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- Síndrome de hemiconvulsión-hemiplejía-epilepsia: caso clínico y uso de dextrometorfanoPublication . Coelho, J; Santos, T; Ezequiel, M; Luis, C; Levy, A
- Mutational mechanism for DAB1 (ATTTC)n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitutionPublication . Loureiro, J; Oliveira, C; Mota, C; Castro, A; Costa, C; Loureiro, J, et al.Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n . Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT-rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process.
- Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting: PROTEC.Publication . Berger, T; Brochet, B; Brambilla, L; Giacomini, PS; Montalbán, X; Salgado, Salgado, AV, e outrosAbstract BACKGROUND: Patient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing-remitting multiple sclerosis (RRMS) disease. OBJECTIVE: The aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic. METHODS: PROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (≤3.5 EDSS and ≤1 relapse in the prior year) patient subgroups were evaluated. RESULTS: Unadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n = 1105) and 84%, 77%, and 71% lower in newly diagnosed, ≤3.5 EDSS, and ≤1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, ≤3.5 EDSS; 88%, ≤1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline. CONCLUSION: At 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective.Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708,
- Mutational mechanism for DAB1 (ATTTC)n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution.Publication . Loureiro, J; Oliveira, C; Mota, C; Castro, A; Costa, C; Loureiro, J, et al.Abstract Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n . Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT-rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process.
- Prescrição de Anti-Inflamatórios Não Esteroides a Doentes com Diabetes Mellitus em PortugalPublication . Vieira, M; Neves, JS; Baptista, R; Leitão, L; Dias, C; Vicente, R, et al.INTRODUCTION: Portugal presents the highest incidence of stage 5 chronic kidney disease in Europe. It is speculated that a high consumption of non-steroidal anti-inflammatory drugs (NSAIDS) may contribute to this high incidence. Our aim was to characterize the prescription of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus in Portugal. MATERIAL AND METHODS: We analyzed the national prescription database in triennium 2015 - 2017. In patients with diabetes mellitus, we evaluated the prescription of non-steroidal anti-inflammatory drugs according to age, gender and region of the patient and specialty of the prescribing physician. We evaluated the prescription of non-steroidal anti-inflammatory drugs in all patients with diabetes mellitus, in patients with presumed renal impairment, and in those with concomitant prescription of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists. RESULTS: We analyzed 23 320 620 prescriptions, corresponding to 610 157 adults, including 104 306 patients with diabetes mellitus. The most prescribed non-steroidal anti-inflammatory drugs were ibuprofen (20.1%), metamizole (14.7%), and diclofenac (11.4%). The prescription of non-steroidal anti-inflammatory drugs was higher in females, in patients aged 51 - 70 years and in the Alentejo region. Non-steroidal anti-inflammatory drugs were prescribed to 70.6% of patients with diabetes mellitus, from which 10.6% were prescribed ≥ 10 packages during the three years. Among patients with diabetes mellitus on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and with presumed reduction in kidney function, 69.3% were prescribed non-steroidal anti-inflammatory drugs and 11.5% were prescribed ≥ 10 packages during the three years. DISCUSSION: The level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus is high. The concern of reducing non-steroidal anti-inflammatory drugs prescription to patients already on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and/or decreased renal function does not seem to exist. CONCLUSION: In Portugal, the level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus should be reduced, particularly in the subgroups identified with higher prescription and with higher risk of progression to stage 5 chronic kidney disease.
