Multiple Sclerosis Journal

Urinary tract infections (UTIs) are commonly reported by people with multiple sclerosis (PwMS) and significantly impact quality of life.

To provide an overview of the problem of UTIs in PwMS and offer a practical approach for the diagnosis and management.

A review of the literature through a Pubmed search up to October 2015 was performed using the following keywords: multiple sclerosis, neurogenic bladder, urinary tract infections, relapse, dipsticks, culture, recurrent and prevention.

Noteworthy topics include the definition of a confirmed symptomatic UTI as a positive urine culture defined by >10⁵ colony-forming units (CFU)/mL or >10⁴ CFU/mL if a urethral catheter urine sample is taken, or any count of bacteria in a suprapubic bladder puncture specimen, both in addition to symptoms including fever, pain, changes in lower urinary tract symptoms or neurological status. Urinalysis is useful to exclude a UTI; however, on its own is insufficient to confirm a UTI, for which urine culture is required. Experts advise asymptomatic UTIs should not be treated except in the context of an acute relapse. From international guidelines, there is no validated strategy to prevent recurrent UTIs in PwMS.

This review provides an overview of the diagnosis, treatment and prevention of UTIs in the setting of multiple sclerosis (MS).

To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported.

To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical–scientific integrity.

We assessed the “standard of care” for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design.

The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide.

The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.

Obesity in childhood and during adolescence has repeatedly been associated with increased risk of developing multiple sclerosis (MS). We aimed to investigate whether the most critical period occurs during childhood or later, during adolescence.

Using a population-based case-control study (1586 cases and 2800 controls), individuals with different body sizes at age 10 and different body mass indices at age 20 were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals. Potential interactions between HLA-DRB1*15 and absence of HLA-A*02, respectively, and both childhood and adolescent obesity were evaluated by calculating the attributable proportion due to interaction.

Regardless of body size at age 10, individuals with adolescent obesity had a 90% increased risk of MS. Among participants who were not obese at age 20, no association was observed between body size at age 10 and subsequent MS risk. An interaction was observed between the HLA MS risk genes and adolescent, but not childhood, obesity.

Our results suggest that BMI during adolescence, rather than childhood, is critical in determining MS risk.

There is contradictory evidence for a role of dietary fat in risk of multiple sclerosis (MS).

To examine the association between usual fat intake (total, saturated, monounsaturated (MUFA), polyunsaturated (PUFA), omega-3 and omega-6) and risk of a first clinical diagnosis of CNS demyelination (FCD).

Multi-centre incident case-control study in four regions of Australia during 2003–2006. Cases were aged 18–59 years and had a FCD; controls were matched to a case on age, sex and location. Dietary data were collected using a validated food frequency questionnaire.

In 267 cases and 517 controls with dietary data, higher intake (per g/day) of omega-3 PUFA (adjusted odds ratio, AOR=0.61 (95% CI 0.40–0.93)), and particularly that derived from fish (AOR=0.54 (95% CI 0.31–0.93)) rather than from plants (AOR=0.75 (95% CI 0.39–1.43)) was associated with a decreased risk of FCD. Total fat intake and intake of other types of fat were not associated with FCD risk.

There was a significant decrease in FCD risk with higher intake of omega-3 PUFA, particularly that originating from fish. There was no evidence to indicate that the intake of other types of dietary fat or fat quantity in the previous 12 months was associated with an altered risk of FCD.

Establishing biomarkers for predicting disease activity in demyelinating disease of the central nervous system is crucial for designing appropriate disease modifiying treatment strategies.

To investigate retinal findings and disease activity in patients with radiologically isolated and clinically isolated syndromes.

We performed retinal optical coherence tomography and cerebral magnetic resonance imaging in healthy control individuals (n=19), in individuals with non-specific white matter lesions (n=18), and in patients with clinically isolated syndromes (n=18) and radiologically isolated syndromes (n=20).

Reduced volume of retinal nerve fibre layer and increased volume of inner nuclear layer at baseline correlated with subsequent disease activity as measured by an increase in cerebral T2 lesion load in patients with radiologically isolated syndromes. Reduced volume of retinal nerve fibre layer and increased volumes of inner and outer nuclear layer were associated with progression into multiple sclerosis in patients with clinically isolated syndromes.

Patients with radiologically and clinically isolated syndromes behave similarly concerning paraclinical disease activity in cerebral magnetic resonance imaging. In both conditions, reduction of retinal nerve fibre layer and increased inner nuclear layer and outer nuclear layer volumes predict disease activity and are associated with progression into multiple sclerosis.

