Multiple Sclerosis Exacerbations Research Articles

Taking the temperature of MS with INO

Many patients with multiple sclerosis (MS) dislike the summer because of the increased fatigue that comes with warm weather.1 Increased body temperature can also lead to temporary reappearance of neurologic symptoms experienced during prior MS exacerbations—Uhthoff's phenomenon.2 Remarkably, an increase in body temperature of less than a degree centigrade can provoke substantial disability, and one of Uhthoff's patients developed symptoms while standing by a hot stove. Cooling may improve such symptoms, although its effectiveness as a clinical treatment in MS (e.g., using cooling vests) is debated.3 Demyelination disrupts normal, saltatory propagation of action potentials in axons to the point that conduction becomes tenuous and may be blocked.4 Thus, conduction in demyelinated axons may fall prey to temperature-induced inactivation of sodium channels, especially during repetitive trains of spikes, when the neural signal is frequency filtered. Conversely, body cooling restores nerve conduction, possibly by prolonging the duration of action potentials, but also by decreasing leukocyte nitric oxide production.4 Study of Uhthoff's phenomenon in patients has required considerable ingenuity because measurement of an observed behavior (e.g., intention tremor) …

Unilateral Neurogenic Pulmonary Oedema and Severe Left Ventricular Dysfunction Secondary to Acute Multiple Sclerosis Exacerbation

Neurological conditions such as stroke, subarachnoid haemorrhage and seizure activity, amongst others, have been associated with the development of pulmonary oedema. The development of clinically significant pulmonary oedema and severe myocardial dysfunction in the setting of acute multiple sclerosis (MS) exacerbation is very rare and poorly understood. The association between MS and neurogenic pulmonary oedema is not clear, nor is the correlation between neurological insults and myocardial dysfunction. Neurological conditions most likely result in cardiopulmonary sequelae as a result of an interplay between enhanced sympathetic tone, inflammatory cytokine release and other factors. Whatever the case, neurogenic pulmonary oedema should always be in the differential diagnosis when patients with presumed neurogenic pathology develop cardiopulmonary compromise. Unilateral pulmonary oedema is also a very rare occurrence, and has not, to our knowledge, been reported in acute MS exacerbation in the past. We present the case of a 31-year-old female who developed respiratory distress with unilateral pulmonary oedema and left ventricular (LV) dysfunction in the context of neurological sequelae and diagnostic evaluation consistent with acute MS exacerbation.

Corticosteroids for the long-term treatment in multiple sclerosis

Short term high dose corticosteroid treatment improves symptoms and short term disability after an acute exacerbation of multiple sclerosis (MS) but it is unknown whether its long-term use can reduce the accumulation of disability. To determine the efficacy and safety of long-term corticosteroid use in MS. We searched the following bibliographic databases: CENTRAL (Issue 1, 2007), MEDLINE (1966 to February 2007) and EMBASE (1980 to February 2007). In an effort to identify further published, unpublished and ongoing trials we searched reference lists and contacted trial authors and one pharmaceutical company. We considered controlled, randomised trials (RCTs), with or without blinding, of long term treatment (i.e. longer than 6 months) of any type of corticosteroid in MS, irrespective of disease course. Reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Three trials, all classified at high risk of bias, contributed to this review (Miller 1961; BPSM 1995; Zivadinov 2001) resulting in a total of 183 participants (91 treated). Corticosteroid therapy did not reduce the risk of being worse at the end of follow-up (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.26 to 1.02) but there was a substantial heterogeneity between studies (I(2): 78.4%). I. v. periodic high dose methylprednisolone (MP) was associated with a significant reduction in the risk of disability progression at 5 years in relapsing-remitting (RR) MS (OR 0.26, 95% CI 0.10 to 0.66), while oral continuous low dose prednisolone was not associated with any risk reduction in disability progression at 18 months (OR 1.23, 95% CI 0.43 to 3.56). Risk of experiencing at least one exacerbation at end of follow-up was not significantly reduced with corticosteroid treatment (OR 0.36; 95% CI 0.10 to 1.25). Only one study recorded adverse events: in one patient i. v. MP was discontinued after the fourth pulse when he developed acute glomerulonephritis; a second patient was removed from the study after the fifth i. v. MP pulse because of severe osteoporosis. There is no enough evidence that long-term corticosteroid treatment delays progression of long term disability in patients with MS. Since one study at high risk of bias showed that the administration of pulsed high dose i. v. MP is associated with a significant reduction in the risk of long term disability progression in patients with RR MS, an adequately powered, high quality RCT is needed to investigate this finding.

