What compensatory motor strategies do patients with multiple sclerosis develop for balance control?

INTRODUCTION: One of the main features of multiple sclerosis (MS) is the deterioration of motor pathway axons, and in some cases, sensory system axons. Consequently, experimental sensori-motor testing with the undisturbed upright stance paradigm might be useful. It can be hypothesized that the postural strategies could be differently affected depending on the degree of dysfunction of both sensory and motor tracts. METHODS: Twelve and fifteen patients, classified from sensory clinical tests as ataxo-spastic (SEP-AS) or only spastic (SEP-S), respectively were included in this study and compared to 12 healthy adults matched for age. The postural strategies were assessed from the centre of pressure trajectories (CP), measured from the force platform on which the subjects were instructed to stand upright eyes open for a trial lasting 51.2 s. biomechanical modelling was applied to these trajectories to compute the movements of the centre of gravity (CG) and consequently, the vertical difference between the CP and then the CP-CG, two elementary movements known to characterize postural performance movements for CGv and horizontal acceleration communicated to the CG for the CP-CG movements, and consequently overall neuro-muscular activity. To estimate the relative contribution of each of these elementary movements, an analysis based on frequency parameters (RMS and MF) was conducted. RESULTS: Both SEP-AS and SEP-S groups demonstrate larger CG and CP-CG movements than the age paired individuals. However, some statistically significant differences has to be emphasised between the two MS subgroups but only for the CP-CG component: the RMS of these movements are largely increased for the SEP-AS group, as compared to the SEP-S one. Biomechanically, this feature expresses the necessity for these very patients to produce exaggerated horizontal forces, and thus an increased energy expenditure, to handle the CG movements. The lack of effect observed for the CG movements underlines the capacity for the SEP-AS group to set appropriate control mechanisms for counteracting these less favourable initial conditions. CONCLUSION: By demonstrating specific trends in the postural organisation aimed at controlling undisturbed upright stance maintenance, this study can be of interest for the practitioner by legitimating this experimental paradigm as a simple and non invasive way to diagnose appropriately the sensori-motor deficiency.     

Induction or escalation therapy for patients with multiple sclerosis?

The concept of induction followed by a long-term maintenance treatment has attracted much attention for the treatment of multiple sclerosis over the 30 past years. It was first demonstrated by the combination of induction therapy with mitoxantrone (six-monthly courses) followed by maintenance therapy with an immunomodulatory treatment such as an interferon-β or glatiramer acetate. Long-term observational studies confirmed that this therapeutic regimen provides a rapid reduction in disease activity and sustained disease control up to at least five years in 60% of patients. A better treatment response was observed in patients with early signs of aggressive disease, as shown in randomised studies (using six-monthly 12 mg/m² of mitoxantrone intravenously at a cumulative dose of 72 mg/m², followed by an interferon-β) as well as in long-term observational studies. But the safety profile of mitoxantrone make it more particularly suitable for young patients with frequent early relapses with incomplete recovery and multiple gadolinium-enhancing T1 lesions or spinal cord lesions on magnetic resonance imaging. More recently approved, the second candidate for an induction strategy is alemtuzumab: phases II and III randomised studies showed the superiority of alemtuzumab 12 mg per day given intravenously for only five days and repeated for 3 days one year later, compared with interferon-β three times a week. Like with mitoxantrone, results supported the concept of long-term benefit after a short induction rather than escalation, in a subset of patients with early very active MS, with a sustained control of the disease for up to 7 years in 60% of patients in the phase III extension studies and in a long-term observational study. On the contrary, when alemtuzumab was first studied later in the disease course, results were disappointing. However, the risk of developing manageable but potentially severe systemic autoimmune diseases within the years following the last course of alemtuzumab make it, like mitoxantrone, more suitable for patients with early aggressive MS. More recently, cladribine an oral immunosuppressant, showed interesting results in a phase III study extension suggesting its potential induction effect, since after two cycles of treatment (5 days repeated 1 month later) at one year of interval, the remained low up to 4 years of follow-up, in the absence of any new treatment. However, today other immunosuppressive drugs have proved to be strongly and rapidly efficacious in treating highly active MS patients but through a mechanism of continuous immunosuppression (i.e., natalizumab and ocrelizumab). Indeed, disease activity can reappear rapidly after stopping these drugs, sometimes associated with a rebound of the inflammatory process, which is the contrary of a mechanism of induction that is associated with a remnant effect. Taking into account advantages and disadvantages of the different DMDs, which enriched the today therapeutic arsenal for MS, we propose in this paper some algorithms summarizing our reflexion about using an escalation strategy or an induction strategy according to disease course and activity.     

