Serum biomarkers at disease onset for personalized therapy in multiple sclerosis.

The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.

Clinical characteristics and impact on patient-reported outcomes and quality of life of people with ambulatory secondary progressive multiple sclerosis: Discover study.

BACKGROUND: People with secondary progressive multiple sclerosis (pwSPMS) experience increasing disability, which impacts negatively on their health-related quality of life (HRQoL). Our aims were to assess the impact of secondary progressive multiple sclerosis (SPMS) on functional status and HRQoL and describe the clinical profile in this population. METHODS: DISCOVER is an observational, cross-sectional, multicenter study with retrospective data collection in real-world clinical practice in Spain. Sociodemographic and clinical variables, functional and cognitive scales, patient-reported outcomes (PROs), and direct healthcare, and non-healthcare and indirect costs were collected. RESULTS: A total of 297 evaluable pwSPMS with a EDSS score between 3-6.5 participated: 62.3 % were female and 18.9 % had active SPMS. At the study visit, 77 % of them presented an Expanded Disability Scale Score (EDSS) of 6-6.5. Nearly 40 % did not receive any disease-modifying treatment. Regarding the working situation, 61.6 % were inactive due to disability. PROs: 99.3 % showed mobility impairment in EuroQoL-5 Dimensions-5 Levels, and about 60 % reported physical impact on the Multiple Sclerosis Impact Scale-29. Fatigue was present in 76.1 %, and almost 40 % reported anxiety or depression. The Symbol Digit Modalities Test was used to assess cognitive impairment; 80 % of the patients were below the mean score. Participants who presented relapses two years before and had high EDSS scores had a more negative impact on HRQoL. PwSPMS with a negative impact on HRQoL presented a higher cost burden, primarily due to indirect costs. CONCLUSIONS: PwSPMS experience a negative impact on their HRQoL, with a high physical impact, fatigue, cognitive impairment, and a high burden of indirect costs.

Acute monocular oligemia in a patient with migraine with aura demonstrated using OCT-angiography: A case report.

INTRODUCTION: Migraine is one of the most common causes of transient visual loss. Optical coherence tomography angiography (OCTA) provides fast and non-invasive imaging of the retinal vessels. We report one case of monocular retinal oligemia demonstrated using OCTA during a migraine attack with aura. CASE DESCRIPTION: A 27-year-old man with a previous history of migraine with visual aura was seen in the emergency room due to acute left hemicranial pain with positive visual symptoms in his right eye. The patient reported a blue stain in his right eye. Optical coherence tomography angiography (OCT-A) showed an extensive area of hypoperfusion in the macular region of his right eye. Forty-eight hours later visual symptoms had improved and the OCT-A showed a significant reduction in the area of hypoperfusion. Seven days later the patient was asymptomatic and retinal perfusion had returned to normal values. CONCLUSION: Monocular involvement suggests that these retinal vascular changes are independent from cerebral vascular changes, supporting the hypothesis of selective retinal ganglion cell layer spreading depression as the possible cause of some cases of retinal migraine.

Risk and prognostic factors for SARS-CoV-2 infection in Spanish population with multiple sclerosis during the first five waves.