The objectives of this paper are to compare in a multicenter setting patterns of regional cortical thickness in patients with relapsing–remitting multiple sclerosis (RRMS) and cognitive impairment (CI) and those cognitively preserved (CP), and explore the relationship between cortical thinning and cognitive performance.

T1-weighted isotropic brain scans were collected at 3T from seven European centers in 60 RRMS patients and 65 healthy controls (HCs). Patients underwent clinical and neuropsychological examinations. Cortical thickness (CTh) measures were calculated using FreeSurfer (failing in four) and both lobar and vertex-based general linear model (GLM) analyses were compared between study groups.

Twenty (36%) MS patients were classified as CI. Mean global CTh was smaller in RRMS patients compared to HCs (left 2.43 vs. 2.53 mm, right 2.44 vs. 2.54 mm, p < 0.001). Multivariate GLM regional analysis showed significantly more temporal thinning in CI compared to CP patients. Verbal memory scores correlated to regional cortical thinning in the insula whereas visual memory scores correlated to parietal thinning.

This multicenter study showed mild global cortical thinning in RRMS. The extent of thinning is less pronounced than previously reported. Only subtle regional differences between CI and CP patients were observed, some of which related to specific cognitive domains.

The in vivo relationship of spinal cord lesion features with clinical course and function in multiple sclerosis (MS) is poorly defined.

The objective of this paper is to investigate the associations of spinal cord lesion features on MRI with MS subgroup and disability.

We recruited 120 people: 25 clinically isolated syndrome, 35 relapsing–remitting (RR), 30 secondary progressive (SP), and 30 primary progressive (PP) MS. Disability was measured using the Expanded Disability Status Scale. We performed 3T axial cervical cord MRI, using 3D-fast-field-echo and phase-sensitive-inversion-recovery sequences. Both focal lesions and diffuse abnormalities were recorded. Focal lesions were classified according to the number of white matter (WM) columns involved and whether they extended to grey matter (GM).

The proportion of patients with focal lesions involving at least two WM columns and extending to GM was higher in SPMS than in RRMS (p = 0.03) and PPMS (p = 0.015). Diffuse abnormalities were more common in both PPMS and SPMS, compared with RRMS (OR 6.1 (p = 0.002) and 5.7 (p = 0.003), respectively). The number of lesions per patient involving both the lateral column and extending to GM was independently associated with disability (p < 0.001).

More extensive focal cord lesions, extension of lesions to GM, and diffuse abnormalities are associated with progressive MS and disability.

Natalizumab is an effective therapy in relapsing–remitting multiple sclerosis (RRMS), as it reduces lymphocyte transmigration through the blood–brain barrier (BBB) and induces lymphocytosis.

To analyse natalizumab-induced lymphocytosis (NIL) as a biomarker of drug efficacy.

We enrolled 50 relapsing–remitting (RR) and progressive–relapsing (PR) natalizumab-treated patients who had received at least 16 infusions and had been tested for lymphocyte count 24 hours before each administration. Clinical, MRI and hematological data were collected. Patients were divided into responders and sub-optimal responders according to the experience of at least one clinical and/or instrumental relapse during the treatment.

In 15 (30%) patients, an instrumental/clinical (14) or only instrumental (one) relapse occurred. We found a statistically significant difference in the mean percentage of the lymphocytes between the two groups over the first ten administrations (p=0.04). The comparison between the time-to-relapse in the groups with high and low levels of lymphocytes showed that the group with a low NIL had a greater risk of relapse (p=0.03).

We suggest that NIL could be a biomarker of therapeutic efficacy in patients with RRMS treated with natalizumab, and that the risk of relapse may be higher in patients with a lower-than-expected NIL.

There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments.

To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS.

In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans.

We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone.

Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS.

Onset of multiple sclerosis (MS) is typically in early adulthood. The impact, if any, of menopause on the MS course is unknown. Our objective was to determine whether menopause is associated with changes in MS severity in a longitudinal clinical cohort.

Responses from an ongoing reproductive questionnaire deployed in all active female CLIMB observational study participants with a diagnosis of clinically isolated syndrome (CIS) or MS were analyzed when the response rate was 60%. Reproductive data were linked with clinical severity measures that were prospectively collected every six months, including our primary measure, the Expanded Disability Status Scale (EDSS).

Over one-half of the respondents (368 of 724 women) were postmenopausal. Median age at natural menopause was 51.5 years. In our primary analysis of 124 women who were followed longitudinally (mean duration 10.4 years) through their menopausal transition (natural or surgical), menopause represented an inflection point in their EDSS changes (difference of 0.076 units; 95% CI 0.010–0.14; p = 0.024). These findings were not explained by vitamin D levels, nor changes in treatment or smoking status over this period. There was no effect of hormone replacement therapy (HRT) exposure, but HRT use was low.