Epstein–Barr virus reactivation and multiple sclerosis

Infection with Epstein-Barr virus (EBV) is considered one of the possible key environmental factors in the aetiology of multiple sclerosis (MS). Whether EBV plays an underlying role as an activator of MS remains, however, controversial. Sixty-one patients with definite relapsing-remitting multiple sclerosis (RRMS) according to the Poser criteria were followed for 1 year. Blood samples were drawn at baseline, months 3, 6 and 12, and in case of any clinical exacerbation. Twenty-three baseline-paired exacerbation samples in the same set were quantitatively analysed to examine whether exacerbations in MS were associated with a change in anti-diffuse component of the EBV-early antigen (EA-D) IgG ratio. All the 61 patients (100%) were anti-viral capsid antigen (VCA) IgG positive, one (2%) was anti-VCA IgM positive and 60 (98%) were anti-EBV nuclear antigen IgG positive. Mean anti-EA-D IgG at baseline was 0.57 (range 0.12-2.70) and at the time of exacerbations 0.61 (range 0.11-2.70). Wilcoxon signed rank test revealed no differences between the 23 baseline and paired exacerbation samples (P = 0.58). Our findings suggest that reactivation of latent EBV infection does not play a significant role for exacerbations in RRMS.

Variants of personality maladaptation in patients with multiple sclerosis

A total of 34 patients with multiple sclerosis (MS) aged 14-52 years, with disease onset at age 24.3 +/- 7.5 years, were studied. Disease severity on the Kurtzke scale (EDSS) was 3.6 +/- 1.7 points. Seven patients were in exacerbation of MS and 27 were in remission. Personality characteristics in terms of MS-associated maladaptation were studied using a modified MMPI (the SMPT method). Neurotic, psychotic, and mixed types of maladaptation were identified. Measures of brain metabolic activity were simultaneously determined (in terms of the rate of glucose utilization) by positron emission tomography (PET). Data were obtained on the relationship between the activity of metabolic processes in the frontal, temporal-parietal, and limbic areas of the cerebral cortex and different variants of personality maladaptation and, respectively, with different personality profiles in the SMPT.

Diminished Myelin-Specific T Cell Activation Associated with Increase in CTLA4 and Fas Molecules in Multiple Sclerosis Patients Treated with IFN-β

Multiple sclerosis (MS) is a chronic inflammatory disease of the white matter of the central nervous system (CNS) characterized by focal areas of demyelination. Interferon-beta (IFN-beta) provides an effective treatment that lessens the frequency and severity of exacerbations in relapsing-remitting multiple sclerosis (RRMS), but the mechanisms by which IFN-beta is efficient remain uncertain. The data presented here demonstrate that IFN-beta impairs the proliferative response to myelin basic protein (MBP) and myelin, as well as increasing the expression of the CTLA4 intracellular molecule. Moreover, this treatment increases the expression of surface Fas molecules and of the soluble form of these molecules. Our hypothesis is that the increase in Fas and CTLA4 molecules in MS patients may lead to lymphocyte apoptosis, which suggests possible mechanisms underlying the therapeutic response to IFN-beta.

Corticosteroids for Multiple Sclerosis: I. Application for Treating Exacerbations

Multiple sclerosis (MS) is an inflammatory demyelinating disorder characterized by a multiphasic course of neurological exacerbations, periods of clinical remission, and, in most patients, ultimately progressive deterioration of functional capabilities. The relapsing-remitting phase of the disease involves acute interruption in neurological functioning relating to areas of inflammation in discrete central-tract systems. The treatment of MS exacerbations with anti-inflammatory agents such as corticosteroids and adrenocorticotropic hormone has represented an established practice throughout the neurology community. Although there is scientific rationale supporting application of these agents for this purpose, the broad diversity of approaches to using these drugs in clinical practice is a derivative of expert opinion and anecdotal experience. Ultimately, the treatment of MS-related exacerbations is part science, but mostly art. This review discusses the pharmacology of these agents, to better understand how they may act to mitigate attacks and to provide some practical formulations for how to use them in the clinic for the benefit of patients.

