Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national registry.

BACKGROUND: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time. OBJECTIVE: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS. METHODS: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data. RESULTS: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(ß)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)). CONCLUSIONS: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.

Cost analysis of multiple sclerosis in Brazil: a cross-sectional multicenter study.

BACKGROUND: Multiple sclerosis (MS) is a central nervous system disease associated with irreversible progression of disability, which imposes a substantial socioeconomic onus. The objective of this study was to determine the economic impact of multiple sclerosis from the Brazilian household and healthcare system perspectives. Secondary objectives were to assess the impact of fatigue on daily living and health-related quality of life (HRQL) of MS patients. METHODS: This is a cross-sectional study in which Brazilian eligible patients attending eight major MS specialized sites answered an interview capturing data on demographics, disease characteristics and severity, comorbidities, resource utilization, fatigue, utilities and health-related quality of life from November/2011 to May/2012 . Costs were assessed considering a prevalence-based approach within 1 year of resource consumption and were estimated by multiplying the amount used by the corresponding unit cost. Patients were classified as having mild, moderate or severe disability according to the Expanded Disability Status Scale (EDSS). RESULTS: In total, 210 patients who met eligibility criteria were included, 40 % had mild, 43 % moderate and 16 % severe disability; disability level was missing for 1 %. The average total direct cost per year was USD 19,012.32 (SD = 10,465.96), and no statistically significant differences were not observed according to MS disability level (p = 0.398). The use of disease modifying therapies (DMTs) corresponded to the majority of direct expenditures, especially among those patients with lower levels of disability, representing around 90 % of total costs for mild and moderate MS patients. It was also observed that expenses with medical (except DMTs) and non-medical resources are higher among patients with more severe disease. Worsening disability also had an important influence on health-related quality of life and self-perceived impact of fatigue on daily living. CONCLUSION: Our data demonstrates the significant economic impact of MS on both Brazilian household and health system, in terms of DMTs and other disease management costs. When patients move upwards on the disease severity scale, costs with health resources other than drugs are significantly increased.

Retinoic Acid Signalling in the Pineal Gland Is Conserved across Mammalian Species and Its Transcriptional Activity Is Inhibited by Melatonin.

The pineal gland is integral to the circadian timing system due to its role in nightly melatonin production. Retinoic acid (RA) is a potent regulator of gene transcription and has previously been found to exhibit diurnal changes in synthesis and signalling in the rat pineal gland. This study investigated the potential for the interaction of these two systems. PCR was used to study gene expression in mouse and human pineal glands, ex-vivo organotypic cultured rat pineal gland and cell lines. The mouse and human pineal glands were both found to express the necessary components required for RA signalling. RA influences the circadian clock in the brain, therefore the short-term effect of RA on clock gene expression was determined in ex vivo rat pineal glands but was not found to rapidly regulate Per1, Per2, Bmal1, or Cry1. The interaction between RA and melatonin was also investigated and, unexpectedly, melatonin was found to suppress the induction of gene transcription by RA. This study demonstrates that pineal expression of the RA signalling system is conserved across mammalian species. There is no short-term regulation of the circadian clock but an inhibitory effect of melatonin on RA transcriptional activity was demonstrated, suggesting that there may be functional cross-talk between these systems.

Astrocytes as a regulated source of retinoic acid for the brain.

Retinaldehyde dehydrogenases (RALDH) catalyze the synthesis of the regulatory factor retinoic acid (RA). Cultured astrocytes express several of the RALDH enzyme family, and it has been assumed that this can be extrapolated to astrocytes in vivo. However, this study finds that few astrocytes in the rodent brain express detectable RALDH enzymes, and only when these cells are grown in culture are these enzymes upregulated. Factors controlling the expression of the RALDHs in cultured astrocytes were explored to determine possible reasons for differences between in vitro versus in vivo expression. Retinoids were found to feedback to suppress several of the RALDHs, and physiological levels of retinoids may be one route by which astrocytic RALDHs are maintained at low levels. In the case of RALDH2, in vivo reduction of vitamin A levels in rats resulted in an increase in astrocyte RALDH2 expression in the hippocampus. Other factors though are likely to control RALDH expression. A shift in astrocytic RALDH subcellular localization is a potential mechanism for regulating RA signaling. Under conditions of vitamin A deficiency, RALDH2 protein moved from the cytoplasm to the nucleus where it may synthesize RA at the site of the nuclear RA receptors. Similarly, in conditions of oxidative stress RALDH1 and RALDH2 moved from the cytoplasm to a predominantly nuclear position. Thus, the RALDHs have been revealed to be dynamic in their expression in astrocytes where they may maintain retinoid homeostasis in the brain.

