A general presentation on how to carry out a CHARMS analysis for prognostic multivariate models.

The CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist was created to provide methodological appraisals of predictive models, based on the best available scientific evidence and through systematic reviews. Our purpose is to give a general presentation on how to carry out a CHARMS analysis for prognostic multivariate models, making clear what the steps are and how they are applied individually to the studies included in the systematic review. This tutorial is aimed at providing such a resource. In addition to this explanation, we will apply the method to a real case: predictive models of atrial fibrillation in the community. This methodology could be applied to other predictive models using the steps provided in our review so as to have complete information for each included model and determine whether it can be implemented in daily clinical practice.

Effectiveness of Fingolimod versus Natalizumab as Second-Line Therapy for Relapsing-Remitting Multiple Sclerosis in Spain: Second-Line GATE Study.

BACKGROUND: There is a lack of head-to-head studies comparing the efficacy of fingolimod (FIN) and natalizumab (NTZ) as second-line therapy for relapsing-remitting multiple sclerosis (RRMS). METHODS: Multicenter, observational study, in which, information of 388 patients randomly selected and treated with FIN or NTZ in routine clinical practice was retrospectively collected with the main objective of comparing the annualized relapse rate (ARR) over the first year, after FIN or NTZ treatment initiation. RESULTS: Mean ARR during the first year of treatment was 0.28 in FIN group and 0.12 in NTZ group (p = 0.0064); nevertheless, the difference between groups lost statistical significance when the propensity score analysis was performed. Time to disability -progression was similar in both treatment groups (12.3 ± 6.7 months in FIN, and 12.8 ± 0.1 months in NTZ; p = 0.4654). Treatment persistence after the first year of treatment was higher in patients treated with FIN (95%) than in those treated with NTZ (84%; p = 0.0014). CONCLUSIONS: After 12 months of treatment, both FIN and NTZ reduced the ARR, but ARR percent reduction was significantly higher with NTZ. Treatment persistence was higher in patients receiving FIN.

Clusters of Cardiovascular Risk Factors and Their Impact on the 20-Year Cardiovascular Risk in a General Population.

BACKGROUND: Clustering of cardiovascular risk factors (CVRFs) is extraordinarily common and is associated with an increased risk of cardiovascular disease (CVD). However, the particular impact of the sum of CVRFs on cardiovascular morbidity and mortality has not been sufficiently explored in Europe. OBJECTIVE: The aim of this study was to analyze the differences in survival-free probability of CVD in relation to the number of CVRFs in a Spanish population. METHODS: A prospective cohort study was conducted from 1992 to 2016 in a Spanish population that included 1144 subjects with no history of CVD (mean age, 46.7 years) drawn from the general population. We calculated the number of CVRFs for each subject (male sex, smoking, diabetes, hypertension, dyslipidemia, obesity, and left ventricular hypertrophy). Cardiovascular morbidity and mortality records were collected, and survival analysis was applied (competing risk models). RESULTS: There were 196 cardiovascular events (17.1%). The differences in total survival-free probability of cardiovascular morbidity and mortality of the different values of the sum of CVRFs were significant, increasing the risk of CVD (hazard ratio, 1.30; 95% confidence interval, 1.13-1.50) per each additional risk factor. CONCLUSION: Differences in survival-free probability of CVD in relation to the number of CVRFs present were statistically significant. Further studies are needed to corroborate our results.

Observational Study of Switching from Natalizumab to Immunomodulatory Drugs.

OBJECTIVE: To determine the effect of disease-modifying drugs (DMDs) on disease activity rebound in patients discontinuing natalizumab (NTZ). METHODS: Twenty-one patients with relapsing-remitting multiple sclerosis (RRMS) treated with NTZ for ≥1 year and who switched to DMDs (glatiramer acetate [GA] or interferon) were followed up for 12 months in clinical practice. Clinical outcomes after NTZ cessation were assessed every 3 months for 1 year and MRI was performed at 12 months. RESULTS: Twelve months after switching from NTZ to DMDs, there were no significant differences in the annualized relapse rate (ARR) compared to the days that NTZ was used (0.3 vs. 0.1; p = 0.083); and the ARR never reached similar values to those prior to NTZ use (1.61; p < 0.001). The percentage of relapse-free patients after switching from NTZ was 71.4%. These patients did not have lower disease activity before NTZ compared with those with clinical relapses (1.3 vs. 1.7; p = 0.302), but they had lower Expanded Disability Status Scale scores (3.4 vs. 5.7; p = 0.001). DMDs had beneficial effects on MRI parameters, as 10 of 16 patients (62.5%) presented no evidence of radiological activity 12 months after NTZ discontinuation. CONCLUSIONS: Patients with RRMS and moderate disability who discontinued NTZ for safety reasons may benefit from the DMDs GA and interferon with no known risk for progressive multifocal leukoencephalopathy.

SARS-CoV-2 Infection in Multiple Sclerosis: Results of the Spanish Neurology Society Registry.

OBJECTIVE: To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments. METHODS: Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome. RESULTS: Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04-1.17) as the only independent risk factor for a fatal outcome. CONCLUSIONS: This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease.

Bilateral akinetic seizures: a clinical and electroencephalographic description.