We observed a possible worsening of MS disability after menopause. Larger cohorts are required to assess any HRT effects.

Multiple sclerosis (MS) is a debilitating disease that negatively impacts patients’ lives.

ENABLE assessed the effect of long-term prolonged-release (PR) fampridine (dalfampridine extended release in the United States) treatment on patient-perceived health impact in patients with MS with walking impairment.

ENABLE was a 48-week, open-label, Phase 4 study of PR-fampridine 10 mg twice daily. Patients who showed any improvement in Timed 25-Foot Walk walking speed at weeks 2 and 4 and any improvement in 12-item MS Walking Scale score at week 4 remained on treatment. The primary endpoint was change from baseline in 36-Item Short-Form Health Survey (SF-36) physical component summary (PCS) score.

At week 4, 707/901 (78.5%) patients met the criteria to remain on treatment. Patients on treatment demonstrated significant and clinically meaningful improvements in SF-36 PCS scores from baseline (mean change (95% confidence interval)) to week 12 (4.30 (3.83, 4.78); p < 0.0001), week 24 (3.75 (3.23, 4.27); p < 0.0001), week 36 (3.46 (2.95, 3.97); p < 0.0001), and week 48 (3.24 (2.72, 3.77); p < 0.0001). Significant improvements from baseline were also demonstrated in secondary health measures in patients on treatment.

PR-fampridine improved patient-perceived physical and psychological health impact of MS measured in a real-life setting.

Despite a growing use of rituximab (RTX) in neuromyelitis optica (NMO), data are lacking in patients with refractory NMO (RNMO), defined as cases with at least one relapse during immunosuppressive therapy.

The purpose of this study was to assess RTX as a maintenance therapy in RNMO.

Out of a total of 305 NMO cases from a population-based cohort, 21 RNMO patients received RTX during a mean follow-up period of 31 months.

After RTX, 11 patients (52.3%) were relapse free, meaning that 47.7% were refractory to RTX. The mean annualized relapse rate decreased from 1.3 to 0.4 (p<0.001) and median EDSS from 5 to 3 (p=0.02). Body mass index (BMI) was predictive of EDSS worsening.

RTX is an effective and well-tolerated treatment in RNMO. BMI could be a predictive factor for efficacy.

Spinal cord involvement in Behçet’s disease is not well studied.

To evaluate the clinical, laboratory and magnetic resonance imaging characteristics of spinal cord involvement in Behçet’s disease.

We retrospectively reviewed 10 spinal cord involvements in seven patients with Behçet’s disease.

The median age of onset for spinal cord involvement was 32 (23–45 years). Two patients showed a secondary progressive course. Cerebrospinal fluid findings revealed mild to moderate pleocytosis and/or elevated protein levels. In eight spinal cord involvements, the lesion was longer than three vertebrae. Serum anti-aquaporin-4 antibody was negative in all four patients tested.

Longitudinally extensive transverse myelitis is a characteristic manifestation of spinal cord involvement in Behçet’s disease.

Myelin oligodendrocyte glycoprotein (anti-MOG) antibody was reported in anti-aquaporin-4 (anti-AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD) patients.

To describe clinical phenotypes associated with anti-MOG.

Seventy consecutive Thai patients with inflammatory idiopathic demyelinating central nervous system disorders (IIDCD) who were previously anti-AQP4 seronegative were tested for anti-MOG.

Anti-MOG was positive in six patients, representing 20.7% of the IIDCD anti-AQP4 seronegative patients with a non-multiple sclerosis phenotype, and most had relapses. All first presented with optic neuritis with good visual recovery after treatment.

Anti-MOG positive patients may have manifestations that mimic NMOSD but differ in their course and prognosis from anti-AQP4 positive NMOSD.

Contrast-enhanced (ce) fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI) has recently been shown to identify leptomeningeal pathology in multiple sclerosis.

To demonstrate leptomeningeal enhancement on three-dimensional (3D) FLAIR in a case of Susac’s syndrome.

Leptomeningeal enhancement was correlated with clinical activity over 20 months and compared to retinal fluorescein angiography.

The size, number, and location of leptomeningeal enhancement varied over time and generally correlated with symptom severity. The appearance was remarkably similar to that of retinal vasculopathy.

Ce 3D FLAIR may aid in diagnosis and understanding of pathophysiology in Susac’s syndrome and may serve as a biomarker for disease activity.