What do we know about the role of IncRNAs in multiple sclerosis?

Multiple sclerosis is a chronic,inflammatory and degenerative disease of the central nervous system of unknown aetiology although well-defined evidence supports...     

Are statins a treatment option for multiple sclerosis?

BACKGROUND: Treatment options for multiple sclerosis (MS) are limited. The immunomodulatory drugs interferon beta and glatiramer acetate are only partly effective in reducing the relapse rate, slowing disease progression, and diminishing the number and volume of lesions on MRI. Mitoxantrone is an immunosuppressant approved for the treatment of active forms of relapsing-remitting or secondary progressive MS, but is dose-limited owing to its potential cardiotoxicity. Thus, identifying new effective therapeutic options with few side-effects is highly desirable. RECENT DEVELOPMENTS: Evidence has emerged that statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, have immunomodulatory effects. Recent reports showed that statins prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, in vitro experiments with human immune cells have shown an immunomodulatory profile of statins comparable to that of interferon beta. An open label clinical trial of simvastatin for MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. WHERE NEXT?: The obvious advantage of statins over existing MS therapies is their oral route of dosing. Statins might be beneficial for MS patients as monotherapy or as an add-on to established disease modifying drugs. As the evidence of the benefit of statins in MS is currently insufficient, large controlled clinical trials are needed. The first of these trials is about to start.     

Can we predict flu-like symptoms in patients with multiple sclerosis treated with interferon-β?

Interferon-beta1b treatment in relapsing-remitting multiple sclerosis can frequently induce systemic side effects such as flu-like symptoms with fever. In vitro stimulation of peripheral blood leukocytes with interferon-beta1b before the beginning of therapy shows that patients who develop fever generally have increased levels of interleukin-6.     

Is malnutrition a problem for multiple sclerosis patients?

Nutritional problems associated with multiple sclerosis (MS) have been observed in a number of studies and case reports. However, the prevalence of malnutrition in MS patients is currently unknown. The primary aim of this study was to assess the prevalence of malnutrition in MS patients and to compare the frequency of malnutrition in MS to that of other diseases. The second aim of the study was to determine whether malnutrition was associated with MS type, disease duration or disability status in MS patients. One hundred two MS patients were included in the current study. The control group consisted of 50 patients with other chronic neurological diseases. Neurological examination scores, Kurtzke Functional System Scale scores, serum albumin levels, sedimentation rate and C reactive protein (CRP) were recorded for all patients. Chronic malnutrition was defined as serum albumin levels below 3.5 g/dl with normal sedimentation rate and CRP levels. Twelve MS patients and one control patient were diagnosed with chronic malnutrition, but the difference was not statistically significant (p = 0.062). In the MS group, MS type, disease duration, number of attacks, Expanded Disability State Score and Functional System Scale scores were not significantly different regardless of patients’ serum albumin levels. We found malnutrition was more prevalent in MS patients than in other chronic diseases. Malnutrition in MS patients was independent of disease course, disease duration, number of attacks, disability status and functional system involvement. These results should be confirmed with further prospective studies in larger MS populations from several facilities.     

