Apolipoprotein E genotype does not associate with disease severity measured by Multiple Sclerosis Severity Score

Objectives – During the last years, the association between apolipoprotein E (APOE) polymorphism and disease severity in multiple sclerosis (MS) has been studied with conflicting results. As a result of a considerable individual variation in the clinical course of MS, there is no consensus method for measuring progression using single assessments of disability. Recently, Multiple Sclerosis Severity Score (MSSS) method has been proposed for comparing disease progression using single data. We evaluate in our population if there is any correlation between APOE genotype and severity according to MSSS. Methods – We studied 82 patients followed up in our Neurology Unit throughout the year 2005, diagnosed with MS, and with disease duration of at least 2 years. We collected data concerning demographic and clinical variables including age of onset, disease duration, Expanded Disability Status Scale (EDSS) score and the total number of relapses. When reached, we determined the latency to EDSS scores of 4.0 and 6.0. We calculated progression index (PI) and relapse rate (RR). We ascertained MSSS for our patients in the global MSSS table. Results – We found four patients heterozygous for the E2 allele and 16 for the E4 allele. No patient was homozygous for E2 or E4. RR (P = 0.017 with 95% CI: 0.005–0.57) and PI (P = 0.016 with 95% CI: 0.004–0.38) were significantly lower in E4 carriers. MSSS scores were not associated with carriership of E2 or E4. Conclusion – Our results show no effect of the APOE genotype on the severity of MS measured by MSSS, as a recently published meta‐analysis has noticed. So, our data do not support a role for APOE in MS severity, in spite of the seeming influence shown using other measures such as PI. MSSS is probably the best method to measure severity with a single measure of disability and should be used more frequently when performing genetic research.     

The Expanded Disability Status Scale Score and Demographic Indexes Are Correlated with the Severity of Cognitive Impairment in Multiple Sclerosis Patients

Background and PurposeCognitive impairment (CI) is a common symptom of multiple sclerosis (MS). Although demographic and clinical factors contribute to MS-dependent CI, previous findings have been inconsistent. This study aimed to identify the cognitive domains that are impaired in MS patients, and to determine the impacts of the Expanded Disability Status Scale (EDSS) score and other clinical and demographic factors on them domains.MethodsThis study enrolled 115 MS patients. Cognitive performance was assessed using the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery. CI severity was assessed based on the number of impaired tasks in the MACFIMS battery, with impairment in two or more tasks defined as CI cases. Correlation analysis was used to determine whether factors including current age, age at disease onset, EDSS score, disease duration, relapse rate, and education level affect the severity of CI.ResultsThe scores on the Paced Auditory Serial Addition Test and Delis-Kaplan Executive Function System were the most and least affected, respectively. EDSS score (r=0.438, p<0.001), current age (r=0.393, p<0.001), and disease duration (r=0.486, p<0.001) were positively correlated with CI severity, whereas education level (r=−0.527, p<0.001) had a negative correlation with CI severity, and age at disease onset and relapse rate were not correlated with CI severity (r=0.150 and p=0.107, and r=0.052 and p=0.530, respectively). However, all variables (except EDSS score) significantly predicted CI severity in a multiple regression model (p<0.001, r=0.668).ConclusionsInformation processing speed and working memory were the most commonly affected cognitive domains in the present MS patients. CI severity had strong positive correlations with current age, EDSS score, and disease duration, and a negative correlation with education level. The relapse rate and age at disease onset were not correlated with CI severity.     

Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS

OBJECTIVE: To determine whether the MS Functional Composite (MSFC) can predict future disease progression in patients with relapsing remitting MS (RR-MS). BACKGROUND: The MSFC was recommended by the Clinical Outcomes Assessment Task Force of the National MS Society as a new clinical outcome measure for clinical trials. The MSFC, which contains a test of walking speed, arm dexterity, and cognitive function, is expressed as a single score on a continuous scale. It was thought to offer improved reliability and responsiveness compared with traditional clinical MS outcome measures. The predictive value of MSFC scores in RR-MS has not been determined. METHODS: The authors conducted a follow-up study of patients with RR-MS who participated in a phase III study of interferon beta-1a (AVONEX) to determine the predictive value of MSFC scores. MSFC scores were constructed from data obtained during the phase III trial. Patients were evaluated by neurologic and MRI examinations after an average interval of 8.1 years from the start of the clinical trial. The relationships between MSFC scores during the clinical trial and follow-up status were determined. RESULTS: MSFC scores from the phase III clinical trial strongly predicted clinical and MRI status at the follow-up visit. Baseline MSFC scores, and change in MSFC score over 2 years correlated with both disability status and the severity of whole brain atrophy at follow-up. There were also significant correlations between MSFC scores during the clinical trial and patient-reported quality of life at follow-up. The correlation with whole brain atrophy at follow-up was stronger for baseline MSFC than for baseline EDSS. CONCLUSION: MSFC scores in patients with RR-MS predict the level of disability and extent of brain atrophy 6 to 8 years later. MSFC scores may prove useful to assign prognosis, monitor patients during early stages of MS, and to assess treatment effects.     

Multiple Sclerosis Impact Scale (MSIS-29): relation to established measures of impairment and disability

OBJECTIVE: To validate the newly developed Multiple Sclerosis Impact Scale (MSIS-29) in a large, well characterized, independent group of MS patients by investigating the relation between the MSIS-29 and the Guy's Neurological Disability Scale (GNDS), the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). METHODS: Two hundred MS patients were recruited at our outpatient department. At the same visit GNDS, EDSS, MSFC and MSIS-29 were assessed. Data obtained from GNDS, EDSS and MSFC assessment were compared to both physical and psychological impact scores of the MSIS-29. In addition the contribution of GNDS subcategories, EDSS functional systems and MSFC components to the physical and psychological impact scores of the MSIS-29 was studied. RESULTS: Median scores were 37.5 for the physical and 22.2 for the psychological impact score of the MSIS-29, 13.0 for GNDS and 4.0 for EDSS. Mean MSFC was 0.07. The physical impact score showed good correlations with both GNDS (0.79) and EDSS (0.68) and a moderate correlation with the MSFC (-0.53). The psychological impact score showed weak correlations with EDSS (0.22) and MSFC (-0.30) and a moderately strong correlation with the GNDS (0.58). In 50 (25%) patients, scores on physical and psychological impact scales diverted, i.e., a relative high score on one scale combined with a relative low score on the other scale. This was related to the clinical disease course. CONCLUSION: Our study supports the use of the MSIS-29 as a measure for the assessment of physical impact of MS on normal daily life. In addition, our data provides a deeper understanding of the factors that determine both physical and psychological disease impact. Discrepancies between the latter two aspects deserve further attention.     

Reconsidering clinical outcomes in Multiple Sclerosis: relapses, impairment, disability and beyond

There is an increasing number of clinical trials testing new compounds which act at different stages of Multiple Sclerosis (MS). To prove their effectiveness several clinical outcome measures are used. The overall quality of clinical trials is increasing steadily due to the growing experience in this area, the increasing awareness of quality standards in the MS community and the more stringent requirements of regulatory authorities for approval of new treatments. Each successful clinical trial provided additional information that could be incorporated into the design of subsequent studies to improve their quality. However, the choice of appropriate outcome measures still presents major challenges. For an individual patient improvement or stability of their disability and to a lesser extent the relapse rate, are the main targets of treatment. As there is yet no scale or assessment, which objectively covers all major issues, it is recommended to use multiple instruments and endpoints as secondary outcome measures.     

Disease severity in children and adults with Pompe disease related to age and disease duration

Information about 255 children and adults with Pompe disease was gathered through a questionnaire. Disease severity was associated with disease duration and not with age; an early manifestation of the disease implied earlier wheelchair or ventilator dependency. The patient group under age 15 included a subgroup with a more severe and rapid course of the disease. They require more intensive follow-up and early intervention, before irreversible damage has occurred.     

Olfactory dysfunction in essential tremor: a deficit unrelated to disease duration or severity

Because olfactory dysfunction is a feature of neurodegenerative diseases, the authors hypothesized that it would be present in essential tremor. Thirty-seven cases and control subjects underwent the University of Pennsylvania Smell Identification Test. Mean score was lower in cases than in control subjects (29.0 +/- 6.1 vs 31.9 +/- 4.6, p = 0.02) and was not correlated with tremor severity or duration.     

