Interrogating large multiple sclerosis registries and databases: what information can be gained?

PURPOSE OF REVIEW: Although substantial progress has been made in understanding the natural history of multiple sclerosis (MS) and the development of new therapies, many questions concerning disease behavior and therapeutics remain to be answered. Data generated from real-world observational studies, based on large MS registries and databases and analyzed with advanced statistical methods, are offering the scientific community answers to some of these questions that are otherwise difficult or impossible to address. This review focuses on observational studies published in the last 2 years designed to compare the effectiveness of escalation vs. induction treatment strategies, to assess the effectiveness of treatment in pediatric-onset and late-onset MS, and to identify the clinical phenotype of secondary progressive (SP)MS. RECENT FINDINGS: The main findings originating from real-world studies suggest that MS patients who will qualify for high-efficacy disease-modifying therapies (DMTs) should be offered these as early as possible to prevent irreversible accumulation of neurological disability. Especially pediatric patients derive substantial benefits from early treatment. In patients with late-onset MS, sustained exposure to DMTs may result in more favorable outcomes. Data-driven definitions are more accurate in defining transition to SPMS than diagnosis based solely on neurologists' judgment. SUMMARY: Patients, physicians, industry, and policy-makers have all benefited from real-world evidence based on registry data, in answering questions of diagnostics, choice of treatment, and timing of treatment decisions.

Treatments in neurogenic bowel dysfunctions: evidence reviews and clinical recommendations in adults.

INTRODUCTION: Neurogenic bowel dysfunction (NBD) is an impairment of defecation control due to any nervous system lesion negatively affecting physical health status and quality of life. We aimed at systematically assessing all available evidence on NBD treatment in adults and providing clinical management guidance and recommendations. EVIDENCE ACQUISITION: PICOs and questions (N.=7) were identified by an expert panel. We searched for and retrieved evidence from the PUBMED and EMBASE databases, limited to the English language and the Western countries context, related to any type of setting and published from 2009 to 2019. Health effects, patient values, preferences and resource use were assessed. Of all, only RCTs, observational studies and systematic reviews on adult population (≥18 years) were analyzed. The study was conducted according to PRISMA guidelines and Cochrane recommendations. The effect size, if possible, was calculated for the interpretation of the outcomes, and evidence was assessed through the GRADE method. EVIDENCE SYNTHESIS: Thirty-one studies were included in our qualitative synthesis. Evidence is generally scarce. Most of the outcomes are narratively described and therefore defined by imprecision. Besides, most of the included studies are affected by risk of bias. Digital stimulation was found to be effective in short term follow-up. The pharmacological treatment choice, combined or alone, needs to be balanced case by case considering clinical history, setting of use and bowel management protocol. According to only one RCT supporting evidence mainly in persons affected by spinal cord injury (SCI), trans-anal irrigation (TAI) improves QoL and patient independency with a significant reduction of time spent for defecation and daily bowel program. History of urinary infections predicts the choice of using TAI. Patient-reported efficacy of colostomy alone or in combination with other surgeries appears evident in terms of patient's satisfaction and QoL over time. Nonetheless, perioperative and late complications can occur and may result in reduced acceptability over time. CONCLUSIONS: Evidence is somehow weak and mainly reported in SCI. The systematic use of assistive interventions does not reduce the need of conservative or invasive approaches. Studies are needed on the role of bowel management in protecting patients from complications secondary to NBD in long term follow-ups.

Experience with rituximab therapy in a real-life sample of multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune, neuroinflammatory, and neurodegenerative disease of the central nervous system. B cells have recently emerged as a promising target to significantly reduce inflammatory disease activity in MS, with successful trial studies using antiCD20 therapies. However, real-life data about safety and efficacy are limited. OBJECTIVES: To analyze the clinical and radiological inflammatory activity, adherence to therapy, and safety of rituximab (RTX) in an MS patients' sample, treated from 2015 to 2018 in our center PATIENTS AND METHODS: Retrospective study on prospectively collected data about relapses, disability progression, and radiological activity (new T2 lesions and Gd-enhancing lesions) were recorded and used to assess no evidence of disease activity (NEDA) at 12 months. RTX-related adverse events were recorded. RTX was administered intravenously at a dosage of 1000 mg twice 2 weeks apart, then every 6 months. RESULTS: Sixty-nine patients were included. Fifty-three (76.8%) had a relapsing-remitting, two a primary progressive course, and 14 a secondary progressive course. The mean follow-up period was 16 ± 9.7 months. Thirty-five (50.7%) patients had relapses in the year prior to RTX therapy, with a mean annualized relapse rate of 0.75, significantly reduced to 0.36 at 12 months (p < 0.001). Among the 36 patients included in the study who had an MRI available at 12 months, MRI activity was reduced from 88% (n = 32) to 8.3% (n = 3) at follow-up (p < 0.001). Twelve (17.4%) patients suspended RTX during the study. CONCLUSIONS: Our real-life experience confirms that off-label therapy with RTX may represent a valid, cost-effective therapeutic option in MS.