Long-term interferon-β treatment for multiple sclerosis

Abstract. The aim of our study was to analyze the dropout rate in patients with relapsing-remitting multiple sclerosis (RRMS) under long-term treatment with the three commercially available interferon beta (IFN) preparations. According to the drug taken, we divided 122 RRMS patients into 4 groups: Betaferon group, 56 patients taking INF-1b (24 MIU weekly, subcutaneous injections); Avonex group, 38 patients taking IFN-1a (6 MIU weekly, intramuscularly); Rebif group, 18 patients taking INF-1b (18 MIU subcutaneously). Ten patients who shifted from Betaferon to Avonex were included in a fourth group. Dropouts were registered every trimester with the related cause. Data were evaluated using Kaplan-Meier survival analysis and log-rank test. During the observation period of five years, 48 patients (39.9%) dropped out: 48% of the patients in Betaferon group withdrew at a median of 758 days, 26% of the Avonex group at 356 days; 38% of the Rebif group at 421 days, and 40% of those who shifted from Betaferon to Avonex at 259 days. The differences between groups were not significant on survival analysis. Patients receiving higher dose treatment (Betaferon and Rebif groups) dropped out mainly for clinical adverse events; conversely, patients receiving lower dose therapy (Avonex group) dropped out most often for inefficacy. Patients who shifted to a lower dose treatment (fourth group) had a dropout rate similar to that of the initial treatment. Our data showed that one-third of the patients stopped the therapy, mostly for adverse events and then for inefficacy, while the remaining two-thirds were still on treatment without problems up to 5 years of follow-up. Compliance seems related to the dose of the drug, but further analysis is needed to confirm our data.     

Assessing relapses in treatment trials of relapsing and remitting multiple sclerosis: can we do better?

Published Phase III immunomodulatory treatment trials in relapsing and remitting multiple sclerosis have demonstrated a modest decline in attack rates, but only a minor effect on disability. As genuine disability progression is difficult to ascertain in relatively short studies with the conventional rating scales available, the acquisition and analysis of relapse data are critical. However, there are as yet unresolved questions related to the latter. We will first discuss the problems associated with relapse definitions by trial investigators, the paucity of the data collected (especially on the magnitude and duration of exacerbations) and statistical issues in their analysis. We will then suggest practical points for obtaining more accurate information on relapses and evaluating them meaningfully. While there is still general consensus among neurologists that primary endpoints for therapeutic trials should be clinical, improvements for future protocols are essential.     

Why treat early multiple sclerosis patients?

Class 1 clinical trials demonstrated that immunomodulatory treatments (interferon beta and glatiramer acetate) reduce the disease activity and the accumulation of disability in relapsing remitting multiple sclerosis. Moreover interferon beta-1b also had similar positive effects in secondary progressive multiple sclerosis. The magnitude of these clinical effects was modest, but the reduction of inflammatory activity, as revealed by magnetic resonance imaging, was marked. Converging evidence from new pathological studies and new magnetic resonance techniques, characterized by increased pathological specificity, has shown that already in the early phases of the disease inflammatory activity determines irreversible axonal damage. Moreover, the amount of inflammatory activity at the clinical presentation of the disease has some value in predicting long-term disability. Taken together, these data indicate that patients may benefit from early treatment; the positive results of the Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study support this conclusion.     

What information do patients with schizophrenia have about their illness and treatment?