Background: Data on coronavirus disease 2019 (COVID-19) incidence in patients with multiple sclerosis (MS) during the first wave have been published but are scarce for the remaining waves. Factors associated with COVID-19 infection of any grade are also poorly known. The aim of this study was to analyze the incidence, clinical features, and risk factors for COVID-19 infection of any grade in patients with MS (pwMS) during waves 1-5. Methods: This study prospectively analyzes the cumulative incidence of COVID-19 from the first to the fifth waves by periodic case ascertainment in pwMS followed at the University Hospital of Getafe (UHG). Global and stratified cumulative incidence was calculated. Logistic regression models were used to estimate the weight of selected variables as risk and prognostic factors. Results: We included 431 pwMS, of whom 86 (20%) were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The overall cumulative incidence of confirmed cases was similar to that of Madrid (13,689 vs. 13,307 per 100,000 habitants) but 3 times higher during the first wave and slightly lower from the second to the fifth waves. The majority (86%) of pwMS developed mild forms of COVID-19. Smoking was the only factor associated with a decreased risk of SARS-CoV2 infection of any grade [odds ratio (OR) 0.491; 95% CI 0.275-0.878; p = 0.017]. Risk factors associated with severe forms were Expanded Disability Severity Scale (EDSS) ≥3.5 (OR 7.569; 95% CI 1.234-46.440) and pulmonary disease (OR 10.763; 95% CI 1.27-91.254). Conclusion: The incidence of COVID-19 was similar in this MS cohort to the general population. Smoking halved the risk of being infected. Higher EDSS and pulmonary comorbidity were associated with an increased risk of severe forms.

Early predictive risk factors for dimethyl fumarate-associated lymphopenia in patients with multiple sclerosis.

BACKGROUND: Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. A pronounced reduction in absolute lymphocyte counts (ALCs) early after treatment initiation has been suggested to be associated with the occurrence of lymphopenia thereafter. OBJECTIVES: To identify risk factors for DMF-induced lymphopenia and evaluate whether the degree of decrease in the ALCs three months after initiation of DMF treatment is a predictor of the subsequent development of lymphopenia. METHODS: In this real-world Spanish prospective multicenter study conducted in MS patients who started DMF between 2014 and 2019, we analyzed the association between DMF-related lymphopenia and the percentage of early ALCs decline using regression models, considering both, significant lymphopenia (grades 2 + 3) and severe lymphopenia (grade 3). The cutoff values of early ALCs declines were obtained using the ROC curve. RESULTS: Among 532 MS patients treated with DMF, 193 (36.3%) developed any grade of lymphopenia. Older age and lower ALCs at treatment onset predicted the risk for lymphopenia but the best predictive risk factor was the reduction of ALCs within the three first months of treatment. Specifically, a reduction in ALCs≥21.2% was associated with a 6.5-fold higher risk of developing significant lymphopenia, and a decrease in ALCs≥40.2% with a 12.7-fold higher risk of developing severe lymphopenia. CONCLUSIONS: A pronounced reduction in ALCs early after initiation of DMF in MS patients is the best predictive risk factor for the subsequent development of significant lymphopenia.

Cancer diagnosis in a Spanish cohort of multiple sclerosis patients under dimethylfumarate treatment.

BACKGROUND: Potential increase of cancer incidence is one of the main safety concerns of the disease-modifying therapies employed in Multiple Sclerosis (MS). OBJECTIVE: Detailed description of patients who developed cancer among a prospective cohort of Spanish MS patients on dimethyl fumarate (DMF) treatment. METHODS: We describe patients who developed cancer among a cohort of 886 MS patients on DMF treatment (2681 patient-years), with a median time of exposure of 39.5 months (IQR 23-51.5), who participated in a multicentre and prospective real-world study conducted in 16 Spanish National Health System hospitals from February 2014 to May 2019. Local researchers were periodically contacted by the investigation team to monitor safety issues. Cancer histories were collected from the medical records and the information was updated at July 30th 2020. RESULTS: Eight Caucasian women developed cancer, which accounts for 0.9% and an accumulated malignancy rate of 298.39 cases per 100,000 patient-years of DMF exposure. At the time of cancer diagnosis, age was between 33 to 67 years and median time on DMF treatment 16.5 months (range 1-53). Two patients had familiar history of cancer. No specific cancer lines were found (breast cancer in 2 cases, thyroid in 3, urothelial carcinoma, cervix and a progression to leiomyosarcoma from a mitotically active leiomyoma). DMF was withdrawn during cancer treatment in 6 patients and reintroduced later. All cancers except one are in complete remission. The patient with leiomyosarcoma died by cancer progression. CONCLUSION: A relationship between cancers and DMF is unlikely because the malignancy rate was similar to that of the age-and sex-matched general population, and because of the absence of specific tumour cell lines. Nevertheless, as with other immunosuppressive DMTs, clinicians treating MS should be aware of any potential cancer symptom and demand proper testing.

