Publications by authors named "Yara Fragoso"

146 Publications

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

Neurol Ther 2021 Mar 18. Epub 2021 Mar 18.

Postgraduation Department, Program on Health and Environment, Universidade Metropolitana de Santos (UNIMES), Santos, SP, Brazil.

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.
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http://dx.doi.org/10.1007/s40120-021-00237-4DOI Listing
March 2021

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

Mult Scler Relat Disord 2021 Feb 24;50:102863. Epub 2021 Feb 24.

Professor of the Postgraduate Program for Health and Environment, Universidade Metropolitana de Santos, Santos, SP, Brazil.

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.
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http://dx.doi.org/10.1016/j.msard.2021.102863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902206PMC
February 2021

Multiple Sclerosis does not affect the muscular strength of the pelvic floor during pregnancy a case control study.

Mult Scler Relat Disord 2021 Jan 10;49:102746. Epub 2021 Jan 10.

Federal University of State of Rio de Janeiro (UNIRIO), Rua Mariz e Barros 775, Tijuca, Rio de Janeiro, RJ, Brazil - ZIP CODE 20270004; Federal University of Rio de Janeiro (UFRJ), Av. Pedro Calmon 550, Cidade Universitária da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil - ZIP CODE 21941-901. Electronic address:

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http://dx.doi.org/10.1016/j.msard.2021.102746DOI Listing
January 2021

Dietary habits in a group of patients with multiple sclerosis are similar to those of healthy control subjects.

Arq Neuropsiquiatr 2020 10;78(10):638-641

Universidade Metropolitanta de Santos, Postgraduate Health and Environment Program, Santos SP, Brazil.

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Over time, patients with MS accumulate neurological disabilities. MS typically affects young adults and is associated with an inflammatory profile of cytokines and lymphocytes. If a patient were to consume a potentially inflammatory diet, it is possible that the evolution of MS in that individual would be more aggressive.

Objective: To investigate whether patients with MS living in and around the city of Santos, São Paulo, Brazil, had a profile of inflammatory diet.

Methods: Patients with MS and healthy control subjects were individually interviewed, and the 24-hour Diet Recall and the Bristol Stool Form Scale were applied. Salt intake was calculated using the WebDiet 2.0 software.

Results: There were no remarkable differences in dietary habits between healthy control subjects (n=34) and patients with MS (n=66), except for higher consumption of carbohydrates by patients. Both patients with MS and control subjects had higher protein and lower carbohydrate intake than the World Health Organization's recommended daily amounts. There was no correlation between food intake and neurological disability in patients with MS.

Conclusion: The dietary patterns of patients with MS and healthy controls were similar in the city of Santos, São Paulo, Brazil, and surrounding towns, except for higher intake of carbohydrates by patients. No profile of pro-inflammatory diets was identified among the patients with MS enrolled in this study.
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http://dx.doi.org/10.1590/0004-282X20200065DOI Listing
October 2020

Sex effects across the lifespan in women with multiple sclerosis.

Ther Adv Neurol Disord 2020 1;13:1756286420936166. Epub 2020 Jul 1.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.
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http://dx.doi.org/10.1177/1756286420936166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331774PMC
July 2020

Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis.

Mult Scler 2021 Apr 15;27(5):755-766. Epub 2020 Jun 15.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.

Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.

Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.

Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37,  < 0.001) and EDSS (β = 0.16,  < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89,  = 0.01) and EDSS (β = -0.06,  < 0.001). Neither presentation was associated with changes in relapse risk.

Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
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http://dx.doi.org/10.1177/1352458520926955DOI Listing
April 2021

Cannabis and multiple sclerosis.

Expert Rev Neurother 2020 08 18;20(8):849-854. Epub 2020 Jun 18.

Departamento De Neurociencias Y Doctorado De Farmacologia, CUCS, Universidad De Guadalajara , Mexico.

Introduction: Patients with multiple sclerosis (MS) may suffer from spasticity and pain during their disease course. Baclofen, dantrolene, diazepam and gabapentin have been used as first-line options to treat these conditions, with modest results. Medical use of marijuana smoking has bypassed traditional clinical trials and has been legalized as a therapeutic option for MS-related spasticity and pain in some countries. Cannabis-derived drugs have been tested and approved for medical use.