Corticosteroids for Multiple Sclerosis: II. Application for Disease-Modifying Effects

Physicians who treat multiple sclerosis (MS) face the challenge of patients exhibiting ongoing disease activity, including exacerbations, loss of functional capabilities, intellectual decline, and radiologic progression, despite being on a disease-modifying agent (DMA). After searching for factors that might at least in part explain these changes--such as nonadherent drug-taking behavior, or the presence of interferon-neutralizing antibodies--some providers may ultimately decide to switch the patient to another DMA. In most circumstances, patients likely derive only partial effects from these agents, even in the absence of compromising factors. Thus, a number of factors must be considered in order to intensify the treatment regimen in response to disease progression. In the context of an inadequate treatment response to a DMA, some clinicians will convert the patient to an alternative therapy, and others will instead use a second agent in combination with the first (the so-called platform agent). In the first of this two-part series, we explored the use of anti-inflammatory CS and ACTH to treat MS exacerbations. Although we underscored the limited availability of evidence-based studies to support specific regimens for this purpose, there is an even greater paucity of data to support the routine use of these agents in order to achieve chronic disease-modifying effects in those who continue to deteriorate clinically, radiographically, or both. Without doubt, a number of factors influence the formulation of combination treatment plan for MS. Nevertheless, we will focus on the rationale and practical schemes that can be considered for using corticosteroids (CS) (and perhaps even ACTH) in an attempt to modify various domains of ongoing disease activity.

Social Conflict Exacerbates an Animal Model of Multiple Sclerosis

A growing body of evidence suggests that social conflict is associated with inflammatory disease onset and exacerbations in multiple sclerosis (MS) patients and in animal models of MS. This review illustrates how animal research can be used to elucidate the biobehavioral mechanisms underlying the adverse health effects of social conflict. The authors review studies indicating that social conflict exacerbates a virally initiated animal model of MS. This research suggests that the deleterious effects of social conflict may be partially mediated by stress-induced increases in pro-inflammatory cytokine levels in the central nervous system. In addition, they provide evidence that the adverse health effects of social conflict can be prevented by blocking the stress-induced increases in cytokine activity. This suggests that interventions designed to prevent or reverse the stress-induced increases in cytokine activity may be able to prevent or reverse some of the negative health effects of social conflict in humans.

Stress and multiple sclerosis

Increasing numbers of studies are reporting an association between stressful life events and exacerbation in multiple sclerosis. We review findings that begin to suggest psychological, social and biological factors that may be involved in this relationship. Depression, negative attributions, poor coping, and low social support have been implicated as aggravating the relationship between stress and exacerbation. A model of glucocorticoid resistance on immune cells is also presented as one potential biological mechanism. It is emphasized that to date there is no evidence of causal relationships. It is argued that a purely causal relationship, in which stressful events alone trigger exacerbation, is unlikely. Rather, we propose that stress may be one factor among many that influence risk of exacerbation.

Interleukin 17-producing T-helper cells and autoimmune diseases: Time for a paradigm shift?

Introduction For almost 20 years, the pathogenic role of helper T cells has been intensively studied in autoimmune diseases. In multiple sclerosis (MS), an autoimmune disorder affecting the brain and spinal cord, overwhelming evidence has indicated that interferon (IFN)–secreting T-helper type 1 (Th1) cells are involved in the inflammatory process leading to the destruction of myelin sheath [1]. Adoptive transfer of Th1 cells reactive to myelin antigen cause an MS-like disease called experimental autoimmune encephalomyelitis (EAE), supporting this postulate. Notably, the role of Th1 cells in MS has been emphasized not only by experiments with laboratory animals but also by unwanted results of clinical trials. In past clinical trials, administration of IFNpromoted exacerbations of MS, whereas recombinant IFNhas been shown to suppress them [2]. In a more recent study, an altered form of myelin basic protein (MBP) peptide was evaluated for its therapeutic potential. However, it caused serious relapses and massive expansion of MBP-reactive Th1 cells [3]. The deleterious effects of IFNand the MBP analogue peptide have been regarded as evidence for the role of Th1 cells in the pathogenesis of MS. On the other hand, T-helper 2 (Th2) cells that secrete interleukin (IL)-4, IL-5, and IL-10 were shown to counterregulate Th1 cell functions via secretion of Th2 cytokines. This finding led to speculation that autoimmune diseases could be cured by shifting the functional balance between Th1 cells and Th2 cells toward Th2. The relevance of this idea has been verified vigorously in numerous studies, which have actually demonstrated that Th2-biasing agents are effective for downmodulating clinical and pathologic manifestations of EAE. Given such theoretic, empiric, and experimental evidence, our understanding of the pathogenesis of autoimmune diseases has been heavily influenced by the Th1/Th2 paradigm [4]. However, contradictory to the “Th1 disease” dogma, EAE and collagen-induced arthritis (CIA) became worse in mice deficient in those molecules that are critical for Th1 cell development (eg, IL-12 receptor 2 and IFN) [5]. Thus, the question has arisen as to whether Th1 cells are truly needed for induction of autoimmune diseases. The recent discovery of a new T-helper cell subset characterized by production of IL-17 has clarified that the IL-17–producing T-helper cells (Th17) would mediate autoimmune disease models including EAE, CIA, and experimentally induced colitis without help from Th1 cells [6–9]. Very recent papers have identified that a combination of proinflammatory cytokine (IL-6) and anti-inflammatory cytokine (transforming growth factor [TGF]) would cause differentiation of Th17 cells [10–12], unveiling a new principle governing the maintenance and disruption of immunologic tolerance.

