Multiple Sclerosis Disorders Research Articles

Randomized Controlled Trial about Effectiveness of Personalized Treatment of Balance Disorders in Multiple Sclerosis: Integration of Visual, Proprioceptive and Vestibular Components

Randomized Controlled Trial about Effectiveness of Personalized Treatment of Balance Disorders in Multiple Sclerosis: Integration of Visual, Proprioceptive and Vestibular Components

Multiple sclerosis: review of eye movement disorders and update of disease-modifying therapies.

To review important eye movement disorders in multiple sclerosis (MS) and update the ophthalmologist on disease-modifying therapies in MS, from the perspective of expert neurologists. A large study confirmed that eye movement abnormalities in MS can be commonly identified by bedside examination. Identifying such ocular motility disturbances can assist in the diagnosis and prognosis for patients with MS. Articles published on such agents as oral teriflunomide and the biologics, natalizumab and alemtuzumab, have defined emerging roles of these treatments in the management of MS. Many patients with MS suffer from isolated or a combination of eye movement disorders. Understanding their ocular motility disturbance patterns can help diagnose MS and correlate with the progression of MS. Exciting advances in MS disease-modifying treatments have been developed. Patients have more options than ever before of injectable, infusion and oral therapies. The therapeutic efficacy in lowering relapse rates is counterbalanced by these drugs' side-effects.

InMS: Chronic insomnia disorder in multiple sclerosis – a Portuguese multicentre study on prevalence, subtypes, associated factors and impact on quality of life

BackgroundSleep may be disrupted in Multiple Sclerosis (MS), but the prevalence of chronic insomnia disorder (CID) using standard diagnostic criteria is unknown. ObjectivesTo determine the prevalence of CID in an MS population, the frequency of CID subtypes, associated factors and impact on quality of life (QoL). MethodsMulticentre, hospital-based cross-sectional study. An adapted version of the Brief Insomnia Questionnaire was applied to a consecutively recruited MS population. The influence of demographic, MS-related features, fatigue, medical and psychiatric comorbidities, nocturnal symptoms, other sleep disorders, dysfunctional beliefs about sleep in CID was evaluated. The relation between CID and QoL was analysed. ResultsOf 206 MS patients, 22.3% fulfilled criteria for CID, with initial insomnia in 11.7%, maintenance insomnia in 11.2% and terminal insomnia in 10.2% of patients. CID was more frequent in female patients, those with nocturnal symptoms, medical comorbidities, higher levels of anxiety, depression and fatigue. Multivariable analysis identified female sex, medical comorbidities, anxiety and fatigue as independent factors for CID. CID patients had a significantly lower self-reported QoL. ConclusionsCID is prevalent in MS patients and associated with psychiatric and medical comorbidities, as well as fatigue. It has a negative impact on QoL.

In multiple sclerosis anxiety, not depression, is related to gender

Background: There is a high prevalence of depressive and anxiety disorders in multiple sclerosis (MS), a disease 2.5 times more frequent in females. Contrary to the general population, in whom studies have demonstrated higher rates of depression and anxiety in females, little is known about the impact of gender on psychiatric sequelae in MS patients. Objectives: We conducted a retrospective study to try to clarify this uncertainty. Methods: Demographic, illness-related and behavioral variables were obtained from a neuropsychiatric database of 896 patients with a confirmed diagnosis of MS. Symptoms of depression and anxiety were obtained with the Hospital Anxiety and Depression Scale (HADS). Gender comparisons were undertaken and predictors of depression and anxiety sought with a linear regression analysis. Results: HADS data were available for 711 of 896 (79.35%) patients. Notable gender differences included a higher frequency of primary progressive MS in males (p = 0.002), higher HADS anxiety scores in females (p < 0.001), but no differences in HADS depression scores. Conclusion: In MS, gender influences the frequency of anxiety only. This suggests that the etiological factors underpinning anxiety and depression in MS are not only different from one another, but also in the case of depression, different from those observed in general population samples.

Time course of changes in the development of gait disorders in multiple sclerosis