Three-Year Effectiveness of Dimethyl Fumarate in Multiple Sclerosis: A Prospective Multicenter Real-World Study.

BACKGROUND: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. OBJECTIVE: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. METHODS: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. RESULTS: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. CONCLUSIONS: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.

Disc Configuration as a Risk and Prognostic Factor in NAION: The Impact of Cup to Disc Ratio, Disc Diameter, and Crowding Index.

Purpose: The presence of the so called disc at risk (a small disc with no cupping) has been considered the main risk factor for the development of non-arteritic anterior ischemic optic neuropathy (NAION). However its role as a prognostic factor has not been studied. Our aim was to determine the weight of disc configuration as a risk and a prognostic factor for NAION. Methods: Case control study. Forty eyes of 40 patients who were diagnosed with NAION between 2008 and 2017, and 120 controls (3 controls for each patient) were included in the study. Disc diameter (DD), cup to disc ratio (CDR), and peripapillar retinal nerve fiber layer thickness (RNFLT) of the non-affected eye were measured using optic coherence tomography (3D OCT 2000, Topcon). Crowding index (CI) was defined as the quotient of average RNFLT and disc area. Mean deviation (MD) at the time of diagnosis and at least three months later was determined using a Humphrey Visual Field Analyzer (SITA standard 24-2 strategy). Visual acuity (VA) was measured using Snellen charts and transformed into LogMAR values. Results: Only CDR was found to be a risk factor for NAION. No correlationship was found between CI and visual loss. Conclusions: DD and CI did not show value as either prognostic or risk factors. Glial tissue may be a part of the content of the optic disc as important as axons. Our results are in line with the latest studies about NAION pathophysiology. Contrary to classic thinking, these papers have not found smaller disc diameters, but smaller values of lamina cribosa depth in NAION patients.

Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome.

The possible role of gammaaminobutyric acid (GABA) in the pathophysiology of restless legs syndrome (RLS) is suggested by the symptomatic improvement achieved with GABAergic drugs. Thalamic GABA levels have shown positive correlation with periodic limb movements indices and with RLS severity. We tried to investigate the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptors (GABR) genes rho1, 2, and 3 (GABRR1, GABRR2, GABRR3), alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) with the risk of developing RLS. We studied the genotype and allelic variant frequencies of the most common SNPs in the GABRR1(rs12200969, rs1186902), GABRR2(rs282129), GABRR3(rs832032), GABRA4(rs2229940), GABRE(rs1139916), and GABRQ(rs3810651) genes in 205 RLS patients and 230 age- and gender-matched healthy controls using specific TaqMan assays. The frequencies of the GABRR3 rs832032TT genotype and the allelic variant GABRR3 rs832032T were significantly higher in RLS patients than in controls (odds ratio [95% confidence intervals] 7.08[1.48-46.44] and 1.66[1.16-2.37], respectively), although only the higher frequency of the rs832032T allele remained as significant after multiple comparison analysis, both in the whole series and in the female gender. The frequencies of the other genotypes of allelic variants did not differ significantly between RLS patients and controls. RLS patients carrying the GABRA4 rs2229940TT genotype showed a significantly younger age at onset of RLS symptoms than those with the other two genotypes. These results suggest association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS.

Temporal and Spatial Correlation Between Choroidal Thickness and Visual Function in a Case of POEMS Syndrome.