PURPOSE: The main feature of akinetic seizures is the inhibition of voluntary movements without impairment of awareness. Most clinical information about akinetic seizures has been obtained from cortical electrical stimulation studies, whereas clinical and video-electroen-cephalography (EEG) features have not been described thoroughly. We aimed to analyze clinical and EEG characteristics of bilateral akinetic seizures (BAS). METHODS: Patients with BAS were retrospectively identified from 1,858 consecutive video-EEG studies. All patients had ictal video-EEG, comprehensive clinical evaluation, neuropsychological testing, and brain magnetic resonance imaging (MRI). RESULTS: Ten patients (nine men) were identified; mean age was 22.5 years (range 0.3-71 years) at the time of epilepsy onset and 34.9 years (range 5-73 years) at the time of evaluation. BAS was the only seizure type in four patients. BAS consisted of sudden speech and motor arrest in eight patients, whereas in two patients seizures were characterized by abrupt freezing precipitated by gait initiation. Startle precipitated BAS in four patients. Magnetic resonance imaging (MRI) showed mesial frontal lobe lesions in six patients. Epileptiform activity was restricted to the frontal midline electrodes in all patients, with variable extension to frontal regions. In five patients, BAS were initially misdiagnosed as generalized seizures or nonepileptic events. DISCUSSION: BAS should be considered in the differential diagnosis of patients reporting paroxysmal inability to move with preservation of awareness, bearing in mind that these seizures can occur spontaneously or be precipitated by startle. The diagnosis can be achieved with video-EEG monitoring, showing stereotyped semiology and distinctive EEG abnormalities, and is often supported by the presence of lesions involving the frontal lobes.

Discontinuation of disease-modifying treatments in multiple sclerosis to plan a pregnancy: A retrospective registry study.

BACKGROUND: For safety reasons multiple sclerosis (MS) treatment guidelines recommend stopping or delaying the onset of disease-modifying therapies (DMT) before a planned pregnancy, but disease stability after DMT discontinuation is not well studied. The objective of this study is to describe the course of MS in patients who interrupted DMT before a planned pregnancy. METHODS: This was a retrospective study using 2008-2016 data from a multicenter register of pregnancies in women with MS. In this paper, we present data from the subgroup of women with relapsing-remitting MS (RRMS) who interrupted DMT to try to conceive. Data from 1 and 3 years before DMT interruption, the period between DMT interruption and conception or resuming DMT, during pregnancy and one year postpartum were analyzed. Annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) scores, and magnetic resonance imaging (MRI), obstetric, and neonatal data were collected. RESULTS: Twenty-seven women interrupted DMT (19 ß-interferon, 5 glatiramer acetate, 2 natalizumab and 1 fingolimod) to try to conceive. After a mean of 10.6 months 6 women stopped trying to conceive and resumed DMT, while 21 women became pregnant after a mean of 7.0 months. In the overall cohort, in the period from when DMT was discontinued to when pregnancy was confirmed or DMT resumed, the ARR was 1.08, which was significantly higher than the ARR 1 year (0.44; p = 0.01) and 3 years (0.4; p = 0.06) before DMT discontinuation. The mean EDSS score when pregnancy was confirmed or DMT resumed was significantly higher than at DMT discontinuation (1.8 vs 1.36, p = 0.011). In the subgroup of patients who became pregnant, the ARR in the untreated period before pregnancy was 0.98, which was significantly higher than the ARR 1 year (0.38; p = 0.03) and 3 years (0.39; p = 0.0077) before DMT discontinuation. The ARR decreased to 0.51 during pregnancy and then increased to 0.76 during the first postpartum trimester (not significant). One year after delivery, the mean EDSS score (1.86) was significantly higher than at DMT cessation (1.35, p = 0.027) or pregnancy confirmation (1.45, p = 0.026). Patients who suffered relapses following DMT cessation before becoming pregnant had an 11-fold higher risk of relapse during pregnancy (relative risk [RR] = 11.1 [95%CI 1.6, 75], p = 0.002) and a 3-fold higher risk during the postpartum year (RR = 3.0 [95%CI 1.3,6.6], p = 0.007) than those who did not suffer relapses in period between DMT withdrawal and pregnancy. CONCLUSIONS: In this retrospective registry study, discontinuation of DMT (mostly immunomodulatory drugs), to try to conceive resulted in an increase in MS relapse rates and disability progression.

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.

Mutation prevalence of cerebral cavernous malformation genes in Spanish patients.

OBJECTIVE: To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients. METHODS: We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing. RESULTS: A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported. CONCLUSIONS: Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations.

Prevalence of Parkinson's disease in Cantalejo, Spain: a door-to-door survey.

We assessed the prevalence of Parkinson's disease in Cantalejo, Spain. In 1994, we screened 1,579 persons (age > or = 40 years) using a high-sensitivity method. Cases fulfilling established clinical criteria were followed for a minimum of 3 years. Prevalences were compared with those from other door-to-door surveys. We detected 27 individuals with parkinsonism, 20 of whom had Parkinson's disease. The prevalence of Parkinson's disease increased with age and, when age-adjusted to European standards, was 9.01 per 1,000 (age 40 years and over; 10.78 in men and 5.23 in women). Of the 11 men, three were in Hoehn & Yahr grades III-IV, but six of the nine women were more severely affected. Overall, we found 18 newly diagnosed cases of parkinsonism, 13 of which were Parkinson's disease, and the majority of which were in men aged 80 years or older with a mean duration of illness of 5 years. Our prevalence figures are the highest reported, apparently because of the inclusion of several very elderly men. Parkinson's disease in Cantalejo is less severe in men than in women, particularly in those newly diagnosed. Despite the low numbers, the high prevalence and sex-related pattern are unexplained but they probably relate to the high sensitivity of the screening method.