Multiple Sclerosis Exacerbations Research Articles

Plasma Exchange for Steroid-Refractory Relapses in Multiple Sclerosis: An Observational, MRI Pilot Study

BackgroundNumerous studies have shown that plasma exchange (PE) is effective as second-line treatment of severe exacerbations of multiple sclerosis (MS) or other idiopathic inflammatory demyelinating diseases of the central nervous system that are nonresponsive to steroid therapy. ObjectiveThe goal of this study was to analyze the effect of PE on clinically active radiologic lesions in steroid-refractory relapses of MS and idiopathic inflammatory demyelinating diseases of the central nervous system. MethodsThis was a prospective, observational pilot study in which the primary end point was the degree of radiologic resolution of active lesions after PE. ResultsA total of 15 patients were included (median age, 36.9 years [age range, 21–67 years]; 60% women). Five (33.3%) of the 15 patients had relapsing-remitting MS, 2 (13.3%) had clinically isolated syndrome that presented with transverse myelitis, 2 (13.3%) had recurrent myelitis, 1 (6.7%) had transverse myelitis, 1 (6.7%) had longitudinally extensive transverse myelitis, 1 (6.7%) had acute disseminated encephalomyelitis, 1 (6.7%) had Baló's concentric sclerosis, and 2 (13.3%) had neuromyelitis optica. Mean increase on the expanded disability status scale scores due to relapses was 4.8 (2.53). After PE, 93.3% showed a marked to moderate clinical improvement, and 46.7% recovered their baseline expanded disability status scale score 3 months post-PE. On the post-PE MRI, 60% showed radiologic resolution (80% mass-effect lesions, 83.3% new-onset disease, and 100% neuromyelitis optica), 20% had partial resolution, and 20% no resolution. A significant relationship was not obtained between degree of resolution of radiologic lesions and the variables: clinical response to PE, new-onset disease, mass-effect lesions, number of PE sessions, and early initiation of PE. ConclusionA marked to moderate clinical improvement post-PE accompanied by a lack of radiologic resolution of the active lesion is not indicative of poor prognosis.

The effect of pulse methylprednisolone plus theophylline treatment on clinical, pulmonary and inflammatory markers in relapses of multiple sclerosis.

The aim of this study was to evaluate whether there was a relationship between severity of multiple sclerosis (MS) exacerbation and pulmonary function test (PFT) and to determine the effect of theophylline, which was added to intravenous methylprednisolone, on serum Tumor Necrosis Factor (TNF)-alpha levels and clinical scores in MS relapses. Double blind randomized controlled trial. The baseline Expanded Disability Status Scale (EDSS) score was determined, PFT was performed and blood was taken for analysis of TNF- alpha in patients with MS exacerbation. Patients were randomly divided into two groups; group 1 received intravenous methylprednisolone+IV theophylline and group 2 intravenous methylprednisolone+placebo for 5 days. PFT and EDSS score were repeated and blood was taken for TNF-alpha on the 5(th) and 30(th) days of the treatment. Twenty-four patients (14 female, 10 male) were included in the study. Mean age was 32.6±9, duration of disease was 5.4±4.2 years, number of exacerbations was 5±2. There was a significant correlation between the number of exacerbations and EDSS score (p=0.000, r=1). Restrictive PFT findings were detected in 8 and decrease in carbon monoxide diffusing capacity (DLCO) in 3 cases. In within-group analysis, EDSS score was found to be decreased on day 5 and still low on day 30 in the theophylline group (baseline 3±1.3; 5(th) day 2.4±1.6; 30(th) day 2±1.7). There was no statistically significant difference in the EDSS score of the placebo group (3±1.6; 2.8±1.7; 2.4±1.9 respectively). While serum TNF-alpha level was not changed in the placebo group, there was a non-significant decrease on day 5 and increase on day 30 in the theophylline group. There was no correlation between the clinical parameters, PFT and TNF-alpha level. There was no correlation between severity of MS and PFT findings. It is suggested that theophylline might be effective in MS exacerbations since it caused decreases in clinical scores; studies with longer treatment duration are needed to clarify its possible anti-inflammatory effect.