- Efficacy and safety of endovascular treatment in acute ischemic stroke due to cervical artery dissection: A 15-year consecutive case seriesPublication . Bernardo, F; Nannoni, S; Strambo, D; Puccinelli, F; Saliou, G; Michel, P, et al.BACKGROUND: Limited observational data are available on endovascular treatment in acute ischemic stroke due to cervical artery dissection. Three studies comparing endovascular treatment with standard medical therapy or intravenous thrombolysis in cervical artery dissection-related acute ischemic stroke did not demonstrate superiority of endovascular treatment. Efficacy and the choice of endovascular treatment technique in this setting remain to be established. AIMS: To assess the potential efficacy and safety of endovascular treatment compared to intravenous thrombolysis alone or to no revascularization treatment in our center. METHODS: We selected all consecutive patients with cervical artery dissection-related acute ischemic stroke and intracranial occlusion from the Acute STroke Registry and Analysis of Lausanne between 2003 and 2017. We compared clinical and neuroimaging data of patients treated by endovascular treatment versus patients receiving intravenous thrombolysis or patients without revascularization treatment. Safety analysis included symptomatic intracranial hemorrhage, major radiological hemorrhages (parenchymal hematoma 1, parenchymal hematoma 2, and subarachnoid hemorrhage) and mortality within seven days. We assessed favorable clinical outcome (modified Rankin Scale 0-2) at three months using a binary logistic regression model. RESULTS: Of the 109 patients included, 24 had endovascular treatment, 38 received intravenous thrombolysis alone, and 47 had no revascularization treatment. Endovascular treatment patients had a higher rate of recanalization at 24 h. Major radiological hemorrhages occurred more often in endovascular treatment patients (all with bridging therapy) than in patients without revascularization treatment (p = 0.026), with no differences in symptomatic intracranial hemorrhage or mortality within seven days. Favorable clinical outcome at three months did not differ between groups (endovascular treatment versus intravenous thrombolysis p = 0.407; endovascular treatment versus no revascularization treatment p = 0.580). CONCLUSIONS: In this single-center cohort of cervical artery dissection-related acute ischemic stroke with intracranial occlusion, endovascular treatment with prior intravenous thrombolysis may increase the risk of major radiological but not symptomatic intracranial hemorrhage. Despite the lack of clear superiority in our cohort, endovascular treatment should currently not be withheld in these patients.
- Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literaturePublication . Bernardo, F; Nannoni, S; Strambo, D; Bartolini, B; Michel, P; Sirimarco, GEfficacy and safety of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) due to intracranial artery dissection (IAD) are currently not established. We aimed to present a single-center experience on IAD-related AIS treated by IVT. We selected all consecutive patients with IAD-related AIS treated by IVT from a prospectively constructed single-center acute stroke registry from 2003 to 2017. We reviewed demographical, clinical and neuroimaging data and recorded hemorrhagic complications, mortality within 7 days and modified Rankin Scale at 3-months. Out of 181 AISs related to cervicocephalic dissections, 10 (5.5%) were due to IAD and five of these patients received IVT. Among these five patients, median age was 62 years; hypertension and dyslipidemia were the most frequent vascular risk factors. IAD locations were distal internal carotid artery, middle cerebral artery (M1), anterior cerebral artery (A2), and, in two cases, the basilar artery. All anterior circulation IADs were occlusive or subocclusive, while the two basilar artery IADs caused arterial stenosis. After IVT, there were no subarachnoid or symptomatic intracranial hemorrhages. One patient had an asymptomatic hemorrhagic infarct type 1. Two patients died within 7 days from ischemic mass effect. The other three patients had favorable clinical outcomes at 3-months. In this small single-center case series of IAD-related AIS, thrombolysis seemed relatively safe. However, IVT efficacy and the likelihood of arterial recanalization are still uncertain in this context. Further studies are needed to assess the safety and efficacy of IVT in these patients.