Areas Covered: With the development of nabiximols by the pharmaceutical industry, more countries have made it possible for patients with MS to have legal access to cannabis-related therapies. The evidence-based data on nabiximols and MS-related spasticity, pain, and urinary symptoms is consistent. There are over 7,500 patients reported in 33 studies (12 from the United Kingdom and 11 from Italy).

Expert Opinion: Nabiximols is safe and effective for patients with MS whose spasticity could not be treated with the first-line oral drugs. At present, legislation, bureaucracy and costs involved in prescribing this drug limit the experience of neurologists from many countries. There is no scientific evidence that smoking marijuana can be beneficial to patients with MS.
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http://dx.doi.org/10.1080/14737175.2020.1776610DOI Listing
August 2020

Early clinical markers of aggressive multiple sclerosis.

Brain 2020 05;143(5):1400-1413

CORe Unit, Department of Medicine, University of Melbourne, Melbourne, Australia.

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awaa081DOI Listing
May 2020

Effects of photobiomodulation on interleukin-10 and nitrites in individuals with relapsing-remitting multiple sclerosis - Randomized clinical trial.

PLoS One 2020 7;15(4):e0230551. Epub 2020 Apr 7.

Universidade Nove de Julho, UNINOVE, São Paulo, SP, Brazil.

Objective: Investigate the effects of photobiomodulation (PBM) on the expression of IL-10 and nitrites in individuals with Relapsing-Remitting multiple sclerosis (MS), as these biomarkers play a fundamental role in the physiopathology of the disease. The modulation of IL-10 and nitrites through treatment with PBM may be a novel treatment modality for MS.

Methods: A randomized, uncontrolled, clinical trial was conducted involving 14 individuals with a diagnosis of Relapsing-Remitting MS and a score of up to 6.0 on the Expanded Disability Status Scale (EDSS).

The Participants Were Randomized To Two Groups: Group 1 -PBM in the sublingual region; Group 2 -PBM over the radial artery. Irradiation was administered with a wavelength of 808 nm and output power of 100 mW for 360 seconds twice a week, totaling 24 sessions. Peripheral blood was analyzed for the determination of serum levels of IL-10 and nitrites.

Results: After treatment with PBM, the expression of IL-10 increased in both the sublingual group (pre-treatment: 2.8 ± 1.4 pg/ml; post-treatment: 8.3 ± 2.4 pg/ml) and the radial artery group (pre-treatment: 2.7 pg/ml ± 1.4; post-treatment: 11.7 ± 3.8 pg/ml). In contrast, nitrite levels were not modulated in the sublingual group (pre-treatment: 65 ± 50 nmol/mg protein; post-treatment: 51 ± 42 nmol/mg protein) or the radial artery group (pre-treatment: 51 ± 16 nmol/mg protein; post-treatment: 42 ± 7 nmol/mg protein).

Conclusion: Treatment with PBM positively modulated the expression of IL-10 but had no effect on nitrite levels. Further studies should be conducted with a larger sample and a control group, as PBM may be a promising complementary treatment for the management of MS. This trial is registered at ClinicalTrials.gov. Identifier: NCT03360487.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230551PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138327PMC
July 2020

Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder.

Mult Scler Relat Disord 2020 Feb 25;38:101868. Epub 2019 Nov 25.

CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia. Electronic address:

Background: Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD.

Method: This MSBase cohort study of AQP4-IgG+NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model.

Results: 206 AQP4-IgG+ patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p<0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (β = 0.45 (per decade), p<0.001) and disease duration (β = 0.07 per year, p<0.001). A slower increase in EDSS was associated with azathioprine (β = -0.48, p<0.001), mycophenolate mofetil (β = -0.69, p = 0.04) and rituximab (β = -0.35, p = 0.024).

Interpretation: This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort.
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http://dx.doi.org/10.1016/j.msard.2019.101868DOI Listing
February 2020

Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype.

Mult Scler 2020 11 31;26(13):1765-1774. Epub 2019 Oct 31.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.

Background: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups.

Objective: We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets.

Methods: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis.

Results: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data ( > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix ( < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex.

Conclusion: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.
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http://dx.doi.org/10.1177/1352458519881994DOI Listing
November 2020

Teaching brainstem anatomy using a sharply-located demyelinating plaque of multiple sclerosis.

Arq Neuropsiquiatr 2019 23;77(9):677. Epub 2019 Sep 23.

Instituto de Pesquisa de Cefaleia e Esclerose Múltipla, Santos SP, Brasil.