1965 – Corticosteroid-induced mania treated with risperidone - a case report

Introduction Corticosteroids have either somatic and psychiatric side effects. Somatic adverse effects are well described while neuropsychiatric have received less attention. Psychiatric symptoms such as depression, psychosis and especially mania are common side effects of corticotherapy. Aims and Objectives Describe a case of a 53-year-old female patient, with no psychiatric history, who developed psychiatric symptoms during the treatment of an acute exacerbation of multiple sclerosis with large parenteral doses of corticosteroids. Three days after the onset of corticotherapy she developed increased energy, elevated mood, increased motor activity, racing thoughts, and diminished need for sleep. She subsequently developed grandiose and persecutory ideation and then feared her grandson was going to die. This lead to her admission to psychiatric unit of our hospital to address these behavioral problems. Her husband noticed that she had become’hyper’ in the past when she received pulse corticosteroid therapy, but the most recent episode was by far the worst. Methods Revision of the scientific literature through Pubmed, Embase and Psychinfo using search terms including corticosteroids, mania, depression, psychosis and mood. Results Prednisone was suspended and Risperidone 2mg was begun for presumed steroid-induced mood disorder, and the patient became calmer and much less guarded over the next 2-3 days. After a week she recovered complete euthymic mood and reverted to normal functioning. Conclusions These data suggest that Risperidone is well tolerated and appears to be useful for mood disturbances associated with corticosteroid therapy. Controlled trials seem warranted to confirm these observations.

Oral versus intravenous steroids for treatment of relapses in multiple sclerosis

This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006921. DOI: 10.1002/14651858.CD006921.pub2).Multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), is characterized by recurrent relapses of CNS inflammation ranging from mild to severely disabling. Relapses have long been treated with steroids to reduce inflammation and hasten recovery. However, the commonly used intravenous methylprednisolone (IVMP) requires repeated infusions with the added costs of homecare or hospitalization, and may interfere with daily responsibilities. Oral steroids have been used in place of intravenous steroids, with lower direct and indirect costs. The primary objective was to compare efficacy of oral versus intravenous steroids in promoting disability recovery in MS relapses <= six weeks. Secondary objectives included subsequent relapse rate, disability, ambulation, hospitalization, immunological markers, radiological markers, and quality of life. A literature search was performed using Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Trials Register (January 2012), abstracts from meetings of the American Academy of Neurology (2008-2012), the European Federation of Neurological Sciences (2008-2012), the European Committee for Treatment and Research in Multiple Sclerosis and American Committee for Treatment and Research in Multiple Sclerosis (2008-2012) handsearching. No language restrictions were applied. Randomized or quasi-randomized trials comparing oral versus intravenous steroids for acute relapses (<= six weeks) in patients with clinically definite MSover age 16 were eligible. Three review authors (JB, PO and MH) participated in the independent assessment of all published articles as potentially relevant to the review. Any disagreement was resolved by discussion among review authors.We contacted study authors for additional information.Methodological quality was assessed by the same three review authors.Relevant data were extracted, and effect size was reported as mean difference (MD), mean difference (MD), odds ratio (OR) and absolute risk difference (ARD). With this current update, a total of five eligible studies (215 patients) were identified. Only one outcome, the proportion of patients with Expanded Disability Status Scale (EDSS) improvement at four weeks, was common to three trials, while two trials examined magnetic resonance imaging (MRI) outcomes. The results of this review shows there is no significant difference in relapse recovery at week four (MD -0.22, 95% confidence interval (95% CI), 0.71 to 0.26, P = 0.20) nor differences in magnetic resonance imaging (MRI) gadolinium enhancement activity based on oral versus intravenous steroid treatment. However, only two of the five studies employed more current and rigorous methodological techniques, so these results must be taken with some caution. The Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Sclerosis (OMEGA) trial and the "Efficacy and Safety of Methylprednisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS) Relapses" (COPOUSEP) trial, designed to address such limitations, are currently underway. The analysis of the five included trials comparing intravenous versus oral steroid therapy for MS relapses do not demonstrate any significant differences in clinical (benefits and adverse events), radiological or pharmacological outcomes. Based on the evidence, oral steroid therapy may be a practical and effective alternative to intravenous steroid therapy in the treatment of MS relapses.