- A multicenter, non-interventional study to evaluate the disease activity in Multiple Sclerosis after withdrawal of Natalizumab in Portugal.Publication . Ladeira, F; Braz, L; Salgado, P; Vaz, S; Leitão, L; Félix, C; Salgado, V, et al.Abstract OBJECTIVES: Natalizumab (NTZ) is very effective for treatment of relapsing-remitting multiple sclerosis (RRMS), its use is mainly limited by safety issues. Discontinuation of NTZ is associated with recurrence of disease activity (reactivation and rebound). The best strategy for subsequent therapy and the predictive factors for recurrence in such patients are areas of active research. We aimed to evaluate predictors of reactivation in a multicentric study. PATIENTS AND METHODS: Multicentric retrospective observational study in five portuguese MS referral centers. Demographic, clinical and imagiological data were collected in the year prior, during and in the year following NTZ discontinuation. Predictors of reactivation and rebound after NTZ suspension were studied using a multivariate Cox model. RESULTS: Sixty-nine patients were included. They were mainly non-naïve patients (97%), with a mean age of 29.1 ± 8.3 years at diagnosis, and a mean age of 37.2 ± 10.3 years at NTZ initiation. The mean annualized relapse rate (ARR) previous, during and after NTZ was 1.6 ± 1.2, 0.2 ± 0.5 and 0.6 ± 1.0, respectively. The median EDSS before, during and after NTZ was 3.5 (IQR 3.3), 3.5 (IQR 3.5) and 4.0 (IQR 3.8), respectively. The median number of infusions was 26.0 (IQR 12.5) and the main reason to NTZ discontinuation was progressive multifocal leukoencephalopathy (PML) risk (70%). After NTZ suspension, reactivation was observed in 25 (36%) patients after a median time of 20.0 (IQR 29.0) weeks. Reactivation predictors in our sample included NTZ suspension for reasons other than PML (adjusted HR = 0.228, 95% CI [0.084- 0.616], p = 0.004), ARR before NTZ (adjusted HR = 1.914 95% [CI 1.330-2.754], p < 0.001) and a longer disease duration at time of NTZ initiation (adjusted HR = 1.154, 95% CI [1.020-1.306], p = 0.023). Rebound occurred in 5 (7%) patients after a median time of 20 (IQR 34.5) weeks. CONCLUSION: Significant predictors of disease reactivation in our cohort were discontinuation of NTZ for reasons other than PML risk, higher disease activity before NTZ treatment, and longer disease duration. Our study provides valuable data of portuguese patients after NTZ withdrawal.
- Neurodevelopmental Outcome Predictors of Term Newborns With Neonatal SeizuresPublication . Martins, R; Coelho, J; Santos, T; Moreno, T; Quintas, S; Levy, AIntroduction: The concrete burden of neonatal seizures in neurodevelopmental outcome of term newborns is still unknown in literature. The aim of this study was to describe prognostic predictors in neonatal seizures. Subjects and methods: Observational prospective study of term neonates with clinical seizures from a tertiary center (2009-2018). Adverse outcome was determined as death, global developmental delay, cerebral palsy or epilepsy. Perinatal characteristics, etiology, electrographic features, neuroimaging and antiepileptic treatment were analyzed in a logistic regression model. Results: A total of 102 newborns were included (52 infants with normal outcome). Twelve fatalities were registered. In the survival group, 38 children had an adverse outcome (28 global developmental delay, 27 cerebral palsy, 21 epilepsy). From the prognostic variables identified in univariate analysis, perinatal complications, seizure onset in the first day of life, moderate to severe abnormal background activity, abnormal amplitude-integrated EEG pattern, and treatment response remained independently associated with adverse outcome after a logistic regression model. Conclusions: There is conflicting data about surrogate markers in neonatal seizures. Aside from confirming the predictive value of previously described variables, we observed that amplitude-integrated EEG monitoring is a forthcoming prognostic tool. Future approaches may include a wider use of amplitude-integrated EEG monitoring, being crucial for timely seizure identification and prompt treatment.
- Extensive Linear Scleroderma en Coup De Sabre With Exertion-Induced Hemiplegic MigrainePublication . Martins, M; Quintas, S; Coelho, J; Santos, T; Levy, AWe report the case of a 9-year-old girl with linear scleroderma en coup de sabre (LSCS) who developed progressive white matter involvement, presenting as intractable hemiplegic migraine-like attacks induced by exercise. After a period of severely aggressive course, clinical and radiological stabilization was achieved under immunosuppressant treatment. Intrathecal synthesis of IgG and lymphocytic pleocytosis provided indirect evidence of a chronic inflammatory process of the central nervous system. We discuss the possible immunopathogenic mechanisms responsible for the neurocutaneous involvement in LSCS, favouring the hypothesis of an autoimmune and inflammatory vasculopathy. The singular occurrence of hemiplegic migraine triggered by exertion add further insight to the currently unknown pathogenesis of scleroderma disorder. In addition, we highlight the importance of intensive immunosuppression approaches in selected cases, contrasting with the classic benign course of LCSC.