Methylthioadenosine is a metabolite of the polyamine pathway that modulates methyltransferase activity, thereby influencing DNA and protein methylation. Since methylthioadenosine produces neuroprotection in models of inflammation, ischemia and epilepsy, we set out to evaluate the role of methylthioadenosine in promoting remyelination, a process that will protect axons in demyelinating diseases and that will aid functional recovery.
Currently, there are few established pharmacogenetic predictors of response to treatment in multiple sclerosis (MS) patients. Commonly used second line treatments include natalizumab that has proven to be successful in slowing MS progression in a subset of patients. Our aim was to identify pharmacogenetic factor(s) associated with MS patients’ response to natalizumab. Ten MS patients not responding to natalizumab and 23 MS patients responsive to natalizumab were selected for exome sequencing. Exome sequences were analyzed and resultant variant was assessed in an additional cohort of 86 MS patients. Exome analysis revealed a missense polymorphism (rs2304166) in glycoprotein VI (GP6) gene (19q13.42, c.940C > G, p.P314A) associated in homozygosity with MS poor response to natalizumab (p = 0.0012). An additional cohort of 86 MS patients of which 19 were natalizumab unresponsive and 67 responsive confirmed rs2304166 CC significant association with poor response to natalizumab (p = 0.0000027). In addition, rs2304166 CC MS patients had increased MS disability despite taking natalizumab (Odds ratio 22.18, 95% CI: 5.758–95.88, p = 0.00000001). Natalizumab is a commonly used second line treatment for MS, and poor response to natalizumab appears to be associated with rs2304166 CC genotype in MS patients. Our findings suggest the need to investigate GP6’s rs2304166 role as a potential pharmacogenetic predictor for MS patients’ response to natalizumab.
In comparison to non-minority patients with multiple sclerosis, minority research in multiple sclerosis continues to be only a few percent of the literature. Often, the comparator group is with the Caucasian populations of the world, who themselves comprise of non-ubiquitous groups. Comparisons between minority groups have not been done as they relate to quality of life, partly because the populations are smaller. Our study will compare the quality life differences between two minority populations living in the same geographic and urban area. This study utilized cross-sectional data from an observational prospective cohort study. A total of 28 minority patients were included in this study. All patients were on a disease modifying therapy. Demographic information was obtained. The primary outcome measure was the MSQLI and all scores were derived from the MSQLI user’s manual. The MSQLI scores of the Mental Health Index were lower in all areas for Hispanic White MS patients as compared to Non-Hispanic African American patients, but 3 of 5 were statistically significant: MHI total score, MHI anxiety, and MHI behavioral control subscores (all p < 0.05). When investigating if EDSS associated with MSQLI measures, independent of minority group, the only noted difference was between the mild (EDSS< or = 3) and the moderate group (EDSS 3.5–5.5) in the Physical Components Score and Health Transition Score (p = 0.028 and p < 0.05). The study begins to elucidate differences in quality life measures between minorities with multiple sclerosis potentially leading to culturally competent care.
Multiple sclerosis ( MS ) is increasingly recognized in the paediatric age. In a smaller, but well-established, proportion of paediatric MS patients [20% of total paediatric MS cases: 0.2% to 0.7% of the total MS patients] the onset of disease is before 10 years of age [pre-pubescent ( childhood ) MS]; in the majority [80%] of paediatric MS patients, however [1.7% to 5.6% of the total MS population], the onset of disease is between 10 and 18 years [post-pubertal ( juvenile ) MS]. Notably, while pre-pubertal MS occurs almost equally in both genders (female/male ratio = 0.9:1; reverting to 0.4–0.6/1 in pre-school MS children) the female/male ratio rises to 2.2/3:1 in the post-pubertal age. Interestingly, precocious puberty has been associated to: ( a ) a higher risk of developing MS; and ( b ) a more severe disease course. In addition to that, males are more susceptible to MS (and manifest more neurodegeneration) than females the latter being however more inflammatory than males; pregnancy however reduces MS relapses. All the above findings led to the suggestion of an underlying female sex hormonal involvement in the pathophysiology of MS vs. a protective role of male sex hormones. Epigenetic perspectives indicate that the interplay between genetic background, environmental triggers and neuroendocrine changes, typically occurring around the time of adolescence , could all play a combined role in initiating and/or promoting MS with onset in the paediatric age including many of the most frequent disease-associated risk factors (e.g., overweight/obesity, low vitamin D levels, reduced sunlight exposure, Epstein-Barr virus infection). According to this proposed complex multifactorial model , susceptibility to MS may be thus acquired during pre-pubertal age and children have probably to wait until the adolescence to manifest their first clinical signs/symptoms.