Anesthetic Technique in a Patient With Multiple Sclerosis Scheduled for Laparoscopic Nephrectomy for a Renal Tumor: A Case Report

Perioperative stress and anesthesia are risk factors for exacerbation of Multiple Sclerosis (MS) attacks. Infection, emotional labiality and hyperpyrexia are also known to increase the risk of postoperative MS attacks. Appropriate preoperative evaluation, administration of a good premedication, control of fever, selection of the anesthetic agents and effective postoperative pain control can prevent problems after prolonged major surgery in patients with MS diagnosed. This report presents the anesthetic technique in a patient who was a known case of MS for past nine years and presented with renal tumor to undergo laparoscopic nephrectomy under general anesthesia.

Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17β‐oestradiol‐receptor‐positive B cells that up‐regulate PD‐1 on CD4+ Foxp3+ regulatory T cells

It is now well accepted that sex hormones have immunoregulatory activity and may prevent exacerbations in multiple sclerosis during pregnancy. Our previous studies demonstrated that oestrogen (17β-oestradiol; E(2) ) protection against experimental autoimmune encephalomyelitis (EAE) is mediated mainly through oestrogen receptor-α (ERα) and the membrane receptor G-protein-coupled receptor 30 (GPR30) and is abrogated in the absence of B cells and the co-inhibitory receptor, Programmed Death-1 (PD-1). To critically evaluate the cell source of the E2 and PD-1 co-inhibitory pathways in EAE regulation, we assessed the requirement for ERs on transferred B cells and downstream effects on expression of PD-1/PD-ligand on CD4+ Foxp3+ regulatory T (Treg) cells in B-cell-replenished, E2-treated B-cell-deficient (μMT-/-) mice with EAE. The results clearly demonstrated involvement of ERα and GPR30 on transferred B cells that mediated the protective E2 treatment effect on EAE and further showed an E2-mediated B-cell-dependent up-regulation of PD-1 on CD4+ Foxp3+ Treg cells. These findings identify regulatory B-cell populations as key players in potentiating Treg-cell activity during E2-mediated protection against EAE.

Central nervous system demyelinating diseases and recombinant hepatitis B vaccination: a critical systematic review of scientific production

The etiology of multiple sclerosis has not yet been fully described. A potential link between the recombinant hepatitis B vaccine and an increased risk of onset or exacerbation of multiple sclerosis emerged in the mid-1990s, leading to several spontaneous reports and studies investigating this association. We conducted a critical systematic review aimed at assessing whether hepatitis B vaccination increases the risk of onset or relapse of multiple sclerosis and other central nervous system demyelinating diseases. MEDLINE and EMBASE were used as data sources, and the search covered the period between 1981 and 2011. Twelve references met the inclusion criteria. No significant increased risk of onset or relapse of the diseases considered was associated with hepatitis B vaccination, except in one study. Most studies included in this review displayed methodological limitations and heterogeneity among them, which rendered it impossible to draw robust conclusions about the safety of hepatitis B vaccination in healthy subjects and patients with multiple sclerosis. Therefore, on the basis of current data there is no need to modify the vaccination recommendations; however, there is a need to improve the quality of observational studies with emphasis on certain considerations that are discussed in this review.

Tumefactive multiple sclerosis lesions under fingolimod treatment

Fingolimod is an oral sphingosine 1-phosphate receptor modulator that prevents recirculation of lymphocyte subsets from lymph nodes. It decreases the number of relapses, slows the progression of disability, and improves MRI endpoints in patients with relapsing-remitting multiple sclerosis (RRMS).1 Infrequent but specific side effects are bradycardia, leukopenia, and macular edema. ### Case report. In November 2010, a 23-year-old woman with RRMS since September 2007 started fingolimod 0.5 mg per day in the setting of the open-label FTY720D2316 trial. Interferon-β treatment was initiated in 2008, but discontinued mid-2010 because of side effects. Her disease course was relatively mild with low frequency and complete recovery of relapses. In March 2011, she presented with a left-sided hemiparesis, headache, and nausea that had gradually developed over 2 weeks. Because she had no clinical signs of infection, an exacerbation of multiple sclerosis (MS) was considered initially and she was admitted for IV methylprednisolone …