Objective : to estimate the time course of changes in foot biomechanical function as multiple sclerosis (MS) progresses in patients with different degrees of disability compared to a control group. Patients and methods. To estimate the time course of changes in gait disorders in MS, changes in foot biomechanical function were explored in 30 patients with relapsing-remitting MS. Their neurological status was evaluated using the expanded disability status scale (EDSS); pedographic examination was made applying a plantar pressure distribution system; all the patients were examined twice. During the first examination, the patients were divided into two groups: 1) minimal neurological disorders (EDSS scores of < 3.0) and 2) moderate ones (EDSS scores of ≥3.0). Results and discussion. The patients with a mild neurological deficit showed increases in foot load and its lateralization by elevating pressure on the heads of the fourth and fifth metatarsal bones, as evidenced by a significant rise in mean pressure, maximum force, and force-time integral. These changes occurred in the absence of the patients’ complaints of changes in movements. Pedographic examination revealed the changes indicating an enlarged anterior transverse arch and the lower role of the hallux in body weight transfer in the patients with a moderate neurological deficit despite the fact that there were no further visible negative changes in a motor process or progression in neurological deficit. The pedographic examination makes it possible to estimate the degree of gait disorders caused by pyramidal and/or cerebellar lesions and to identify a leading role of this or that functional system in their genesis. Pyramidal dysfunction has impact on the pressurization of the heads of the second and third metatarsal bones. Computed pedography can identify clinically subtle movement changes and estimate the time course of changes in movement disorders in MS patients, including those to evaluate the efficiency of therapy and rehabilitation measures.

Correlations between depression, cognitive status, functional scores, disability and lesion load in multiple sclerosis treated with interferon beta 1a

Abstract Introduction: Depression and cognitive impairment are the most frequent mental disorders in multiple sclerosis (MS) and represent an important cause of morbidity and mortality. The aim of the study was to analyse the main determinants of depression in multiple sclerosis. Materials and methods: Thirty-two patients with relapsing remitting multiple sclerosis (RRMS), treated with Interferon Beta 1a, without relapses and corticosteroid treatment in the last 30 days, were included in the study. The mean age of the patients was 35.4±9.2 years, M/F ratio 0.33. Depression level was evaluated by the Romanian version of Beck Depression Inventory (BDI) and the cognitive function with Paced Auditory Serial Addition Test 3 (PASAT 3), Symbol Digit Modalities Test (SDMT). The functional status and disability level of the patients were evaluated with Multiple Sclerosis Functional Composite and Expanded Disability Status Scale. In all patients a cerebral MRI with intravenous contrast administration was performed using a 1.5T MRI device. Results: Twenty-three patients were free of depression (score 1-10), 4 patients presented mild mood disturbance (score 11-16), 3 borderline clinical depression (score 17-20) and 2 moderate depression (score 21-30). The mean BDI score was 8.71±7.16. BDI score correlated significantly with EDSS (R=0.38, p=0.03), PASAT 3 (R=-0.42, p=0.01), SDMT (R=-0.58, p=0.0007), Timed 25-Foot Walk (R=0.43, p=0.01) and 9-Hole Peg Test (R=0.45, p=0.008). From the EDSS functional scores, significant correlations were found with the urinary score (R=0.4, p=0.01) and sensitive score (R=0.49, p=0.004). BDI score correlated significantly with the total number of T2 lesions (R=0.31, p=0.05) while there was no correlation with the number of active lesions. Conclusions: The main determinants of depression in RRMS patients are the cognitive impairment, the affection of fine hand movements (9-HP), gait impairment (T25FT) and bladder and sensitive dysfunction.

Chapter 36 - Hearing disorders in multiple sclerosis

Multiple sclerosis (MS) is a disease that is both a focal inflammatory and a chronic neurodegenerative disease. The focal inflammatory component is characterized by destruction of central nervous system myelin, including the spinal cord; as such it can impair any central neural system, including the auditory system. While on the one hand auditory complaints in MS patients are rare compared to other senses, such as vision and proprioception, on the other hand auditory tests of precise neural timing are never "silent." Whenever focal MS lesions are detected involving the pontine auditory pathway, auditory tests requiring precise neural timing are always abnormal, while auditory functions not requiring such precise timing are often normal. Azimuth sound localization is accomplished by comparing the timing and loudness of the sound at the two ears. Hence tests of azimuth sound localization must obligatorily involve the central nervous system and particularly the brainstem. Whenever a focal lesion was localized to the pontine auditory pathway, timing tests were always abnormal, but loudness tests were not. Moreover, a timing test that included only high-frequency sounds was very often abnormal, even when there was no detectable focal MS lesion involving the pontine auditory pathway. This test may be a marker for the chronic neurodegenerative aspect of MS, and, as such could be used to complement the magnetic resonance imaging scan in monitoring the neurodegenerative aspect of MS. Studies of MS brainstem lesion location and auditory function have led to advances in understanding how the human brain processes sound. The brain processes binaural sounds independently for time and level in a two-stage process. The first stage is at the level of the superior olivary complex (SOC) and the second at a level rostral to the SOC.