PURPOSE: To report the correlation between visual function and subfoveal choroidal thickness (SChT) in a case of POEMS syndrome. CASE REPORT: A 53 year old man diagnosed with POEMS syndrome was referred due to blurred vision. Best corrected visual acuity (BCVA) was 0.5 in his right eye (RE) and 0.7 in his left eye (LE), with a mild perimetric defect in the RE. SChT was 356 and 263 µm in his RE and LE. After an autologous peripheral blood stem-cell transplantation, both visual and systemic symptoms improved. At the most recent visit, SChT was 284 and 222 µm in his RE and LE, BCVA was 1.2 in both eyes and the perimetric defects had improved. CONCLUSIONS: SChT was inversely correlated with visual function in space and time. Due to the high sensitivity of choroidal tissue to vascular endothelial growth factor, SChT might be useful to monitor disease activity in POEMS.

Association Between the rs1229984 Polymorphism in the Alcohol Dehydrogenase 1B Gene and Risk for Restless Legs Syndrome.

Background/Objectives: Several studies have raised the possibility of an association between alcohol consumption and the risk of developing restless legs syndrome (RLS). Moreover, an important percentage of patients under alcohol detoxification therapy develop RLS symptoms that fulfil the criteria for idiopathic RLS during alcohol withdrawal. We have aimed to establish the possible association between two common single nucleotide polymorphisms (SNPs) in the alcohol-dehydrogenase 1B (ADH1B) gene and the risk for RLS. Methods: We studied, using specific TaqMan assays, the genotype and allelic variant frequencies of ADH1B rs1229984 and ADH1B rs6413413 SNPs in 205 RLS patients and 505 gender-matched healthy controls. Results: The sum of the frequencies of rs1229984CT and rs1229984TT genotypes, as well as the frequency of the rs1229984T allelic variant, was significantly higher in RLS patients than in controls, both in the whole group and in females. The frequencies of genotypes and allelic variants of the rs6413413 SNP were similar between the two groups. RLS patients with the rs1229984CT genotype were younger, and those with the rs122984TT genotype older, at onset of RLS symptoms than those with the rs1229984CC genotype. None of the studied SNPs were related either with positivity of family history for RLS or with RLS severity. Conclusions: These results suggest an association between rs1229984 SNP and the risk for RLS.

Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl-transferase (HNMT) gene and risk for restless legs syndrome.

A recent meta-analysis suggests an association between the rs11558538 single nucleotide polymorphism in the histamine-N-methyl-transferase (HNMT) gene and the risk for Parkinson's disease. Based on the possible relationship between PD and restless legs syndrome (RLS), we tried to establish whether rs11558538 SNP is associated with the risk for RLS. We studied the genotype and allelic variant frequencies of HNMT rs11558538 SNP 205 RLS patients and 410 healthy controls using a TaqMan assay. The frequencies of the HNMT rs11558538 genotypes allelic variants were similar between RLS patients and controls, and were not influenced by gender, family history of RLS, or RLS severity. RLS patients carrying the genotype rs11558538TT had an earlier age at onset, but this finding was based on three subjects only. These results suggest a lack of major association between HNMT rs11558538 SNP and the risk for RLS.

Association Between Vitamin D Receptor rs731236 (Taq1) Polymorphism and Risk for Restless Legs Syndrome in the Spanish Caucasian Population.

Several recent works suggest a possible role of vitamin D deficiency in the etiology or restless legs syndrome (RLS). We analyzed the possible relationship of 2 common single nucleotide polymorphisms (SNPs) in the vitamin D3 receptor (VDR) gene with the risk for RLS.We studied the genotype and allelic variant frequencies of VDR rs2228570 and VDR rs731236 SNPs in 205 RLS patients and 445 healthy controls using a TaqMan essay.The frequencies of the rs731236AA genotype and the allelic variant rs731236A were significantly lower in RLS patients than in controls (P < 0.005 and < 0.01, respectively). Restless legs syndrome patients carrying the allelic variant rs731236G had an earlier age at onset, and those carrying the rs731236GG genotype had higher severity of RLS, although these data disappeared after multivariate analyses. None of the SNPs studied was related with the positivity of family history of RLS.These results suggest a modest, but significant association between VDR rs731236 SNP and the risk for RLS.