Increase in multiple sclerosis activity after assisted reproduction technology

Our objective was to evaluate risk of exacerbations in multiple sclerosis (MS) patients undergoing assisted reproduction technology (ART) infertility treatment. Sixteen patients with relapsing-remitting MS subjected to 26 ART treatment cycles receiving gonadotropin-releasing hormone (GnRH) agonists and recombinant follicle-stimulating hormone were studied prospectively. The baseline study period encompassed 12 months prior to the first cycle and 9 months after final ART cycle. Neurological examinations, brain magnetic resonance imaging (MRI), and immunology testing were conducted every 3 months. Anti-myelin-oligodendrocyte glycoprotein (MOG) antibody production, interleukin (IL)-4, IL-8, IL-10, IL-12, IL-17, interferon (IFN)-γ, and transforming growth factor (TGF)-β secretion by myelin basic protein- and MOG-peptide-specific T cells, as well as ex vivo isolated peripheral blood mononuclear cells (PBMCs), were studied using enzyme-linked immunospot. vascular endothelial growth factor (VEGF) production by PBMCs was assessed using enzyme-linked immunosorbent assay. ART was associated with a 7-fold increase in risk of MS exacerbation, and a 9-fold increase in risk of enhanced disease activity on MRI. Worsening was associated with higher number of cells producing IL-8, IL-12, IFN-γ, and TGF-β, as well as increased VEGF production by CD4(+) T cells and CXCL-12 plasma levels, all GnRH-mediated effects. A rise in 17-β estradiol production associated with ART increased anti-MOG antibody titers, as well as B-cell survival factor BAFF (B-cell activating factor) and antiapoptotic molecule Bcl-2 levels from purified CD19(+) B cells. Finally, ART facilitated PBMC transmigration across an in vitro blood-brain barrier model, an effect mediated by IL-8, VEGF, and CXCL-12. Results indicate a significant increase in MS disease activity in patients receiving ART, a risk that neurologists should be aware of. Reproductive hormones appear to exert an important role in regulating immune responses during the course of autoimmune diseases.

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS)1, it has been difficult to demonstrate which variants are causal and what role they play in disease. Moreover, the modest contribution these variants make to disease risk has raised questions regarding their medical relevance2. We have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes TNF receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS)3,4, but not with other autoimmune conditions such as rheumatoid arthritis (RA)5, psoriasis6 and Crohn’s disease7. By analyzing MS GWAS3,4 data in conjunction with the 1000 Genomes Project data8 we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF blocking drugs can promote onset or exacerbation of MS9-11, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.

Acute exacerbation of multiple sclerosis presenting with facial metamorphopsia and palinopsia

We discuss the case of a patient with a known history of relapsing–remitting multiple sclerosis (MS) who presented with the isolated complaint of altered visual perception in the absence of abnormalities on ophthalmological examination. To the best of the authors’ knowledge, this is the first documented case of both facial metamorphopsia and palinopsia occurring as the symptoms of demyelinating brain lesions consistent with an acute MS exacerbation. These symptoms appear to be related to active demyelination that either involved the optic radiations in the visual pathway or the visual association area in the temporo-occipital region of the left hemisphere.

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.

Vaccination against infection in patients with multiple sclerosis

Bacterial and viral infections have been shown to induce relapses and accelerate the progression of multiple sclerosis (MS). Vaccination to prevent communicable disease in such patients is, therefore, of key importance. Reports of potentially detrimental effects of immunization on the course of MS, however, have prompted patients and physicians to adopt a cautious attitude towards the use of vaccines. The risks associated with a number of vaccines have been investigated in patients with MS. Vaccines against some diseases, such as tetanus and hepatitis B, are not associated with an elevated risk of MS exacerbation, whereas vaccines against other diseases, such as yellow fever, are contraindicated in patients with MS. Many patients with MS receive immunosuppressive or immunomodulatory therapy, which could make them more susceptible to infectious diseases and might also affect their ability to respond to immunization. Here, we review the indications for and possible adverse effects of vaccines in patients with MS, and address issues of vaccination in the context of immunomodulatory therapy for MS.

Treatment of Exacerbations of Multiple Sclerosis without the Use of Corticosteroids: The Role of Metabolic and Antioxidant Therapy

A multicenter randomized post-registration case-control study was performed with 94 patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) in exacerbation. The patients were divided into two groups: group 1 (n = 53) received Cytoflavin and basal therapy (Trental and group B vitamins), while group 2 (n = 41) received only basal therapy. After five days, treatment results were used to further divide each group into two subgroups: patients of subgroup 1A (n = 22), with clear positive treatment effects, continued to receive Cytoflavin and basal therapy; group 1B (n = 31) additionally received corticosteroid (methipred) pulse therapy; subgroup 2A (n = 14), with significant positive effects, continued to receive basal therapy; group 2B (n = 27) additionally received corticosteroid pulse therapy. The complex treatment, with Cytoflavin, Trental, group B vitamins, and corticosteroids, was found to be safe and well tolerated. The positive effects of including Cytoflavin in complex treatment consisted of a reduction in the need for corticosteroids: 41.5% of patients receiving Cytoflavin no longer needed them, compared with 34% of patients receiving only basal therapy. Patients given Cytoflavin showed more significant regression of neurological symptomatology on the EDSS than the group not given Cytoflavin; there were no patients with no treatment response; lipid peroxidation and anti-myelin basic protein antibody levels decreased; cognitive functions improved.