Structural ‘connectomic’ alterations in the limbic system of multiple sclerosis patients with major depression

Background: Major depression (MD) is a common psychiatric disorder in multiple sclerosis (MS). Despite the negative impact of MD on the quality of life of MS patients, little is known about its underlying brain mechanisms. Objective: We studied the whole-brain connectivity patterns that were associated with MD in MS. Alterations were mainly expected within limbic circuits. Methods: Diffusion tensor imaging data were collected in 20 MS patients with MD, 22 non-depressed MS patients and 16 healthy controls. We used deterministic tractography and graph analysis to study the white-matter connectivity patterns that characterized MS patients with MD. Results: We found that MD in MS was associated with increased local path length in the right hippocampus and right amygdala. Further analyses revealed that these effects were driven by an increased shortest distance between both the right hippocampus and right amygdala and a series of regions including the dorsolateral and ventrolateral prefrontal cortex, orbitofrontal cortex, sensory-motor cortices and supplementary motor area. Conclusion: Our data provide strong support for neurobiological accounts positing that MD in MS is mediated by abnormal ‘communications’ within limbic circuits. We also found evidence that MD in MS may be linked with connectivity alterations at the limbic-motor interface, a group of regions that translates emotions into survival-oriented behaviors.

86. Efficacy of botulinum toxin on pain and spastic gait disorders in multiple sclerosis

To assess the efficacy of botulinum toxin (BT-A) and additional physiotherapy in subjects affected by progressive multiple sclerosis (MS) with chronic lower limb spasticity. 15 patients able to walk with assistance were consecutively recruited in a open-label study. All patients received a set of intramuscular injections of BT-A performed with EMG-guidance, according to each patient’s individual pattern of spasticity, followed by additional physiotherapy. Each patient was assessed at baseline, 6 and 12 weeks for muscle tone, spasms frequency, leg pain, gait velocity, self-analysis of gait function. 7 patients received a further treatment session after 4 months and were retested after 4 and 8 months. We observed a significant (P < 0.05) reduction of muscle tone, spasm frequency and pain and a partial improvement of gait velocity and function after 6 weeks. The results did not change at 12 week follow-up. The seven patients who received a second set of injections maintained their scores after 4 months e three of them after 8 months. Injections of BT-A, followed by additional physiotherapy, are effective on spasms and pain in patients affected with multiple sclerosis. BT-A injections can otherwise improve gait function for several months in patients able to walk with assistance.

Treatment of mood disorders in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with a significant comorbidity with depressive disorders. Prevalence rates for major depressive disorder (MDD) range from 36% to 54% and the rate is around 22% for adjustment disorders. Selective serotonin reuptake inhibitors (SSRIs) are considered well-tolerated first-line treatment. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are generally reserved for second-line use after SSRIs, because of sedating or anticholinergic side effects. SNRIs, with the exception of duloxetine, and combinations of newer antidepressants have failed to treat depression due to their side effects profile and frequent interaction with other drugs. Among SSRIs, sertraline is usually the first option, starting at 25mg/day and increasing to 50mg/day; and waiting a few weeks to assess drug effects before increasing the dose. The maximum is generally 200mg/day in a single dose. Paroxetine is the second choice, starting at 10mg/day for the first 5days, and then at 20mg/day thereafter. The maximum dose is about 50mg/day in a single dose. Fluvoxamine is used at 100-200mg/day, starting with 25mg/day, and increasing 25mg/day every 5days until 200mg/day is reached. We should take into account increasing blood level amounts of MS treatments (corticosteroids and cyclophosphamide) with fluvoxamine. With duloxetine, doses will be at 60-120mg/day. The initial dose for depression is 40mg/day in two doses; it can increase to 60mg/day in one to two doses if necessary. The maximum dose is generally 120mg/day. Duloxetine may increase liver problems through interaction with these MS treatments: teriflunomide, interferon beta-1a, and interferon beta-1b. Considering psychotherapy, only cognitive behavior therapy and mindfulness-based interventions have shown efficacy in improving depression disorders in MS. A comprehensive treatment for depression should include pharmacotherapy and psychotherapy.

Routine depression screening in an MS clinic and its association with provider treatment recommendations and related treatment outcome.

Depression, a frequent concomitant disorder in multiple sclerosis (MS), can impact MS treatment adherence and quality of life. Depression screening in MS care settings may facilitate needed intervention when providers are responsive to screening findings. This study sought to examine the relationship between depression screening results and provider depression treatment recommendations documented in the medical records of 283 patients receiving care in an integrated MS clinic. Forty-six percent of patients screening positive for depression received a treatment recommendation; females, those with past mental health diagnoses, on psychotropic medications, and those with higher symptom severity were more likely to receive a treatment recommendation. On subsequent screenings, patients reported fewer depressive symptoms regardless of whether a formal treatment recommendation was documented. These findings suggest that while depression screening does lead to depression related intervention in many cases, more research is necessary to determine who is most likely to benefit and under what conditions.