Abnormal cerebellar functional MRI connectivity in patients with paediatric multiple sclerosis.

OBJECTIVES: We investigated resting state functional connectivity (RSFC) of the cerebellar dentate nuclei in paediatric MS patients and its correlations with clinical, neuropsychological and structural MRI measures. METHODS: RSFC analysis was performed using a seed-region correlation approach and SPM8 from 48 paediatric MS patients and 27 matched healthy controls. RESULTS: In both groups, dentate nuclei RSFC was significantly correlated with RSFC of several cerebellar and extra-cerebellar brain regions. Compared with healthy controls, paediatric MS patients had reduced RSFC between the right dentate nuclei and the bilateral caudate nuclei and left thalamus as well as increased RSFC between the right dentate nuclei and the left precentral and postcentral gyri. Cognitively impaired patients showed a reduced RSFC between the dentate nuclei and bilateral regions located in the parietal, frontal and temporal lobes. Decreased RSFC was correlated with longer disease duration and higher T2 lesion volumes, whereas increased RSFC correlated with shorter disease duration, lower T2 lesion volume and a better motor performance. CONCLUSIONS: Modifications of cerebellar RSFC occur in paediatric MS and are influenced by the duration of the disease and brain focal lesions. Decreased RSFC may reflect early maladaptive plasticity contributing to cognitive impairment.

Regional hippocampal involvement and cognitive impairment in pediatric multiple sclerosis.

OBJECTIVES: We assessed global and regional hippocampal volume abnormalities in pediatric multiple sclerosis (MS) patients and their correlations with clinical, neuropsychological and magnetic resonance imaging metrics. METHODS: From 53 pediatric MS patients and 18 healthy controls, global hippocampal volume was computed using a manual tracing procedure. Regional hippocampal volume modifications were assessed using a radial mapping analysis. MS patients with abnormal performance in three or more tests of a neuropsychological battery for children were classified as cognitively impaired. RESULTS: Global hippocampal volume was reduced in MS patients compared with controls, but did not correlate with clinical, neuropsychological and magnetic resonance imaging measures. Compared to controls, MS patients experienced bilateral radial atrophy of the cornu ammonis, subiculum and dentate gyrus subfields as well as radial hypertrophy of the dentate gyrus subfield. Regional hippocampal volume modifications correlated with brain T2 lesion volume as well as attention and language abilities. Global hippocampal volume did not differ between cognitively impaired (n=12) and cognitively preserved MS patients. Compared to cognitively preserved, cognitively impaired MS patients had atrophy of the subiculum and dentate gyrus subfields of the right hippocampus. CONCLUSIONS: Hippocampal subregions have different vulnerability to damage in pediatric MS. Regional rather than global hippocampal involvement contributes to global cognitive impairment as well as to deficits of selected cognitive tests.

Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis.

In patients with multiple sclerosis (MS), grey matter damage is widespread and might underlie many of the clinical symptoms, especially cognitive impairment. This relation between grey matter damage and cognitive impairment has been lent support by findings from clinical and MRI studies. However, many aspects of cognitive impairment in patients with MS still need to be characterised. Standardised neuropsychological tests that are easy to administer and sensitive to disease-related abnormalities are needed to gain a better understanding of the factors affecting cognitive performance in patients with MS than exists at present. Imaging measures of the grey matter are necessary, but not sufficient to fully characterise cognitive decline in MS. Imaging measures of both lesioned and normal-appearing white matter lend support to the hypothesis of the existence of an underlying disconnection syndrome that causes clinical symptoms to trigger. Findings on cortical reorganisation support the contribution of brain plasticity and cognitive reserve in limiting cognitive deficits. The development of clinical and imaging biomarkers that can monitor disease development and treatment response is crucial to allow early identification of patients with MS who are at risk of cognitive impairment.

Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial.

OBJECTIVE: To assess in multiple sclerosis (MS) the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) vs mitoxantrone (MTX) on disease activity measured by MRI. METHODS: We conducted a multicenter, phase II, randomized trial including patients with secondary progressive or relapsing-remitting MS, with a documented increase in the last year on the Expanded Disability Status Scale, in spite of conventional therapy, and presence of one or more gadolinium-enhancing (Gd+) areas. Patients were randomized to receive intense immunosuppression (mobilization with cyclophosphamide and filgrastim, conditioning with carmustine, cytosine-arabinoside, etoposide, melphalan, and anti-thymocyte globulin) followed by AHSCT or MTX 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years following randomization. Secondary endpoints were the cumulative number of Gd+ lesions, relapse rate, and disability progression. Safety and tolerability were also assessed. Twenty-one patients were randomized and 17 had postbaseline evaluable MRI scans. RESULTS: AHSCT reduced by 79% the number of new T2 lesions as compared to MTX (rate ratio 0.21, p = 0.00016). It also reduced Gd+ lesions as well as the annualized relapse rate. No difference was found in the progression of disability. CONCLUSION: Intense immunosuppression followed by AHSCT is significantly superior to MTX in reducing MRI activity in severe cases of MS. These results strongly support further phase III studies with primary clinical endpoints. The study was registered as EUDRACT No. 2007-000064-24.

Cognitive impairment in paediatric multiple sclerosis patients is not related to cortical lesions.

We investigated the contribution of cortical lesions to cognitive impairment in 41 paediatric MS patients. Thirteen (32%) paediatric MS patients were considered as cognitively impaired. T2-hyperintense and T1-hypointense white matter lesion volumes did not differ between cognitively impaired and cognitively preserved MS patients. Cortical lesions number, cortical lesions volume and grey matter volume did not differ between cognitively impaired and cognitively preserved patients, whereas white matter volume was significantly lower in cognitively impaired versus cognitively preserved MS patients (p=0.01). Contrary to adult MS, cortical lesions do not seem to contribute to cognitive impairment in paediatric MS patients, which is likely driven by white matter damage.

Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up.

OBJECTIVE: The aim of the study was to perform a third cognitive assessment in our pediatric-onset multiple sclerosis (MS) patient cohort and determine predictors of the individual cognitive outcome. METHODS: After 4.7 ± 0.7 years from baseline evaluation, 48 of 63 patients in the original cohort were reassessed on an extensive neuropsychological battery and compared with 46 healthy controls. Two alternate versions of the tests were used at different assessment points. Cognitive impairment was defined as the failure of ≥3 tests; individual change in the cognitive impairment index was measured. RESULTS: At year 5, 38% of the subjects with MS fulfilled our criterion for impairment. Between years 2 and 5, regarding individual cognitive impairment index change, 66.7% of the patients improved. However, comparing baseline and 5-year testing (when the same versions of the tests were used), cognitive impairment index deterioration was observed in 56% of the patients, improvement in 25%, and stability in 18.8%. A deteriorating performance was related to male sex, younger age and age at MS onset, and lower education. None of these variables, however, was retained in the multivariate analysis. CONCLUSIONS: Cognitive outcome in pediatric-onset MS can be heterogeneous. Progression of cognitive problems in a few subjects and potential for compensation and improvement in others call for systematic cognitive screening in this population and development of effective treatment strategies.

Intranetwork and internetwork functional connectivity abnormalities in pediatric multiple sclerosis.