New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19.

We report on nine patients (eight cases of MS and one case of NMOSD) who presented a disease relapse in close temporal association with their first AZD1222 vaccination dose against COVID-19. These patients had been stable for a median period of six years, with no evidence of disease activity and no change in their medication. After a median of 13 days (7 to 25 days) from vaccination, they developed a new relapse with increased disability and new lesions on magnetic resonance imaging. Although this association may be rare, it might be an adverse event of AZD1222.

COVID-19 in a temporal relation to the onset of multiple sclerosis.

Neurological complications of COVID-19 have been described. We present the case of a 27-year-old woman who developed COVID-19 in April 2020. She continued to present anosmia and ageusia eight months later. Six months after contracting COVID-19, she developed dysesthesia, hypoesthesia and hyperreflexia. Her magnetic resonance imaging showed demyelinating lesions, of which two were enhanced by gadolinium. She was positive for oligoclonal bands in her spinal fluid. This patient developed multiple sclerosis with a temporal relationship to COVID-19. We believe that SARS-CoV-2 led to her autoimmune disease through a virus-induced neuroimmunopathological condition.

Evidence-Based Recommendations for the Oral Health of Patients with Parkinson's Disease.

INTRODUCTION: Patients with Parkinson's disease (PD) present a variety of oral disease that can be worsened by xerostomia and sialorrhea. The patients' physical limitations, for example rigidity and tremor, add to the difficulty of oral care by the general dental surgeon. The objective of the present review was to organize a list of evidence-based recommendations for the oral care of patients with PD. METHODS: A systematic review of the literature was carried out by specialists who selected the relevant papers and created a list of recommendations based upon the literature. RESULTS: Fourteen papers (data reported in 16 articles) were included in this review. Patients with PD had reduced quality of oral health and hygiene, and high prevalence of gingival recession, periodontal disease, dental calculus, tooth decay, tooth mobility and loss, drooling, xerostomia, dysphagia and temporomandibular disorders. Most studies offered class IV evidence, while one paper had class II evidence. CONCLUSION: Patients with PD present poor oral health with conditions that are mostly preventable.

Coronavirus disease 2019 in Latin American patients with multiple sclerosis.

Patients with multiple sclerosis (MS) who present coronavirus disease 2019 (COVID-19) are of particular interest to neurologists. These patients have a neuroimmune disease and receive immunomodulatory or immunosuppressive therapies in the long-term. We present here data from 73 patients with MS and a confirmed diagnosis of COVID-19 from five Latin American countries. Fifteen patients (20.5%) were hospitalized and two patients died. The use of anti-CD20 therapies was the only risk factor associated to hospitalization and death. Despite the small sample size, this study highlights the awareness regarding therapeutic options for MS during the pandemic.

Severe Exacerbation of Multiple Sclerosis Following Withdrawal of Fingolimod.

BACKGROUND: Fingolimod is an effective therapy for multiple sclerosis (MS). Isolated reports of very aggressive MS rebound after discontinuation of fingolimod are drawing neurologists' attention to this potentially severe complication of the drug. OBJECTIVE: Our objective was to collect literature data on cases of MS rebound following fingolimod withdrawal. In addition, we report six new cases of this adverse event in Brazil. METHODS: We carried out a systematic review of published data on cases of MS rebound after fingolimod was discontinued. In addition, the study reports a retrospective data series of Brazilian patients presenting this rebound reaction. RESULTS: Twenty papers have been published reporting on 52 patients with severe MS rebound after fingolimod withdrawal. Six new patients are included in the present paper, all of them with aggressive rebound and accumulated disability sequelae. CONCLUSION: We recommend gradual discontinuation of fingolimod with replacement by other treatment. The washout period should not exceed 4 weeks.