Treating depressed multiple sclerosis patients

Approximately one in two multiple sclerosis patients will develop a major depression over the course of their lifetime. This is associated with a decreased quality of life and a high risk of completed suicide. A literature review suggests pharmacotherapy with a selective serotonin-reuptake inhibitor or tricyclic antidepressant is effective, the former likely better tolerated. Limited data show that psychotherapy, namely cognitive–behavioral and insight-oriented therapies, is effective, although cognitive–behavioral therapy is the only modality shown to rival medication in bringing about symptom response. Electroconvulsive therapy should be reserved for severe cases of depression as it may increase the risk of multiple sclerosis exacerbation. In treating the depressed multiple sclerosis patient, clinicians should always be on the lookout for comorbid anxiety.

Current treatment options in multiple sclerosis

Advances in our understanding of the pathogenesis of multiple sclerosis (MS) lesions are leading to the development of more targeted therapies. Axonal transection is likely an important cause of accumulating disability in disease progression and suggests the importance of early and aggressive therapy. Early treatment with disease-modifying therapy should be considered in patients with first episode of demyelination and presence of MRI lesions consistent with MS. Intravenous steroids are the mainstay of treatment of acute MS exacerbations. Although their benefits must be weighed against the potential for complications, natalizumab and mitoxantrone significantly decrease relapses and MRI lesions in patients with relapsing MS. Many new therapies, including oral and infrequently administered infusion therapies, are currently in phase III trials and will likely become available over the next 3 to 4 years.

Interferons in multiple sclerosis: Ten years' experience

Interferons (IFNs) were considered for the treatment of patients with multiple sclerosis (MS) after the demonstration, based on small studies, of the efficacy of type IFNβ in decreasing the frequency of exacerbations in relapsing-remitting multiple sclerosis when administered intrathecally, subcutaneously, or intramuscularly. Three preparations of IFNβ are now approved in Europe and North America: chronologically IFNβ-1b (Berlex/Schering), IFNβ-1a given intramuscularly (Biogen), and IFNβ-1a given subcutaneously (Ares Serono). These treatments have now been in use for more than 10 years, and are supposed to decrease relapse rates. However a lot of questions remain unanswered: it is difficult to compare the various preparations; there remain controversies about the effects of different routes of administration and of different dosage preparations; the role of neutralizing antibodies remains partially understood; and the long term effect on disability has not yet been demonstrated.

Varicella-zoster virus at relapses of multiple sclerosis

The possible participation of different herpes viruses was studied during exacerbations of multiple sclerosis (MS). We searched for the presence of DNA from the following herpes viruses: varicella zoster virus (VZV), herpes-simplex viruses 1 and 2; Epstein-Barr virus (EBV) and human herpes-virus-6 (HHV6) in mononuclear cells from patients with MS during relapse (n = 40), MS during remission (n = 131) and controls (n = 125). Additionally, immune cells containing viral antigens were quantified by flow cytometry, and VZV load was determined by real time PCR in 2 MS patients at various times during relapse and remission. DNA from VZV was found in 95% of MS patients during relapse and in 17% during remission; all controls were negative; by contrast, DNA from HHV6 was found in 24% of MS patients during relapse and in 2% during remission; DNA from herpes simplex viruses was not found in any subject; and DNA from EBV was found in a similar percentage of subjects from all groups. Sequential quantification of VZV-load showed a curve that increased during relapse and disappeared at remission. Also, VZV antigens were found inside a large number of immune cells from MS patients during relapse as compared with MS patients on remission and controls. In the typical forms of VZV infection, varicella and herpes-zoster, DNA from VZV is found in mononuclear cells exclusively during brief periods at the beginning of the active infection, but not during latency; thus, the conspicuous presence of VZV during relapses of MS may indicate a period of active infection and suggests the participation of VZV in the pathogenesis of MS.