Active motor functional magnetic resonance imaging (fMRI) studies have shown that pediatric multiple sclerosis (MS) patients have a strictly lateralized pattern of activations and a preserved functional connectivity (FC) within the motor system when compared to age-matched healthy controls. However, it is still not clear whether a preserved FC in pediatric MS is present only in the motor system, or involves other relevant functional system. Resting-state (RS) fMRI is a valuable tool for an unbiased investigation of FC abnormalities of multiple networks. This study explored abnormalities of RS FC within and between large-scale neuronal networks from 44 pediatric MS patients and 27 controls and their correlation with clinical, neuropsychological, and conventional MRI measures. Compared to controls, pediatric MS patients had a decreased FC of several regions of the sensorimotor, secondary visual, default-mode (DMN), executive control, and bilateral working memory (WMN) networks. They also experienced an increased FC in the right medial frontal gyrus of the attention network, which was correlated with T2 lesion volume. Cognitively impaired patients had decreased RS FC of the right precuneus of the left WMN. An increased FC between the sensorimotor network and the DMN, and between the L WMN and the attention network as well as a decreased FC between L WMN and the DMN were also found. A distributed pattern of FC abnormalities within large-scale neuronal networks occurs in pediatric MS patients, contributes to their cognitive status, and is partially driven by focal white matter lesions. Internetwork connectivity is relatively preserved in these patients.

Clinical case reviews in multiple sclerosis spasticity: experiences from around Europe.

Spasticity is one of the main symptoms associated with multiple sclerosis (MS). Epidemiological studies indicate that approximately two-thirds of MS patients experience spasticity and, in a relevant proportion of this group, spasticity is moderate to severe. Yet, spasticity remains largely undertreated. The most commonly used oral antispasticity agents (e.g., baclofen, tizanidine, gabapentin) generally do not reduce spasticity adequately at dosages that are well tolerated by patients. This review of MS spasticity cases from around Europe presents current knowledge of considerations for administration of a new agent (tetrahydrocannabinol/cannabidiol-based nabiximols [Sativex®] oromucosal spray) for management of MS spasticity, with the aim of ensuring appropriate and optimal use for best outcomes. Assessment of the European clinical experience is intended to provide a better understanding of the prescribing regulations for MS spasticity treatments, facilitate identification of suitable candidate patients for Sativex and increase awareness of alternative management approaches for MS-related spasticity.

Current recommendations for multiple sclerosis treatment in pregnancy and puerperium.

As multiple sclerosis (MS) typically starts at about 30 years of age, and is twice more frequent in females than in males, women with MS frequently face issues related to pregnancy and to the effects of medications commonly used in MS treatment. In this review, the authors provide and summarize literature data addressing the effect of MS and its treatments on pregnancy, delivery, postpartum and conception. There is a strong evidence that relapses are fewer during pregnancy but more frequent during postpartum, and that IFN-ß and glatiramer acetate do not expose patients and their babies to relevant adverse events; nevertheless, these drugs should be discontinued during pregnancy and before conception. However, if their preventive withdrawal exposes patients to a high risk of disease activity, these medications could be continued until proven conception. Little information is available on the effect of natalizumab and fingolimod.

Relevance of cognitive deterioration in early relapsing-remitting MS: a 3-year follow-up study.

OBJECTIVE: To assess longitudinally cognitive functioning in relapsing-remitting multiple sclerosis (RRMS) patients and its relationship with clinical and MRI variables. METHODS: Early RRMS patients and matched healthy controls were assessed in parallel in three testing sessions over 3 years, using the Rao's Brief Repeatable Battery of Neuropsychological Tests. Patients also underwent an MRI analysis of T2-weighted lesion volume (T2LV), number of gadolinium-enhanced lesions and whole brain atrophy. Forty-nine RRMS patients (mean age 36.9 ± 8.9 years; mean disease duration 2.9 ± 1.7 years, mean Expanded Disability Status Scale, 1.7 ± 0.7) and 56 healthy controls were recruited. RESULTS: At baseline, cognitive impairment was detected in 15 patients (30.6%). After 3 years, cognitive functioning worsened in the 29.3% of patients, whereas Expanded Disability Status Scale progression was observed in only three patients. The most sensitive test to detect cognitive deterioration over time was the Symbol Digit Modalities Test (SDMT). Only the presence of moderate cognitive impairment at baseline predicted further cognitive deterioration (p = 0.03). Among MRI variables, T2LV showed a weak to moderate relationship with some cognitive tasks. CONCLUSIONS: Over a 3-year period cognitive deterioration can be expected in approximately one-third of MS patients with relatively short disease duration. The SDMT is particularly suitable for longitudinal assessment of MS-related cognitive changes.