A unified cell biological perspective on axon-myelin injury.

Demyelination and axon loss are pathological hallmarks of the neuroinflammatory disorder multiple sclerosis (MS). Although we have an increasingly detailed understanding of how immune cells can damage axons and myelin individually, we lack a unified view of how the axon–myelin unit as a whole is affected by immune-mediated attack. In this review, we propose that as a result of the tight cell biological interconnection of axons and myelin, damage to either can spread, which might convert a local inflammatory disease process early in MS into the global progressive disorder seen during later stages. This mode of spreading could also apply to other neurological disorders.

Sleep disorders in multiple sclerosis in China: clinical, polysomnography study, and review of the literature.

Sleep disorders are common in multiple sclerosis (MS). The aim of this study was to assess the subjective and objective sleep disturbances in patients with MS and to investigate their relationships with fatigue and excessive daytime sleepiness. All participants completed standardized questionnaires and underwent nocturnal polysomnography. English literature regarding MS and sleep disorders was systematically reviewed through PubMed searches. Eleven patients with MS with fatigue, 10 patients with MS without fatigue, and 11 controls were included in the study. According to the Pittsburg sleep quality index, 61.9% of the patients with MS were poor sleepers and based on the Epworth sleepiness scale, 38.1% of the patients with MS met the criteria of excessive daytime sleepiness. Additionally, patients with MS had more disturbed sleep with higher total arousal index (P < 0.01) and periodic limb movement arousal index (P < 0.001) than controls. None of the patients or controls had an apnea/hypopnea index greater than five. One patient had restless legs syndrome and four had rapid eye movement sleep behavior disorder. Our study shows that sleep disorders and excessive daytime sleepiness are frequent in MS.

Differential roles of microglia and monocytes in the inflamed central nervous system.

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

Clinical and urodynamic evaluations of urinary disorders in multiple sclerosis

Urinary dysfunction is a major clinical problem and a significant cause of disability in multiple sclerosis (MS) patients. Indeed, the bothersome symptom of urinary dysfunction may adversely affect social relationships and activities in MS patients. Since many causes of urinary dysfunction are described, a thorough evaluation including history, clinical examination and evaluation of quality of life is necessary. Generally, diagnosis of urinary disorders is complex with intricated pathophysiologic factors. In these cases, urodynamic investigations are necessary to better understand symptoms pathophysiology and choose the best treatment.

Urinary disorders in multiple sclerosis: Algorithm and guidelines, the FLUE-MS

Urinary disorders in multiple sclerosis: Algorithm and guidelines, the FLUE-MS

Sexual disorders in multiple sclerosis: Evaluation and management

Sexual disorders in multiple sclerosis: Evaluation and management

Nocturnal urinary disorders in Multiple Sclerosis: Clinical and urodynamic study of 309 patients

Nocturnal urinary disorders in Multiple Sclerosis: Clinical and urodynamic study of 309 patients

Psychiatric Disorders in Multiple Sclerosis

Psychiatric Disorders in Multiple Sclerosis

Genetic inactivation of PERK signaling in mouse oligodendrocytes: Normal developmental myelination with increased susceptibility to inflammatory demyelination

The immune-mediated central nervous system (CNS) demyelinating disorder multiple sclerosis (MS) is the most common neurological disease in young adults. One important goal of MS research is to identify strategies that will preserve oligodendrocytes (OLs) in MS lesions. During active myelination and remyelination, OLs synthesize large quantities of membrane proteins in the endoplasmic reticulum (ER), which may result in ER stress. During ER stress, pancreatic ER kinase (PERK) phosphorylates eukaryotic translation initiation factor 2α (elF2α), which activates the integrated stress response (ISR), resulting in a stress-resistant state. Previous studies have shown that PERK activity is increased in OLs within the demyelinating lesions of experimental autoimmune encephalomyelitis (EAE), a model of MS. Moreover, our laboratory has shown that PERK protects OLs from the adverse effects of interferon-γ, a key mediator of the CNS inflammatory response. Here, we have examined the role of PERK signaling in OLs during development and in response to EAE. We generated OL-specific PERK knockout (OL-PERK(ko/ko) ) mice that exhibited a lower level of phosphorylated elF2α in the CNS, indicating that the ISR is impaired in the OLs of these mice. Unexpectedly, OL-PERK(ko/ko) mice develop normally and show no myelination defects. Nevertheless, EAE is exacerbated in these mice, which is correlated with increased OL loss, demyelination, and axonal degeneration. These data indicate that although not needed for developmental myelination, PERK signaling provides protection to OLs against inflammatory demyelination and suggest that the ISR in OLs could be a valuable target for future MS therapeutics.