Treatment algorithms for neuromyelitis optica spectrum disorder (NMOSD) vary, and sparse data exist regarding the impact of initial treatments on disease course. We aimed to determine whether administration of rituximab during first hospitalization reduces 1-year readmission rates.
The scenario of multiple sclerosis (MS) treatment has changed profoundly in recent decades. In this setting, one of two strategies is usually used: escalation or induction. The first involves a pyramid of possible treatments of increasing efficacy (but also increasing safety risks) that are introduced progressively as needed. The induction strategy, on the other hand, immediately pursues higher efficacy, since drugs with a higher risk profile are used from the outset. Understanding which of these treatment strategies is the more suitable for a given patient is the first step in the therapeutic decision-making process. Prognostic factors evaluated on the basis of the clinical presentation and any disease activity on magnetic resonance imaging (MRI) should guide and help clinicians in making their choices. Even though the pathogenesis of MS is not yet completely understood, specific pathological changes are known to occur in the adaptive and innate immune system over the course of the disease. To date, treatment has been based mainly on two drugs, mitoxantrone and cyclophosphamide, autologous haematopoietic stem cell therapy (within clinical trial setting), but new compounds are now emerging. Among the new treatments, alemtuzumab and cladribine appear to be valid candidates as induction drugs. In this review we provide an overview of induction strategies based on literature evidence and our own past experiences, providing descriptions of clinical cases. We also outline the future perspectives in this field.
There are few reports about the actual state of diagnosis for multiple sclerosis (MS) in Japan. In addition, in late years multiple disease-modifying drugs (DMDs) were released in Japan, but there are few reports of the actual treatment situation including the choice of DMD as well. Therefore, we conducted a questionnaire survey involving neurologists across Japan to investigate the current practices of diagnosing and determining the treatment strategy for MS.
Progressive brain atrophy is a major feature of multiple sclerosis (MS) pathology and is actually considered a major determinant of the progressive accumulation of physical and cognitive disability in MS patients. Although brain atrophy may have different pathological substrates, several lines of evidence suggest that in disease modifying drug (DMD)-treated MS patients, the higher is the anti-inflammatory effect of the DMD the lower is the progression of brain volume loss, grey matter atrophy and the accumulation of disability.
Alemtuzumab (Lemtrada®) is a humanized anti-CD52 IgG1 monoclonal antibody that depletes CD52-expressing cells from the circulation. Robust clinical and radiologic data, derived from clinical trials and long-term observational studies, indicate that alemtuzumab induces a marked immunosuppression related to the depletion of circulating T and B lymphocytes. However, recent advances suggest that the long-term clinical effects of alemtuzumab are probably due to unique qualitative changes in the process of lymphocyte repopulation of the immune system. This leads to a particular rebalancing of the immune system. In this paper we review the immunomodulatory mechanisms underlying the therapeutic effect of alemtuzumab in pre-clinical models and in patients with relapsing remitting multiple sclerosis (RRMS), and stress the importance of a monoclonal antibody-based immunosuppression for treating the severe forms of RRMS. Alemtuzumab has many features of the ideal immunomodulatory drug: rapid biological and clinical actions and and long-lasting benefit. Alemtuzumab can be used as rescue therapy or as first line drug in severe-onset MS. Thus, the availability of alemtuzumab constitutes a significant step forward in the therapy of MS.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with a very high economic impact. Peginterferon beta-1a is the first approved pegylated interferon beta-1a for the treatment of relapsing-remitting multiple sclerosis (RRMS). Its efficacy and safety were demonstrated in the placebo-controlled ADVANCE trial. A complete path to the assessment of a new health technology requires, in addition to a clinical evaluation, also an economic evaluation. In Italy, two economic evaluations were conducted and recently published.
Mitoxantrone (MX) has been used as second line therapy for aggressive multiple sclerosis (MS). Potential cardiotoxic effects of MX limit its use; a cumulative dose of up to 100 mg/m2, has been long considered relatively safe. We calculated the frequency of cardiac side effects in MS patients treated with MX.