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http://dx.doi.org/10.1590/0004-282X20190099DOI Listing
April 2020

Alice in Wonderland syndrome: "Who in the world am I?"

Arq Neuropsiquiatr 2019 23;77(9):672-674. Epub 2019 Sep 23.

Multiple Sclerosis & Headache Research Institute, Santos SP, Brasil.

Alice in Wonderland syndrome (AIWS) is a paroxysmal, perceptual, visual and somesthetic disorder that can be found in patients with migraine, epilepsy, cerebrovascular disease or infections. The condition is relatively rare and unique in its hallucinatory characteristics. OBJECTIVE To discuss the potential pathways involved in AIWS. Interest in this subject arose from a patient seen at our service, in which dysmetropsia of body image was reported by the patient, when she saw it in her son. METHODS We reviewed and discussed the medical literature on reported patients with AIWS, possible anatomical pathways involved and functional imaging studies. RESULTS A complex neural network including the right temporoparietal junction, secondary somatosensory cortex, premotor cortex, right posterior insula, and primary and extrastriate visual cortical regions seem to be involved in AIWS to varying degrees. CONCLUSIONS AIWS is a very complex condition that typically has been described as isolated cases or series of cases.
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http://dx.doi.org/10.1590/0004-282X20190094DOI Listing
April 2020

Migraine in 746 patients with multiple sclerosis.

Arq Neuropsiquiatr 2019 23;77(9):617-621. Epub 2019 Sep 23.

Universidade Positivo, Curitiba PR, Brazil.

Migraine adds to the burden of patients suffering from multiple sclerosis (MS). The ID-migraine is a useful tool for screening migraine, and the Migraine Disability Assessment questionnaire can evaluate disease burden. The aim of the present study was to assess the presence and burden of migraine in patients with MS. METHODS Patients diagnosed with MS attending specialized MS units were invited to answer an online survey if they also experienced headache. RESULTS The study included 746 complete responses from patients with MS and headache. There were 625 women and 121 men, and 69% of all the patients were aged between 20 and 40 years. Migraine was identified in 404 patients (54.1%) and a moderate-to-high burden of disease was observed in 68.3% of the patients. CONCLUSION Migraine is a frequent and disabling type of primary headache reported by patients with MS.
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http://dx.doi.org/10.1590/0004-282X20190100DOI Listing
April 2020

Risk of secondary progressive multiple sclerosis: A longitudinal study.

Mult Scler 2020 01 9;26(1):79-90. Epub 2019 Aug 9.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia/L4 Centre, Melbourne Brain Centre at Royal Melbourne Hospital, Parkville, VIC, Australia.

Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested.

Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis.

Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed.

Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02,  < 0.001), longer disease duration (HR = 1.01,  = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30,  < 0.001), more rapid disability trajectory (HR = 2.82,  < 0.001) and greater number of relapses in the previous year (HR = 1.07,  = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62,  = 0.039) and disease-modifying therapy exposure (HR = 0.71,  = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion.

Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.
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http://dx.doi.org/10.1177/1352458519868990DOI Listing
January 2020

Late Onset of Neuromyelitis Optica Spectrum Disorders.

Neurol Ther 2019 Dec 2;8(2):477-482. Epub 2019 Jul 2.

Department of Neurology, Universidade Estacio de Sa, Rio de Janeiro, RJ, Brazil.

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. NMOSD starting after the age of 50 years is considered a "late onset" (LO-NMOSD) and seems to be particularly aggressive. The objective of this paper is to present a series of 37 Brazilian patients with LO-NMOSD.

Methods: Retrospective data collection from medical records of patients with LO-NMOSD seen at 14 Brazilian specialized units.

Results: The ratio of women to men in the sample was 4.3 to 1. The patients were followed up for a median period of 4 years. Sex, age at disease onset, and ethnic background were not associated with the number of relapses or disability outcomes. Extensive longitudinal myelitis affected 86% of patients, while optic neuritis affected 70%, and brainstem syndromes were present in only 16% of these patients. Six patients are currently using some type of support for walking or are wheelchair-bound. Three have died. Therapeutic options for NMOSD were particularly complicated for these elderly patients, since medications for controlling NMOSD are, in essence, immunosuppressive. Long-term use of corticosteroids can be an issue when the patients have high blood pressure, diabetes mellitus, or dyslipidemia (conditions often seen in elderly individuals).