Practical Issues Concerning the Approval and Use of Biosimilar Drugs for the Treatment of Multiple Sclerosis in Latin America.

The use of biosimilar drugs for multiple sclerosis (MS) has become widespread in Latin America, with the goal of reducing costs of treatments, promoting the sustainability of healthcare systems, and improving patient access to these therapies. There is currently a need to define and comply with requirements to guarantee the efficacy, safety, and quality of these drugs. Thus, the objective of the present study was to compile up-to-date information from each Latin American country assessed on (a) approval of biosimilar drugs by regulatory agencies; (b) use of biosimilar drugs, pharmacovigilance plans, risk management; and (c) update in the knowledge on different molecules. To do so, a group of experts from Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Panama, Peru, Uruguay, and Venezuela met to discuss the current situation regarding good practices and risks associated with the use of biosimilar drugs in their respective countries. Regulation, risk management plans, and pharmacovigilance in the whole continent must guide the strategies on the commercialization and access of biosimilar drugs and copies of complex molecules. Current regulations must be implemented for the registration of biosimilar drug products and complex molecules. It is paramount to ensure that new products follow the best quality standards at all stages beyond being safe and efficient. Uncontrolled interchangeability between original biological and biosimilar should be avoided. Latin America requires the implementation and full use of strong pharmacovigilance programs. National and multinational clinical studies are required to demonstrate the similarity in safety, efficacy, and immunogenicity profiles of complex molecules, as well as biological and biosimilar products. Plain language summary available for this article.

Specificities of Children with Multiple Sclerosis and Neuromyelitis Optica.

BACKGROUND: Chronic demyelinating diseases of the central nervous system (CNS) are autoimmune conditions that, although rarely fatal, may lead to severe disability. Among these diseases, Multiple Sclerosis (MS) and neuromyelitis optica (NMO) are particularly important and subject of worldwide research. MS and NMO are chronic types of CNS disease, with recurrent episodes of demyelination. For many years, these two conditions were considered to be only one, but lately it is known that they have different epidemiological, physiopathological and prognostic characteristics. The present study aims at reviewing the specificities of MS and NMO affecting patients before they complete 18 years of age. METHODS: Literature review on data about MS and NMO in patients below the age of 18 years. RESULTS: There are no clinical trials for any drug used to treat MS and NMO in children or adolescents. Data are mainly on anedoctal cases, case series and recommendations from experts. At present, there is no evidence-based treatment to be recommended for patients with MS and NMO before the age of 18 years. CONCLUSION: Despite being a particularly vulnerable population for severe disability in the future, there are no evidence-based guidelines for the treatment of MS and NMO in children and adolescents.

Profile and costs involved in long-term compulsory hospitalization of psychiatric patients.

OBJECTIVE: Involuntary hospitalization for acute psychiatry cases can be acceptable when there is potential harm. However, there are few reasons for a patient committed on these grounds to stay in an institution for a long period. The objective of the present study was to identify the profile and costs of compulsory hospitalizations over 20 days in a public psychiatric hospital in the coastal region of the state of São Paulo. METHODS: Retrospective data were collected from the medical records of 1,064 patients admitted between July 2013 and June 2016 from an intensive mental healthcare unit in Santos, state of São Paulo, Brazil. RESULTS: Records were found of 527 patients who had been hospitalized for at least 21 days during the study period. Long-term hospitalization related to judicial mandates represented 5.9% of the total sample. These patients stayed in the hospital for an average period of 142 days, while patients hospitalized for any other reason stayed an average period of 35 days (p < 0.001). The cost of a long-term court-ordered hospitalization averaged US$ 21,311 per patient. CONCLUSION: Judicial mandate has been an important reason for the long-term hospitalization of chronic psychiatric patients in Santos, Brazil.

Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis.

Retinoic acid (RA) is a potent regulator of gene transcription via its activation of a set of nuclear receptors controlling transcriptional activation. Precise maintenance of where and when RA is generated is essential and achieved by local expression of synthetic and catabolic enzymes. The catabolic enzymes Cyp26a1 and Cyp26b1 have been studied in detail in the embryo, where they limit gradients of RA that form patterns of gene expression, crucial for morphogenesis. This paracrine role of RA has been assumed to occur in most tissues and that the RA synthetic enzymes release RA at a site distant from the catabolic enzymes. In contrast to the embryonic CNS, relatively little is known about RA metabolism in the adult brain. This study investigated the distribution of Cyp26a1 and Cyp26b1 transcripts in the rat brain, identifying several novel regions of expression, including the cerebral cortex for both enzymes and striatum for Cyp26b1. In vivo use of a new and potent inhibitor of the Cyp26 enzymes, ser 2-7, demonstrated a function for endogenous Cyp26 in the brain and that hippocampal RA levels can be raised by ser 2-7, altering the effect of RA on differential patterning of cell proliferation in the hippocampal region of neurogenesis, the subgranular zone. The expression of CYP26A1 and CYP26B1 was also investigated in the adult human brain and colocalization of CYP26A1 and the RA synthetic enzyme RALDH2 indicated a different, autocrine role for RA in human hippocampal neurons. Studies with the SH-SY5Y human neuroblastoma cell line implied that the co-expression of RA synthetic and catabolic enzymes maintains retinoid homeostasis within neurons. This presents a novel view of RA in human neurons as part of an autocrine, intracellular signaling system.

[How children aged 7 to 11 explain their headache]. / Como as crianças de 7 a 11 anos explicam sua cefaléia.

The aim of the present study was to observe the ability of children aged 7 to 11 in describing their headache during anamnesis. For this purpose, two evaluations of 94 children were performed in individual assessments, done by the same Pediatrician, within a six to eight week interval, without the presence of adults. The characteristics of headache in these children could be properly evaluated during the interviews. There were no remarkable conflicting information between the two interviews. Although the headache of the child is usually described by the accompanying adult during the consultation, childhood headache should really be informed by the patient. In this group of young children (7 to 11 years old), information could be obtained without difficulty since we allowed the child enough time and the use of his (her) own words.

We know how to prescribe natalizumab for multiple sclerosis, but do we know how to withdraw it?

Natalizumab is a potent immunosuppressive monoclonal antibody used for the treatment of multiple sclerosis (MS). While definite guidelines for the safety of natalizumab prescriptions are available in all countries, there are no specific recommendations on how to withdraw the drug if the need arises. There are reports describing MS complications after natalizumab infusions were stopped. Most neurologists seem to stop natalizumab treatment according to their idea on how to best carry out the withdrawal. The present study shows the very different manners in which expert neurologists from 14 MS units in Brazil stopped natalizumab in their patients. The authors concluded that pharmacovigilance on natalizumab must persist after the drug is withdrawn in order to have enough data for adequate recommendations.

Profile and costs involved in long-term compulsory hospitalization of psychiatric patients

Objective: Involuntary hospitalization for acute psychiatry cases can be acceptable when there is potential harm. However, there are few reasons for a patient committed on these grounds to stay in an institution for a long period. The objective of the present study was to identify the profile and costs of compulsory hospitalizations over 20 days in a public psychiatric hospital in the coastal region of the state of São Paulo. Methods: Retrospective data were collected from the medical records of 1,064 patients admitted between July 2013 and June 2016 from an intensive mental healthcare unit in Santos, state of São Paulo, Brazil. Results: Records were found of 527 patients who had been hospitalized for at least 21 days during the study period. Long-term hospitalization related to judicial mandates represented 5.9% of the total sample. These patients stayed in the hospital for an average period of 142 days, while patients hospitalized for any other reason stayed an average period of 35 days (p < 0.001). The cost of a long-term court-ordered hospitalization averaged US$ 21,311 per patient. Conclusion: Judicial mandate has been an important reason for the long-term hospitalization of chronic psychiatric patients in Santos, Brazil.