Psychological Stress and Cytokine Production in Multiple Sclerosis

Psychological variables such as perceived stress appear to play a role in symptom onset or disease exacerbation in multiple sclerosis (MS). The authors sought to determine if perceived stress is indeed associated with the expression of pro-inflammatory cytokines and disease symptoms in individuals with MS. To do so, the authors examined the relationships among disease symptomatology, perceived stress, and cytokine production from peripheral blood mononuclear cells in 42 outpatients with MS and 36 normative controls. The authors drew peripheral blood from all subjects prior to the completion of a series of psychological instruments. The authors measured stress using the Perceived Stress scale and negative mood with the Profile of Mood States. Disease symptoms were measured using the Multiple Sclerosis Symptom Checklist. Cytokine production was induced separately by lipopolysaccharide and a combination of phytohemagglutinin and phorbol-12-myristate-13-acetate. In MS subjects, the induced production of interleukin (IL)-6 and IL-10 positively correlated with psychological stress, mood disturbance, and disease symptomatology. In contrast, psychological stress in control subjects significantly correlated with level of tumor necrosis factor-alpha (TNF-α), and mood disturbance correlated with levels of TNF-α and interferon-gamma. As well, compared to controls, MS subjects exhibited a significant fourfold increase in the production of IL-12. There is, in those with MS, a pattern of IL-6 and IL-10 production that correlates significantly with perceived stress and disease symptomatology.

Human Herpesvirus 6 and 7 Reactivation and Disease Activity in Multiple Sclerosis

Recent studies have focused on the associations between human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), and multiple sclerosis (MS). The aim of this study was to investigate the associations between HHV-6 and HHV-7 reactivation and MS disease activity, and interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α) production. The frequency of plasma viremia by nested polymerase chain reaction and transcription of viral mRNA in peripheral blood mononuclear cells by reverse transcriptase-polymerase chain reaction (RT-PCR) of 14 relapsing/remitting (RR) and 14 secondary progressive (SP) MS patients were studied in comparison with clinical manifestation of the disease. Serum concentrations of cytokines IL-12 and TNF-α were analyzed by enzyme-linked immunosorbent assay. Plasma samples from 25 of the 28 MS patients with estimated latent/persistent HHV-6 and/or HHV-7 infection were examined during relapse and remission/relative remission. HHV-6 reactivation was found in 4 of the 7 RRMS and 4 of the 7 SPMS patients, and HHV-7 reactivation was identified in 3 of the 7 RRMS and 1 of the 7 SPMS patients (all in relapse). In 2 of the 3 RRMS patients without viremia in relapse, HHV-6 mRNA transcription was detected. In RRMS and SPMS patients with active HHV-6 and HHV-7 infection in relapse, the serum concentrations of IL-12 and TNF-α were significantly higher than in those with latent virus infection. HHV-6 and HHV-7 reactivation could be implicated in the exacerbation of MS via activation of Th1 lymphocyte subsets.

Seasonal and H1N1v influenza vaccines in MS: Safety and compliance

BackgroundViral infections may induce exacerbation of multiple sclerosis (MS), and attempts should be made to prevent them in MS patients by means of vaccines, but immunization is considered to possibly trigger autoimmune disease activity. AimsWe studied the safety and patient compliance of seasonal influenza and H1N1v influenza vaccines. MethodsClinical data on 101 consecutive patients with MS who participated in the study conducted between December, 2009 and February, 2010 were retrieved from the patients' charts. They all filled in a questionnaire on demographics, clinical symptoms and, when applicable, date of being vaccinated for seasonal influenza and/or H1N1v influenza. ResultsFive of the 49 vaccinated patients reported side effects of fever or flu-like symptoms associated with the administration of either of the vaccines: there were no complications or need for hospitalization. No patient reported any new neurological symptoms following the use of either vaccine. It emerged that many MS patients did not receive at least one of the vaccines, and that a substantial number of physicians were unsure of how to advise on vaccinations. ConclusionsOur results are intended to help reassure patients with MS and their physicians about the safety of seasonal influenza and H1N1v influenza vaccines.