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Restless Legs Syndrome.

Several neurochemical, neuropathological, neuroimaging, and experimental data, suggest that iron deficiency plays an important role in the pathophysiology of restless legs syndrome (RLS). Heme-oxygenases (HMOX) are an important defensive mechanism against oxidative stress, mainly through the degradation of heme to biliverdin, free iron, and carbon monoxide. We analyzed whether HMOX1 and HMOX2 genes are related with the risk to develop RLS.We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations (CNVs) of these genes in 205 subjects RLS and 445 healthy controls.The frequencies of rs2071746TT genotype and rs2071746T allelic variant were significantly lower in RLS patients than that in controls, although the other 3 studied SNPs did not differ between RLS patients and controls. None of the studied polymorphisms influenced the disease onset, severity of RLS, family history of RLS, serum ferritin levels, or response to dopaminergic agonist, clonazepam or GABAergic drugs.The present study suggests a weak association between HMOX1 rs2071746 polymorphism and the risk to develop RLS in the Spanish population.

Actividad asistencial neurológica en un hospital comarcal de reciente creación: modelo de alta eficiencia / Neurological health care activity in a recently created district hospital: model of high efficiency

Objetivo. Analizar la actividad asistencial de un hospital comarcal de reciente creación, con especial énfasis en los indicadores asistenciales en consultas externas y en actos médicos de pacientes ingresados. Pacientes y métodos. Describimos la actividad asistencial realizada por nuestra sección de neurología durante los años 2008-2013. Se comparan nuestros indicadores asistenciales de los años 2012 y 2013 (quinto y sexto año de actividad), tanto en consultas externas como en pacientes ingresados, con los de otros dos hospitales de características similares, otros tres de nivel secundario y otros cuatro de nivel terciario. Resultados. La sección de neurología de nuestro hospital fue la que realizó mayor número de primeras consultas por facultativo, tuvo el mejor índice de consultas sucesivas/primeras y el mayor porcentaje de consultas de alta resolución, tuvola menor estancia media en los dos grupos relacionados por el diagnóstico (GRD) más frecuentes en nuestra especialidad, y fue la segunda en ingresos por facultativo del GRD ‘ictus con infarto’ y la tercera en ingresos por facultativo del GRD ‘otros trastornos del sistema nervioso’. Conclusiones. Los indicadores asistenciales de la sección de neurología de nuestro hospital muestran un modelo de muy alta eficiencia, al cual sólo se aproximan los de otros dos de características y desarrollo similares al nuestro. La implantación gradual de modelos similares al de estos tres hospitales en los niveles secundario y terciario podría ser de utilidad en la mejora de su eficiencia asistencial (AU)

Aim. To analyze the neurological attention of a county hospital of recent creation, with a special emphasis in the health care indicators, both in hospital out-patients consultations and in patients admitted to the hospital. Patients and methods. We have made a descriptive analysis of the neurological attention developed by our Neurology Section between the years 2008 and 2013. We also made a comparative analysis of health care indicators corresponding to the years 2012 and 2013 (5th and 6th years of clinical activity) of our hospital with those of two other hospitals with similar features, other three hospitals of secondary level, and four of tertiary level. Results. The Neurology Section of our hospital was the best in the number of first visits divided by number of physicians, in the follow-up/first visit index, in the percentage of high-resolution visits, and was the best in the mean stay in hospital for the two most frequent diagnostic related groups (DRG) in our speciality, the second in number of hospital admissions divided by number of physicians for the DRG ‘stroke with infarction’ and the third in number of hospital admissions divided by number of physicians for the DRG ‘other nervous system disorders’. Conclusions. The health care indicators of the Neurology Section of our hospital showed a very high efficiency model of medical assistance, which was only followed by other two hospitals with similar features to ours. The gradual implementation of assistance models similar to that used in these hospitals in other of secondary or tertiary levels could be useful in theimprovement of their health care efficiency (AU)