Evoked potentials and CSF-immunoglobulins in MS: relationship to disease duration, disability, and functional status

In 100 MS patients, BAEP and tibial SEP abnormality rates increased significantly with disease duration and clinical disability. VEP correlated non-linearly with disease duration, and median nerve SEP correlated with disability. In multifactorial analysis, however, BAEP correlated significantly only with clinical brainstem and cerebellar signs. These results suggest that evoked potentials correlate more strongly with neurological status of the functional subsystems than either overall disability or disease duration. These findings indirectly suggest that evoked potentials may be useful monitors during large therapeutical trials in MS patients.     

Multiple sclerosis: assessment of disability and disability scales

Attempting to measure the impact of multiple sclerosis (MS) on the individuals patients has become a major issue stimulated by both the emergence of new therapeutic agents and the increasing demand to incorporate the patient’s perspective. Disability has been the main focus. Recently, new disability scales have been developed and generic scales evaluated in an attempt to replace or complement the constantly used and much criticized Expanded Disability Status Scale (EDSS). There is, however, the growing realization that it is important to incorporate broader aspects of disease input such as are contained within the concepts of health-related quality of life. Current scales in this area are limited in either their scientific soundness and/or clinical usefulness, and it may be appropriate to consider the development of a new MS-specific measure of disease impact for use in clinical trials. Received: 27 September 1997 Accepted: 27 October 1997     

Pediatric Multiple Sclerosis: an Update

Purpose of Review

Diagnostic criteria for pediatric-onset multiple sclerosis (POMS) and related demyelinating disorders have been updated, neuroimaging studies have revealed new insights, biological assays identify patients with specific antibodies that influence both diagnosis and treatment, clinical trials are informing on treatment efficacy and safety, and longitudinal studies of neurological, cognitive and quality of life outcomes are informing on the impact of these diseases. We provide updates to assist providers caring for these children.

Recent Findings

The recent 2017 McDonald Criteria for MS provide a simplified means to confirm diagnosis at onset and over time, and have been shown to be equally applicable for POMS. MRI analyses demonstrate that brain volume is reduced at onset, and that both volumetric and tissue integrity measures decline over time, indicating that POMS shares the degenerative aspects that also characterize adult-onset disease. The presence of myelin oligodendrocyte glycoprotein (MOG) antibodies at onset is detected in more than 50% of children with acute disseminated encephalomyelitis. When persistent over time, they are associated with relapsing disease. The first randomized clinical trials of disease supports superiority of fingolimod over subcutaneous interferon beta 1a, and demonstrated a favorable safety profile. Finally, while Expanded Disability Status Scale (EDSS) scores remain low in the first 10 years post-onset, POMS is associated with high rates of patient-reported fatigue and reduced engagement in exercise and carries a risk for cognitive impairment.

Summary

The past 15 years have borne witness to a marked expansion in recognition and research in POMS. There are now more specific diagnostic criteria, antibodies to CNS proteins appear to define diagnostically distinct disorders, clinical trials have successfully launched and one has completed, and we are gaining increasing appreciation of the impact of MS and related disorders on the lived experience of children and adolescents.

     

Neuroinflammatory Imaging Biomarkers: Relevance to Multiple Sclerosis and its Therapy

Magnetic resonance imaging is an established tool in the management of multiple sclerosis (MS). Loss of blood brain barrier integrity assessed by gadolinium (Gd) enhancement is the current standard marker of MS activity. To explore the complex cascade of the inflammatory events, other magnetic resonance imaging, but also positron emission tomographic markers reviewed in this article are being developed to address active neuroinflammation with increased sensitivity and specificity. Alternative magnetic resonance contrast agents, positron emission tomographic tracers and imaging techniques could be more sensitive than Gd to early blood brain barrier alteration, and they could assess the inflammatory cell recruitment and/or the associated edema accumulation. These markers of active neuroinflammation, although some of them are limited to experimental studies, could find great relevance to complete Gd information and thereby increase our understanding of acute lesion pathophysiology and its noninvasive follow-up, especially to monitor treatment efficacy. Furthermore, such accurate markers of inflammation combined with those of neurodegeneration hold promise to provide a more complete picture of MS, which will be of great benefit for future therapeutic strategies.