Astrocytic activation in relation to inflammatory markers during clinical exacerbation of relapsing-remitting multiple sclerosis

The study aimed to assay the cerebrospinal fluid (CSF) levels of protein S100B, a biomarker of astrocyte activation in relation to kynurenic acid (KYNA) and nitric oxide (NO) metabolites, nitrate/nitrite (NOx) concentrations in acute relapse multiple sclerosis (MS) patients. Twenty relapsing-remitting MS (RR-MS) patients and 10 controls were enrolled. RR-MS patients were assessed on the expanded disability status scale (EDSS) and underwent lumbar puncture. The CSF KYNA, NOx and S100B levels were significantly higher in RR-MS group compared to controls (p = 0.01, 0.001, 0.04, respectively). There was a significant correlation between CSF S100B and KYNA (p = 0.01) but not NOx (p > 0.05) in RR-MS. CSF KYNA, NOx or S100B concentrations did not correlate with disease characteristics of MS patients. Our study suggests the activation of the kynurenine pathway leading to the increase of neuroprotective KYNA in the CSF of MS patients during acute relapse what contrasts with chronic phases of the disease.

Stress regulation in multiple sclerosis – current issues and concepts

Since its first description by Charcot, psychological stress has been considered a triggering factor for exacerbations in multiple sclerosis, but until recently the clinical evidence for a causal relation was weak. Over the past years, a growing number of studies have started to elucidate this association and highlight potential mechanisms, including brain-immune communication. On 5 June 2005, a panel of international researchers discussed the current evidence. This article summarizes the observational, animal experimental, as well as human experimental findings on stress regulation in MS, as well as studies on the functioning of the major stress response systems, ie, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomous nervous system (ANS) in MS. Consensus statements from the group to these aspects are given. Research objectives and strategies are delineated, as well as clinical implications. Multiple Sclerosis 2007; 13: 143–148. http://msj.sagepub.com

Possible mechanisms of the formation of chronic fatigue syndrome in the clinical picture of multiple sclerosis

A frequent manifestation of multiple sclerosis (MS) is chronic fatigue syndrome, which can be defined as a subjective decrease in the level of physical and/or mental energy. Chronic fatigue syndrome can be divided into asthenia (fatigue at rest), pathological fatigability (fatigue on physical loading), and fatigue on the background of deterioration of other symptoms (exacerbation of MS). There are both central and peripheral mechanisms for the formation of fatigue. The combination of fatigue and affective disturbances, especially depression and sleep disorders (insomnia, restless legs syndrome) is common in MS and may provide evidence that they share common mechanisms--decreases in the activity of the serotoninergic and noradrenergic systems. An important component in the formation of chronic fatigue syndrome consists of endocrine and autoimmune factors, the latter having a greater effect on asthenia than on pathological fatigue. Further studies of the pathogenetic mechanisms of the formation of asthenia and pathological fatigue and clarification of their differential diagnostic signs should allow not only a better understanding of the nature of this syndrome, but also better selection of individual treatment.

Multiple Sclerosis Exacerbations: Simultaneous Activation of the Immune System by Multiple Immunogens

Multiple Sclerosis Exacerbations: Simultaneous Activation of the Immune System by Multiple Immunogens

Propofol hemisuccinate suppression of experimental autoimmune encephalomyelitis

Propofol hemisuccinate is a prodrug water soluble form of the lipophilic, phenolic compound propofol (2,6-di-isopropylphenol), that is the active ingredient in the widely used anesthetic agent Diprovan. Propofol binds to GABAA receptors but also has a phenolic structure that confers antioxidant properties to the molecule. The effects of propofol hemisuccinate in rat experimental autoimmune encephalomyelitis (EAE) were studied using different doses and time regimes. Propofol hemisuccinate, 100 mg/kg given three times a day from day 7 or day 12 until day 16 after disease initiation, significantly reduced maximal EAE score. Histology studies supported the clinical findings demonstrating reduction in the inflammatory response in the lumbar spinal cord in animals treated with propofol hemisuccinate. Decreased levels of nitrotyrosine and unchanged levels of induced nitric oxide synthase suggest propofol hemisuccinate crossed the blood brain barrier and exerted its effects by lowering reactive oxygen species levels. The results suggest that propofol hemisuccinate may provide an alternative mode of treatment for acute exacerbations of multiple sclerosis.