Conclusion: This series of LO-NMOSD cases highlights the importance of prompt diagnosis and treatment for these patients.
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http://dx.doi.org/10.1007/s40120-019-0143-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858916PMC
December 2019

Severe Exacerbation of Multiple Sclerosis Following Withdrawal of Fingolimod.

Clin Drug Investig 2019 Sep;39(9):909-913

Universidade Federal Fluminense, Niteroi, RJ, Brazil.

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.
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http://dx.doi.org/10.1007/s40261-019-00804-6DOI Listing
September 2019

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

Neurol Ther 2019 Dec 24;8(2):207-214. Epub 2019 May 24.

MS Section, Hospital Británico de CABA, Buenos Aires, Argentina.

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.
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http://dx.doi.org/10.1007/s40120-019-0139-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858893PMC
December 2019

Implementing the 2017 McDonald criteria for the diagnosis of multiple sclerosis.

Nat Rev Neurol 2019 08;15(8):441-445

Department of Neurology, University of California-San Francisco, San Francisco, CA, USA.

The latest revision of the McDonald criteria for the diagnosis of multiple sclerosis (MS) was published online in 2017. New features of the criteria, which were designed to facilitate earlier diagnosis of MS, include the recognition of oligoclonal bands in the cerebrospinal fluid as a possible marker of dissemination of MS pathology in time, the introduction of symptomatic lesions as a parameter to demonstrate spatial or temporal pathology dissemination, and the use of cortical lesions to demonstrate dissemination in space. In this Viewpoint, a panel of world-renowned MS specialists share their personal experiences of the new criteria to date.
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http://dx.doi.org/10.1038/s41582-019-0194-0DOI Listing
August 2019

Clinical Characteristics of Patients With Neuromyelitis Optica Spectrum Disorders With Early Onset.

J Child Neurol 2019 08 23;34(9):487-490. Epub 2019 Apr 23.

2 Department of Neurology, University Hospital Getulio Vargas, Manaus, AM, Brazil.

Neuromyelitis optica spectrum disorder is a severe and disabling disease that manifests with severe relapses of optic neuritis, longitudinally extensive myelitis, and/or brainstem syndromes. The disease is complex and, although onset typically occurs in middle age, children and adolescents may be affected. The present study adds to the literature through detailed clinical data from 36 Brazilian patients with neuromyelitis optica spectrum disorder starting before age 21. This was a retrospective assessment of medical records from 14 specialized units in Brazil. The results showed that the course of neuromyelitis optica spectrum disorder was worse in patients with disease onset before the age of 12 years. Gender and ethnic background did not influence disability accumulation. Over a median period of 8 years, 14% of the patients who presented the initial symptoms of neuromyelitis optica spectrum disorder before the age of 21 years died. In conclusion, the present study adds to the reports from other authors examining the severity of early-onset neuromyelitis optica spectrum disorder.
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http://dx.doi.org/10.1177/0883073819842421DOI Listing
August 2019

Clinical characteristics of 153 Brazilian patients with neuromyelitis optica spectrum disorder (NMOSD).

Mult Scler Relat Disord 2019 Jan 28;27:392-396. Epub 2018 Nov 28.

Department of Neurology, New York University, New York, NY, USA.

Background: The 2015 criteria for diagnosing neuromyelitis optica spectrum disorder (NMOSD) have encouraged several groups across the world to report on their patients using these criteria. The disease typically manifests with severe relapses of optic neuritis, longitudinally extensive myelitis and/or brainstem syndromes, often leading to severe disability. Some patients are seropositive for antibodies against aquaporin-4 (AQP4), others are positive for anti-myelin oligodendrocyte glycoprotein (MOG), while a few are negative for both biomarkers. The disease is complex, and only now are specific therapeutic clinical trials being carried out. The present study adds to the literature through detailed clinical data from 153 medical records of Brazilian patients.

Methods: Retrospective assessment of medical records from nine specialized units in Brazil.

Results: NMOSD was more prevalent in females (4.1:1), who had significantly fewer relapses than males (p = 0.007) but presented similar levels of disability over time. African ancestry was associated with higher levels of disability throughout the disease course (p < 0.001), although the number of relapses was similar to that observed in white patients. Concomitant autoimmune diseases were relatively rare in this population (6.5%). Positivity for anti-AQP4 antibodies was identified in 62% of the patients tested, while 3% presented anti-MOG antibodies. Anti-AQP4 antibodies were not associated to worse disease course. The last medical record showed that six patients had died and 13 were wheelchair-bound. Seventy percent of the patients did not respond to first-line therapy (azathioprine and/or corticosteroids), and five patients continued to relapse even after four different courses of treatment.

