CLIPPERS syndrome with atypical distribution of lesions in magnetic resonance imaging of the brain

Introducción. El síndrome CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) es un proceso inflamatorio del sistema nervioso central cuyo rasgo distintivo son las lesiones puntiformes en el troncoencéfalo captantes en los estudios de resonancia magnética. Clínicamente, cursa con disartria, ataxia y diplopía, y suele responder a corticoides. Anatomopatológicamente, aparecen infiltrados de linfocitos T en los espacios perivasculares troncoencefálicos. Caso clínico. Mujer de 40 años con cuadro de instauración subaguda de diplopía binocular, ataxia y disartria. En la resonancia magnética cerebral presentó lesiones puntiformes hipertintensas en secuencia T2 en el tronco, cerebelo, diencéfalo y áreas córtico-subcorticales bihemisféricas, que realzaron con contraste. Se realizó un estudio etiológico para descartar un origen infeccioso, neoplásico o inflamatorio subyacente, que resultó negativo. La paciente recibió tratamiento en dos ocasiones con metilprednisolona, con descenso progresivo de la dosis, con buena respuesta. Conclusiones. La diplopía y la ataxia, como en nuestro caso, están presentes prácticamente siempre. Los hallazgos en la RM consisten en lesiones captantes puntiformes localizadas en la protuberancia con extensión hacia el cerebelo, ganglios basales y cuerpo calloso, con gradiente de captación menor conforme se alejan rostralmente hacia la corteza, y caudalmente hacia la médula. En el caso de nuestra paciente, este gradiente no se respeta, encontrándose una densidad similar de las lesiones a nivel supratentorial. El diagnóstico diferencial es amplio y justifica un estudio diagnóstico extenso, y en casos seleccionados la biopsia cerebral. El curso de la enfermedad es remitente-recurrente, y el pronóstico mejora cuanto más precoz y prolongado es el tiempo de corticoterapiaIntroduction. CLIPPERS syndrome (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is an inflammatory process of the central nervous system whose distinguishing features are the enhancing punctiform lesions in the brainstem that appear in the magnetic resonance images. Clinically, it is accompanied by dysarthria, ataxia and diplopia, and usually responds to treatment with corticoids. Pathologically, T lymphocytes appear infiltrated in the perivascular spaces of the brainstem. Case report. We report the case of a 40-year-old woman with an initial subacute clinical picture of binocular diplopia, ataxia and dysarthria. The magnetic resonance brain scan revealed T2 hyperintense punctiform lesions in the stem, cerebellum, diencephalons and cortico-subcortical areas of both hemispheres, which were enhanced with contrast. An aetiological study was performed to rule out any underlying infectious, neoplastic or inflammatory origin, the results being negative. The patient was treated on two occasions with methylprednisolone, with a gradual lowering of the dosage, the response being favourable. Conclusions. Diplopia and ataxia, as in our case, are practically always present. The MR findings consist of punctiform enhancing lesions located in the pons extending towards the cerebellum, basal ganglia and corpus callosum, the enhancement gradient becoming lower as the distance increases rostrally away from the cortex, and caudally towards the spinal cord. In the case of our patient, this gradient is not respected, and the density found was similar to that of lesions at the supratentorial level. The differential diagnosis is wide-ranging and justifies an extensive diagnostic study with, in certain cases, a biopsy study of brain tissue. The disease courses in a relapsing-remitting pattern and the earlier steroid therapy is established and the more prolonged it is, the better the prognosis will b

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

Deciphering Multiple Sclerosis Progression

Esclerosi múltiple; NeurodegeneracióEsclerosis múltiple; NeurodegeneraciónMultiple sclerosis; NneurodegenerationMultiple sclerosis (MS) is primarily an inflammatory and degenerative disease of the central nervous system, triggered by unknown environmental factors in patients with predisposing genetic risk profiles. The prevention of neurological disability is one of the essential goals to be achieved in a patient with MS. However, the pathogenic mechanisms driving the progressive phase of the disease remain unknown. It was described that the pathophysiological mechanisms associated with disease progression are present from disease onset. In daily practice, there is a lack of clinical, radiological, or biological markers that favor an early detection of the disease's progression. Different definitions of disability progression were used in clinical trials. According to the most descriptive, progression was defined as a minimum increase in the Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 from a baseline level of 0, 1.0–5.0, and 5.5, respectively. Nevertheless, the EDSS is not the most sensitive scale to assess progression, and there is no consensus regarding any specific diagnostic criteria for disability progression. This review document discusses the current pathophysiological concepts associated with MS progression, the different measurement strategies, the biomarkers associated with disability progression, and the available pharmacologic therapeutic approaches