Improved compliance with antipsychotic medication is a major issue in schizophrenic management. For this purpose educational programs have been used, but up to now, little or no information has been gathered or published in France concerning schizophrenic patients' opinion on information they have about their disease and their treatment. Thus we conducted a survey in concert with 78 psychiatrists from the French psychiatric health service. From this cross sectional survey we assessed 336 outpatients (male: 72%; mean age: 36 +/- 10.4 years) with schizophrenia according to the DSM IV (paranoid sub type: 57%, disorganized: 12%, catatonic: 1%, undifferentiated: 12%, residual: 18%). The mean duration of the illness was 11.6 years (sd: 8.5) and the mean duration of the follow up with the same psychiatrist was 5.4 years (sd: 5.1). Patients completed a questionnaire which assessed their level of information on mental illness and treatment. The diagnosis of schizophrenia has been told to their patients by 39% of the psychiatrists, and treatment has been explained to the patients by 96% of the practitioners. Results indicate less than half of the patients (45%) felt ill, only 46% thought they knew their illness well or very well (nevertheless only 31% of them named spontaneously the diagnosis of schizophrenia or psychosis), and 61% considered that they had been given sufficient information. Most of the patients (79%) were persuaded that their treatment was useful, and 75% of patient were completely satisfied with their treatment. Surprisingly 92% reported taking their medication regularly. Most patients think that a high level of information about their illness (74%) and treatment (79%) help them to cope better with their schizophrenia. Analysis performed according to patients characteristics indicated that paranoid patients felt more ill (p = 0.035) than others, thought to know less about their illness (p = 0.0065), and were less satisfied with their treatment (p = 0.04) and their level of information (p = 0.03). Patients with a duration of their illness longer than 10 years were more convinced of the utility of their treatment (p = 0.02) and had debated more on the choice of their treatment with their psychiatrist (p = 0.047). Patients older than 35 years were more satisfied with their information (p = 0.002). More patients with atypical antipsychotics accepted to take their treatment on a regular basis (p = 0.035) compared to patients under classical neuroleptics. This survey underlines that mental health consumers' opinions can be obtained even in the field of schizophrenia, and argues in favour of further such investigations. It also highlights the need for educational programs on schizophrenia and antipsychotic medications.     

What role for genetics in the prediction of multiple sclerosis?

For most of us, the foundations of our understanding of genetics were laid by considering Mendelian diseases in which familial recurrence risks are high, and mutant alleles are both necessary and sufficient. One consequence of this deterministic teaching is that our conceptualization of genetics tends to be dominated by the notion that the genetic aspects of disease are caused by rare alleles exerting large effects. Unfortunately, the preconceptions that flow from this training are frequently erroneous and misleading in the context of common traits, where familial recurrence risks are modest, and for the most part the relevant alleles are neither rare, necessary, nor sufficient. For these common traits, the genetic architecture is far more complex, with susceptibility rather than causality resulting from the combined effects of many alleles, each exerting only a modest effect on risk. None of these alleles is sufficient to cause disease on its own, and none is essential for the development of disease. Furthermore, most are carried by large sections of the population, the vast majority of which does not develop the disease. One consequence of our innate belief in the Mendelian paradigm is that we have an inherent expectation that knowledge about the genetic basis for a disease should allow genetic testing and thereby accurate risk prediction. There is an inevitable feeling that the same should be true in complex disease, but is it? ANN NEUROL 2010;67:3–10     

Prorating WAIS – IV summary scores for patients with relapsing-remitting multiple sclerosis

We evaluated the utility of prorating appropriate combinations of two, six and eight Wechsler Adult Intelligence Scale – Fourth Edition (WAIS – IV) subtests for estimating the Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Full Scale IQ (FSIQ) and General Ability Index (GAI) in a sample of individuals diagnosed with multiple sclerosis (MS). Forty-eight outpatients completed the WAIS – IV and Wechsler Memory Scale – Fourth Edition (WMS – IV) as part of a comprehensive neuropsychological battery. Means for age, education and duration of diagnosis were 42.35, 14.21 and 8.30 years, respectively. Paired t-tests showed no significant differences between prorated and standard means for VCI (93.46 vs. 93.73), PRI (90.19 vs. 89.44), FSIQ (88.53 vs. 88.47) or GAI (90.56 vs. 90.65). Correlations between prorated and standard composites were ≥0.89 in every instance. Correlations between the standard and prorated composites and education, disability status and WMS – IV indexes did not reveal a single contrast, where the correlations were significantly different. The present findings support the use of the two-subtest VCI and PRI composites and the eight-subtest FSIQ and four-subtest GAI in the assessment of patients with MS.     

What should we do with a discontinued shunt?

Purpose  

The reported rate is up to 10% of shunt disconnection or fracture, either ventriculoperitoneal or subduroperitoneal. However, not all of shunt discontinuity is associated with shunt malfunction. We analyzed the discontinuity of the shunt system and related factors and tried to present a follow-up policy.