Conclusion: The present study adds to the reports from other countries presenting original data on Brazilian patients diagnosed with NMOSD according to the 2015 criteria.
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http://dx.doi.org/10.1016/j.msard.2018.11.031DOI Listing
January 2019

Pharmacogenetics in multiple sclerosis: the long and winding road ahead of us.

Arq Neuropsiquiatr 2018 10;76(10):647-648

Universidade Metropolitana de Santos, Departamento de Neurologia, Santos SP, Brasil.

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http://dx.doi.org/10.1590/0004-282X20180115DOI Listing
October 2018

Seroconversion of JCV antibodies is strongly associated to natalizumab therapy.

J Clin Neurosci 2019 Mar 3;61:112-113. Epub 2018 Nov 3.

Hospital Universitario Getulio Vargas, Manaus, AM, Brazil.

Previous infection with John Cunningham virus (JCV) increases the risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) undergoing treatment with natalizumab. Patients who test negative for JCV antibodies must be assessed every six months due to the risk of seroconversion. Data from the United States of America, Portugal, Holland, France, United Kingdom and Sweden have shown a strong correlation between the use of natalizumab and JCV seroconversion. The authors present now data on patients from Brazil, as there are no data from Latin American countries published on this subject yet. A group of 86 patients with MS with negative results for antibodies against JCV were included in this analyses with at least two JCV antibodies testing. Twenty-five patients (29% of the total group) did not use natalizumab at any time, while the remaining 71% used natalizumab for a median period of 800 days (equivalent to 28 monthly infusions). Seroconversion was observed in 19 patients (22.1%). There was no association of seroconversion with gender, age, previous pulses of corticosteroid or specific MS-modifying drugs. The use of natalizumab was strongly associated to seroconversion (p < 0.0001). The present results confirm the influence of natalizumab therapy on JCV antibodies in several countries and continents.
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http://dx.doi.org/10.1016/j.jocn.2018.10.128DOI Listing
March 2019

Serological profile of John Cunningham virus (JCV) in patients with multiple sclerosis.

Arq Neuropsiquiatr 2018 09;76(9):588-591

Universidade Metropolitana de Santos, Departamento de Neurologia, São Paulo SP, Brasil.

Treatment options for multiple sclerosis (MS) have changed over the last few years, bringing about a new category of drugs with more efficient profiles. However, these drugs have come with a whole new profile of potential adverse events that neurologists have to learn well and quickly. One of the most feared complications of these MS treatments is progressive multifocal leukoencephalopathy caused by the reactivation of the John Cunningham virus (JCV).

Objective: To identify the serologic profile of JCV in patients with MS.

Methods: Data on serum antibodies for JCV were obtained using the enzyme-linked immunosorbent assay provided by the STRATIFY-JCV program.

Results: A total of 1,501 blood tests were obtained from 1,102 patients with MS. There were 633 patients (57.1%) who were positive for antibodies for JCV and 469 patients who were negative (42.9%). Twenty-three patients became positive after initially having negative JCV antibody status. The rate of seroconversion was 18.5% over 22 months.

Conclusion: The JCV serologic profile and seroconversion in Brazilian patients were similar to those described in other countries.
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http://dx.doi.org/10.1590/0004-282X20180083DOI Listing
September 2018

Pediatric acute-onset neuropsychiatric syndrome (PANS) misdiagnosed as autism spectrum disorder.

Immunol Lett 2018 11 15;203:52-53. Epub 2018 Sep 15.

Department of Neurology, Universidade Metropolitana de Santos, UNIMES, Santos, SP, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.imlet.2018.09.009DOI Listing
November 2018

Practical Evidence-Based Recommendations for Patients with Multiple Sclerosis Who Want to Have Children.

Neurol Ther 2018 Dec 30;7(2):207-232. Epub 2018 Aug 30.

Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

Multiple sclerosis (MS) management presently aims to reach a state of no (or minimal) evidence of disease activity. The development and commercialization of new drugs has led to a renewed interest in family planning, since patients with MS may face a future with reduced (or no) disease-related neurological disability. The advice of neurologists is often sought by patients who want to have children and need to know more about disease control at conception and during pregnancy and the puerperium. When MS is well controlled, the simple withdrawal of drugs for patients who intend to conceive is not an option. On the other hand, not all treatments presently recommended for MS are considered safe during conception, pregnancy and/or breastfeeding. The objective of the present study was to summarize the practical and evidence-based recommendations for family planning when our patients (women and men) have MS.Funding TEVA Pharmaceutical Brazil.
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http://dx.doi.org/10.1007/s40120-018-0110-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283793PMC
December 2018

High levels of alexithymia in patients with multiple sclerosis.