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

Esclerosis múltiple; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVEsclerosi múltiple; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVMultiple sclerosis; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVObjective 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.This work was funded by the Spanish Society of Neurology for the writing, editorial assistance, statistical analysis and the Article Processing Charge. Other contributions related to financial support for writing, statistical analysis, and editorial assistance were supported by Biogen, Bristol-Myers Squibb, Merck, Roche, Sanofi, and Teva

Cost-Analysis of Subcutaneous vs Intravenous Administration of Natalizumab Based on Patient Care Pathway in Multiple Sclerosis in Spain

Análisis de costes; Administración subcutánea; Esclerosis múltipleAnàlisi de costos; Administració subcutània; Esclerosi múltipleCost-analysis; Subcutaneous administration; Multiple sclerosisIntroduction A subcutaneous (SC) formulation of natalizumab has been recently authorised for multiple sclerosis patients. This study aimed to assess the implications of the new SC formulation, and to compare the annual treatment costs of SC versus intravenous (IV) natalizumab therapy from both the Spanish healthcare system (direct health cost) and the patient (indirect cost) perspectives. Methods A patient care pathway map and a cost-minimisation analysis were developed to estimate SC and IV natalizumab annual costs over a 2-year time horizon. Considering the patient care pathway and according to natalizumab experience (IV) or estimation (SC), a national expert panel involving neurologists, pharmacists, and nurses provided information/data regarding resource consumption for drug and patient preparation, administration, and documentation. One hour of observation was applied to the first six (SC) or 12 (IV) doses, and 5 min for successive doses. The Day hospital (infusion suite) facilities at a reference hospital were considered for IV administrations and the first six SC injections. For successive SC injections, either a reference hospital or regional hospital in a consulting room was considered. Productivity time associated with travel (56 min to reference hospital, 24 min to regional hospital) and waiting time pre- and post-treatment (SC 15 min, IV 25 min) were assessed for patients and caregivers (accompanying 20% of SC and 35% of IV administrations). National salaries for healthcare professionals were used for cost estimation (€, year 2021). Results At years 1 and 2, total time and cost savings (excluding drug acquisition cost) per patient, driven by saving on administration and patient and caregiver productivity for SC at a reference hospital versus IV at a reference hospital, were 116 h (a reduction of 54.6%) and €3682.82 (a reduction of 66.2%). In the case of natalizumab SC at a regional hospital, the total time and cost saving were 129 h (a reduction of 60.6%) and €3883.47 (a reduction of 69.8%). Conclusions Besides the potential benefits of convenient administration and improving work–life balance, as suggested by the expert panel, natalizumab SC was associated with cost savings for the healthcare system by avoiding drug preparation, reducing administration time, and freeing up infusion suite capacity. Additional cost savings could be derived with regional hospital administration of natalizumab SC by reducing productivity loss

Cognitive impairment in multiple sclerosis: diagnosis and monitoring

Multiple sclerosis; Neurophysiological monitoring; Neuropsychological testsEsclerosi múltiple; Monitorització neurofisiològica; Proves neuropsicològiquesEsclerosis múltiple; Monitoreo neurofisiológico; Pruebas neuropsicológicasIntroduction Cognitive impairment (CI) has a prevalence of 45–70% in people with multiple sclerosis (MS), producing a negative impact on their quality of life, personal life, and work. Early detection of CI has become an important aspect to be considered for an adequate follow-up, to optimize social adaptation and to implement specific cognitive rehabilitation strategies. The aim of this work is to propose a suitable cognitive evaluation of patients with MS based on available and efficient tools for diagnosis and monitoring purposes well supported by literature review and clinical experience. Methods A multidisciplinary panel of professionals from the field of neurology, neuropsychology, and neuroimaging performed a literature review of the topic of cognitive impairment assessment. This was combined and completed with their clinical experience to produce a set of recommendations. Results Some limitations to cognitive evaluation are described: shortage of time and resources during the neurology consultation, scarceness or absence of specialized professionals’ availability, importance of tests adaptation, and doubts about its use to define therapeutic efficiency. We recommend a baseline and annual screening evaluation, and we suggest a baseline and periodic neuropsychological assessment. The latter ought to change to a recommendation with the presence of either positive screening test, or subjective to cognitive complaints, screening-test results and patient or family report mismatch, or in specific social/work situations. Conclusions Cognitive evaluation should be performed on all patients diagnosed with MS and throughout follow-up. It is necessary to support the creation of multidisciplinary MS teams to optimize the evaluation and follow-up of MS patients

Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod : The Spanish GILENYA registry