Along with vitamin D, smoking, body mass index and others, Epstein Barr virus, other herpesviruses and human endogenous retroviruses represent plausible environmental risk factors for multiple sclerosis. However, it is difficult to obtain direct proof of their involvement in the etiology of this condition.
Despite intense research, the causes of various neurological diseases remain enigmatic to date. A role for viral or bacterial infection and associated molecular mimicry has frequently been suggested in the etiology of neurological diseases, including demyelinating autoimmune disorders, such as multiple sclerosis. Pathogen mimics of myelin-derived autoimmune peptides have been described in the literature and shown to induce myelin autoimmune responses in animal models.
Cognitive impairment is very frequent during multiple sclerosis (MS), involving approximately 40–70% of the patients, with a profound impact on patient’s life. It is now established that among the various central nervous system (CNS) structures involved during the course of MS, the hippocampus is particularly sensitive to the detrimental effects of neuroinflammation. Different studies demonstrated hippocampal involvement during MS, in association with depression and cognitive impairment, such as verbal and visuo-spatial memory deficits, even during the earlier phases of the disease. These cognitive alterations could represent the visible consequences of a hidden synaptic impairment. Indeed, neuronal and immune functions are intertwined and the immune system is able to modulate the efficacy of synaptic transmission and the induction of the main forms of synaptic plasticity, such as long term potentiation (LTP). Hippocampal synaptic plasticity has been studied during the last decades as the physiological basis of human learning and memory and its disruption can be associated with behavioral and cognitive abnormalities. The aim of the present work is to review the available evidence about the presence of hippocampal synaptic plasticity alterations in experimental models of MS, specifically during the course of experimental autoimmune encephalomyelitis (EAE) and to discuss their relevance with regard to human MS. Indeed, the failure of synapses to express plasticity during neuroinflammation could potentially lead to a progressive failure of the brain plastic reserve, possibly contributing to disability progression and cognitive impairment during MS.
First recognized at the beginning of twentieth century and named after three authors who independently described some affected patients, Vogt-Koyanagi-Harada syndrome is a rare multisystemic autoimmune disease targeting melanin-containing tissues of the eye, meninges, inner ear and skin. It predominantly affects Asian people, but also people with darker skin pigmentation such as Native Americans and Hispanics (Mestizos), whose ancestors moved from Asia across the Bering strait to North America and further down to Central and South America. Heterogenous presentation is observed, especially among different ethnic groups. Here we describe the case of an Hispanic South American patient presenting with multiple visual relapses and thus mimicking recurrent optic neuritis; we provide insights into the differential diagnosis and a brief review of the literature concerning the epidemiology of Vogt-Koyanagi-Harada syndrome in Hispanic patients compared with other ethnic groups.
To assess the association between objective bladder function parameters in relation to urinary symptoms, and to analyze the sensitivity and specificity of subjective urinary symptom-assessment in predicting objective bladder dysfunction in a multiple sclerosis (MS) population.
Fingolimod is an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) and there is class I evidence that it is superior to standard care in reducing relapse rate. However, real-world data investigating its effectiveness and potential predictors of response are still scarce.
We prospectively assessed the influence of JCV- status on disability’s accrual in RRMS patients treated with Natalizumab at two tertiary MS centres, settled in Italy.
Cognitive dysfunction is frequent in multiple sclerosis patients and has important and negative consequences for daily activities and quality of life of subjects. Disease modifying treatments for multiple sclerosis reduce the incidence of relapses and may prevent disease progression, but the influence on cognitive impairment is unclear, due to several limitations of the available studies. Moreover, symptomatic drugs for the improvement of already established cognitive deficits have been tested in small pilot studies, providing conflicting or mainly negative results. Currently, specific pharmacological therapies for the management of cognitive deficits in MS have not yet been developed. We will provide an updated overview of available evidence of pharmacological approaches for ameliorating cognitive deficits, based either on disease modifying treatments or symptomatic drugs.
Clinical manifestations are similar in adolescents and adults with MS, however in very young subjects MS frequency at onset is similar in males and females, with a higher frequency of brainstem/cerebellar involvement and acute polysymptomatic/ADEM like onset;