Association between headache and temporomandibular joint disorders in children and adolescents.

The aim of the present study was to assess the relationship between temporomandibular joint disorder (TMJD) and headache in children and adolescents. A prospective cross-sectional cohort study was carried out involving 93 children and adolescents (6 to 14 years of age) at the outpatient service of a dental school. All participants underwent a clinical examination involving Axis 1 of the Research Diagnostic Criteria for Temporomandibular Disorders, along with a characterization of headache and an anthropometric evaluation. Statistical analysis involved the chi-squared test for quantitative variables and the Student's t-test, ANOVA and Tukey's test for quantitative data. An adjusted logistic regression model was used to determine significant associations among gender, age, TMJD and headache. Mild TMJD was identified in 35.8% of the sample and was not associated the presence of headache. Moderate TMJD was found in 25.8% of patients and severe TMJD was found in 11.8%; both forms of TMJD were associated with headache. A significant correlation was found between the intensity of TMJD and the risk of headache. The present findings demonstrate a positive correlation between TMJD and headache in children and adolescents, independently of gender and age.

Long-term effects of exposure to disease-modifying drugs in the offspring of mothers with multiple sclerosis: a retrospective chart review.

INTRODUCTION: Multiple sclerosis (MS) mainly affects women of fertile age. To date, the only recommendation for women with MS intending to become pregnant is to stop all treatment. This recommendation reflects the concerns about the effects of disease-modifying drugs (DMDs) on the offspring. The objective of the present study was to assess the potential long-term effects of maternal exposure to DMDs on the offspring. METHOD: This was a retrospective study revising medical data on the offspring of women with MS. These women now have children aged at least 1 year and include a group of patients that were not exposed to any DMDs for at least 3 months prior to pregnancy and during the whole gestation (control group). Another group of patients had at least 2 weeks of exposure to DMDs, mainly to interferon beta or glatiramer acetate RESULTS: The women with MS participating in this study have children currently aged, on average, 6.6 years (range 1-39 years). There was no pattern of drug-related adverse events or complications in the children whose mothers were exposed to DMDs. No specific long-term adverse events were observed in the offspring of women with MS who were exposed to drugs during pregnancy. The profile of relevant diagnoses in their children was similar to that of children whose mothers had not been exposed to DMDs. CONCLUSIONS: The present retrospective study did not show a specific profile of long-term deleterious drug effects on children born from mothers who were exposed to drugs for MS treatment.

Long-term use of glatiramer acetate by 11 pregnant women with multiple sclerosis: a retrospective, multicentre case series.

BACKGROUND: Glatiramer acetate is a US FDA category B drug with regard to use by pregnant women with multiple sclerosis (MS). There are no data currently available for the continuous use of glatiramer acetate during pregnancy. OBJECTIVE: To assess the risks and benefits of glatiramer acetate used throughout pregnancy among women with active MS. DESIGN: Retrospective and multicentre case series. SETTINGS: Outpatient services of academic and private institutions caring for patients with MS in Brazil. PATIENTS: Eleven women with MS and their children were assessed. INTERVENTION: Retrospective evaluation of women with MS who received glatiramer acetate continuously for at least 7 months during pregnancy. This evaluation was performed by the neurologist responsible for the patient. Children aged 1 year and over, born to mothers who received glatiramer acetate during pregnancy, were assessed using the Denver II developmental screening test. MAIN OUTCOME MEASUREMENTS: Obstetric, neonatal and developmental outcomes. RESULTS: No drug-related obstetric complications were observed. No specific drug-related malformations, neonatal complications or developmental abnormalities were observed in the children. Postnatal MS relapse rates remained significantly lower than antenatal rates in these patients. CONCLUSIONS: No deleterious effects from glatiramer acetate were observed in these pregnant women with MS or in their offspring. No increment in postnatal relapse rate was observed. However, the use of glatiramer acetate during pregnancy should be restricted to the most difficult cases, in which the benefits clearly outweigh the risks.