Objective To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. Methods An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Results Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p<0.001). This significant reduction in the ARR continuedto be observed in all subgroups. After 4 years, the EDSS showed a minimal deterioration, with the EDSS scores from year 1 to year 4 remaining mostly stable. The percentage of patients without T1 Gd+ lesions progressively increased from 45.6% during the year prior to fingolimod initiation to 88.2% at year 4. The proportion of patients free from new/enlarged T2 lesions after 4 years of fingolimod treatment was 80.3%. This trend in both radiological measures was also observed in the subgroups. Adverse events (AEs) were experienced by up to 41.6% of patients (most commonly: lymphopenia [12.5%] and urinary tract infection [3.7%]). Most AEs were mild in severity, 3.6% of patients had serious AEs. Conclusions The patient profile was similar to other observational studies. The results obtained from the long-term use of fingolimod showed that it was effective, regardless of prior DMT, and it had adequate safety results, with a positive benefit-risk balance

Quantifying the patient´s perspective in neuromyelitis optica spectrum disorder: Psychometric properties of the SymptoMScreen questionnaire

Background: The assessment of self-reported outcomes in neuromyelitis optica spectrum disorder (NMOSD) is limited by the lack of validated disease-specific measures. The SymptoMScreen (SyMS) is a patient-reported questionnaire for measuring symptom severity in different domains affected by multiple sclerosis (MS), but has not been thoroughly evaluated in NMOSD. The aim of this study was to assess the psychometric properties of the SyMS in a sample of patients with NMOSD. Methods: A non-interventional, cross-sectional study in adult subjects with NMOSD (Wingerchuk 2015 criteria) was conducted at 13 neuroimmunology clinics applying the SyMS. A non-parametric item response theory procedure, Mokken analysis, was performed to assess the underlying dimensional structure and scalability of items and overall questionnaire. All analyses were performed with R (v4.0.3) using the mokken library. Results: A total of 70 patients were studied (mean age: 47.5 ± 15 years, 80% female, mean Expanded Disability Status Scale score: 3.0 [interquartile range 1.5, 4.5]). Symptom severity was low (median SyMS score: 19.0 [interquartile range 10.0, 32.0]). The SyMS showed a robust internal reliability (Cronbach's alpha: 0.90 [95% confidence interval 0.86, 0.93]) and behaved as a unidimensional scale with all items showing scalability coefficients > 0.30. The overall SyMS scalability was 0.45 conforming to a medium scale according to Mokken's criteria. Fatigue and body pain were the domains with the highest scalability coefficients. The SyMS was associated with disability (rho: 0.586), and physical and psychological quality of life (rho: 0.856 and 0.696, respectively). Conclusions: The SyMS shows appropriate psychometric characteristics and may constitute a valuable and easy-to-implement option to measure symptom severity in patients with NMOSD

Perception of Stigma in Patients with Neuromyelitis Optica Spectrum Disorder

Background: Perception of stigma was associated with low self-esteem, psychological problems, and decreased health-seeking behavior among patients with different neurological disorders. The purpose of this study was to assess stigmatization and its impact in patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: A non-interventional study was conducted at thirteen neuroimmunology clinics in Spain. Patients with a diagnosis of NMOSD (2015 Wingerchuk criteria) were included. The 8-item Stigma Scale for Chronic Illness (SSCI-8), the Expanded Disability Status Scale (EDSS), the 29-item Multiple Sclerosis Impact Scale (MSIS-29), the Beck Depression Inventory-Fast Screen (BDI-FS), the MOS Pain Effects Scale (MOS-PES) and the Fatigue Impact Scale for Daily Use (D-FIS) were used to assess the perception of stigma, disability, quality of life, mood, pain, and fatigue, respectively. Associations between outcome measures were analyzed using Spearman's rank correlation. Results: Seventy-one patients were studied (mean age: 47.4 years ± 14.9, 81.7% female, mean time since disease onset: 9.9 years ± 8.1). The median EDSS score was 3.0 (interquartile range 1.5, 4.5). Stigma prevalence was 61.4% (n=43). Thirty-one patients (43.6%) had depression. The SSCI-8 score showed a significant correlation with both physical (rho=0.576, p<0.0001) and psychological (rho=0.608, p<0.0001) MSIS-29 scales scores, EDSS score (rho=0.349, p=0.0033), BDI-FS score (rho= 0.613, p<0.0001), MOS-PES score (rho= 0.457, p<0.0001), and D-FIS score (rho=0.556, p<0.0001). Conclusion: Stigma is a common phenomenon affecting over 6 out of 10 patients with NMOSD. Understanding stigma may be useful to develop educational strategies improving NMOSD knowledge