect of early treatment on the risk of conversion to clinically definite MS in Iranian patients. Methods – Eligible patients had presented with a first episode of neurological dysfunction suggesting MS within the previous 3 months and had abnormal brain magnetic resonance imaging (MRI). Patients were randomly assigned to receive intramuscular interferon beta 1a 30 μg or placebo once a week for 3 years. Results – Of the 217 patients randomized, 202 patients completed the study; 104 received Avonex and 98 received placebo. Fewer patients converted to clinically definite multiple sclerosis in the treated group than in the placebo group during the study (36.6% vs 58.2%, P

Choreoacanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder characterized by progressive onset of hyperkinetic movements and red cell acanthocytosis. The most striking clinical feature is that of the orofacial and lingual movement abnormalities leading to severe feeding difficulties. Maintenance of proper nutrition in ChAc is a challenge. We report on a case of ChAc in a 32-year-old male in whom dramatic weight loss due to orolingual dyskinesia was the major consequence of the disease. This case report warrants more attention to the impact of orolingual dyskinesia on nutritional status in patients with ChAc.

Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system and is considered to be multifactorial with an autoimmune component. Prolactin (PRL) is a neuroendocrine peptide with potent immunomodulatory properties. Hyperprolactinemia enhances several autoimmune disorders and may play a role in the pathogenesis of MS. The aim of this study was to compare serum PRL levels in MS patients with those of healthy controls.There were 43 patients with definite MS and 43 sex- and age-matched healthy controls. Conditions leading to a rise in PRL, such as pregnancy, lactation, and specific underlying diseases and drugs, were excluded. PRL levels were measured in fasting blood samples. For the MS group, disease duration and subtype, clinical manifestations, and expanded disability status scores (EDSS) were also recorded.There were no significant differences in serum PRL levels between the case and control groups in both women and men (376.78+/-231.11 mIU/l in female patients with MS vs. 364.19+/-202.55 mIU/l in female controls, 266.00+/-200.83 mIU/l in male patients with MS vs. 197.25+/-65.25 mIU/l in male controls). We also found no significant relationship between PRL and disease activity, disease duration, and EDSS.Our findings do not support the hypothesis that MS patients are in a hyperprolactinemic state. However, further studies in more homogenous MS subgroups are needed.