Dement Neuropsychol 2018 Apr-Jun;12(2):212-215

Department of Neurology, Universidade Metropolitana de Santos, Santos, SP, Brazil.

Alexithymia is a personality trait characterized by difficulties identifying and describing feelings. Some researchers describe high levels of alexithymia among patients with multiple sclerosis (MS) but literature data on this subject are scarce.

Objective: The objective of the present study was to characterize findings of alexithymia in patients with MS.

Methods: This cross-sectional case-control study included 180 patients with MS and a matched control group. Data for patients with MS included disease duration, number of demyelinating relapses and degree of neurological disability, as assessed by the Expanded Disability Scale Score (EDSS). In addition, the Hospital Anxiety and Depression (HAD) scale and the Toronto Alexithymia Scale (TAS) were used.

Results: There were 126 women and 54 men in each group, with median age of 37 years and median education of 16 years. Patients with MS had higher degrees of depression (p<0.01), anxiety (p=0.01) and alexithymia (p<0.01) than did control subjects. For individuals with MS, depressive traits (p<0.01), anxious traits (p=0.03), higher age (p=0.02), lower education level (p=0.02), higher degree of disability (p<0.01) and not being actively employed (p=0.03) were associated with higher rates of alexithymia.

Conclusion: Alexithymia was a relevant finding in patients with MS.
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http://dx.doi.org/10.1590/1980-57642018dn12-020015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022982PMC
July 2018

There is no benefit in the use of postnatal intravenous immunoglobulin for the prevention of relapses of multiple sclerosis: findings from a systematic review and meta-analysis.

Arq Neuropsiquiatr 2018 Jun;76(6):361-366

Universidade Metropolitana de Santos, Departamento de Neurologia, Santos SP, Brasil.

Objective: Multiple sclerosis (MS) is a complex autoimmune and neurodegenerative disease of the central nervous system. Since MS affects mostly fertile women, pregnancy issues often arise in daily practice. The present study assessed the use of postpartum intravenous immunoglobulin (IVIG) in MS.

Methods: The authors individually searched for records using PubMed, Medline, EMBASE, Cochrane, SciELO, LILACS, and Google Scholar, using the terms "multiple sclerosis" OR "MS" AND "pregnancy" OR "gestation" OR "partum" OR "post-partum" OR "puerperium" AND "immunoglobulin".

Results: The initial search returned 321 papers. There were 11 eligible articles selected for the review. In total, 380 patients had received post-natal IVIG to reduce the number of postpartum relapses. The unadjusted number needed to treat was 6.3 for the quantitative and 5.8 for the qualitative analyses.

Conclusion: The therapeutic effect of IVIG for prevention of postnatal relapses in MS could not clearly be established in this meta-analysis.
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http://dx.doi.org/10.1590/0004-282X20180041DOI Listing
June 2018

Normative values of the Brief Repeatable Battery of Neuropsychological Tests in a Brazilian population sample: discrete and regression-based norms.

Arq Neuropsiquiatr 2018 03;76(3):163-169

Departamento de Neurologia, Universidade de Campinas, Campinas, SP, Brasil.

Objective Cognitive dysfunction is common in multiple sclerosis. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was developed to assess cognitive functions most-frequently impaired in multiple sclerosis. However, normative values are lacking in Brazil. Therefore, we aimed to provide continuous and discrete normative values for the BRB-N in a Brazilian population sample. Methods We recruited 285 healthy individuals from the community at 10 Brazilian sites and applied the BRB-N version A in 237 participants and version B in 48 participants. Continuous norms were calculated with multiple-regression analysis. Results Mean raw scores and the 5th percentile for each neuropsychological measure are provided, stratified by age and educational level. Healthy participants' raw scores were converted to scaled scores, which were regressed on age, sex and education, yielding equations that can be used to calculate predicted scores. Conclusion Our normative data allow a more widespread use of the BRB-N in clinical practice and research.
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http://dx.doi.org/10.1590/0004-282x20180006DOI Listing
March 2018