Towards the next generation of anti-TNF drugs

Although pivotal to the immune system homeostasis, tumor necrosis factor (TNF) becomes deleterious when de-regulated. The currently marketed TNF blockers are highly efficacious in rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, uveitis and inflammatory bowel disease; reactivation of tuberculosis and exacerbation of pre-existing multiple sclerosis remain their most important safety issues. The endogenous protein progranulin binds TNF receptor-1 (TNFR1) and TNFR2, thus blocking their interactions with TNF. Domains of the extracellular region of TNFR, termed preligand-binding assembly domain (PLAD), mediate receptor-chain trimerization which is essential for signaling. Therapeutic administration of either progranulin or soluble versions of TNFR1 PLAD in mouse models of diseases in which TNF is relevant yielded beneficial results, opening the door to the next generation of non-antibody anti-TNF drugs for a variety of non-infectious inflammatory conditions. Whether these drugs may target TNF in a more refined way than the current blockers, perhaps being more efficacious without compromising the protective role of TNF in host defense and (auto)immunity, remains to be seen.

Incidence of various cardiac arrhythmias and conduction disturbances due to high dose intravenous methylprednisolone in patients with multiple sclerosis

Background High-dose intravenous methylprednisolone is the most common therapeutic modality to treat acute exacerbations in multiple sclerosis (MS). Various cardiac arrhythmias have been reported during corticosteroid pulse therapy. This study was conducted to detect cardiac rhythm changes in patients with MS while receiving high dose methylprednisolone. Methods We enrolled 52 consecutive MS patients with acute relapse to perform cardiac monitoring 4 h before, during and 18 h after infusion of 1000 mg intravenous (IV) methylprednisolone. Results Sinus tachycardia was the most common change in cardiac rhythms before, during, and after corticosteroid pulse therapy. Up to 41.9% of the patients, developed sinus bradycardia after pulse infusion. Sinus arrest and sinus exit block were observed in 12 patients. Atrial fibrillation and ventricular tachycardia were observed in three patients and one patient, respectively. The most important cardiac arrhythmias including ventricular tachycardia, sinus arrest, and sinus exit block, were correlated with smoking and more commonly observed during 12 h post infusion. Sinus bradycardia and atrial fibrillation were detected more commonly in patients with history of urinary dysfunction. Conclusion High dose intravenous prednisolone might cause different types of arrhythmias in MS patients. Cigarette smokers and patients with autonomic disturbances like sphincter and bowel problems have more chance to develop arrhythmias while receiving high dose steroids.

Stress and the risk of multiple sclerosis

Several studies have shown that stressful life events are associated with a subsequent significant increase in risk of multiple sclerosis (MS) exacerbations. We wanted to study prospectively whether stress can increase the risk of developing the disease itself. We studied 2 cohorts of female nurses: the Nurses' Health Study (NHS) (n = 121,700) followed from 1976 and the Nurses' Health Study II (NHS II) (n = 116,671) followed from 1989. The risk of MS after self-report on general stress at home and at work in the NHS in 1982 was studied prospectively using Cox regression. Logistic regression was used to retrospectively estimate the effects of physical and sexual abuse in childhood and adolescence collected in the NHS II 2001. We identified 77 cases of MS in the NHS by 2005 and 292 in the NHS II by 2004. All analyses were adjusted for age, ethnicity, latitude of birth, body mass index at age 18, and smoking. We found no increased risk of MS associated with severe stress at home in the NHS (hazard ratio 0.85 [95% confidence interval (CI)] 0.32-2.26). No significantly increased risk of MS was found among those who reported severe physical abuse during childhood (odds ratio [OR] 0.68, 95% CI 0.41-1.14) or adolescence (OR 0.77, 95% CI 0.46-1.28) or those having been repeatedly forced into sexual activity in childhood (OR 1.47, 95% CI 0.87-2.48) or adolescence (OR 1.21, 95% CI 0.68-2.17). These results do not support a major role of stress in the development of the disease, but repeated and more focused measures of stress are needed to firmly exclude stress as a potential risk factor for MS.