Generation of RRMS and PPMS specific iPSCs as a platform for modeling Multiple Sclerosis.

The advent of cellular reprogramming technology converting somatic cells into induced pluripotent stem cells (iPSCs) has revolutionized our understandings of neurodegenerative diseases that are otherwise hard to access and model. Multiple Sclerosis (MS) is a chronic demyelinating, inflammatory disease of central nervous system eventually causing neuronal death and accompanied disabilities. Here, we report the generation of several relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) iPSC lines from MS patients along with their age matched healthy controls from peripheral blood mononuclear cells (PBMC). These patient specific iPSC lines displayed characteristic embryonic stem cell (ESC) morphology and exhibited pluripotency marker expression. Moreover, these MS iPSC lines were successfully differentiated into neural progenitor cells (NPC) after subjecting to neural induction. Furthermore, we identified the elevated expression of cellular senescence hallmarks in RRMS and PPMS neural progenitors unveiling a novel drug target avenue of MS pathophysiology. Thus, our study altogether offers both RRMS and PPMS iPSC cellular models as a good tool for better understanding of MS pathologies and drug testing.

Prevention of rebound effect after natalizumab withdrawal in multiple sclerosis. Study of two high-dose methylprednisolone schedules.

BACKGROUND: Natalizumab (NTZ) is a disease-modifying treatment (DMT) in multiple sclerosis (MS) whose discontinuation can produce a "rebound effect", consisting of severe clinical deterioration and/or evidence of disease reactivation on magnetic resonance imaging (MRI). OBJECTIVE: To analyze the efficacy of two treatment schedules with intravenous methylprednisolone (IVMP) administered during the washout period of natalizumab (i.e., before starting another DMT) in preventing the rebound phenomenon. METHODS: Five-year retrospective study of NTZ withdrawals after at least 24 uninterrupted doses. Two IVMP schedules were tested. In schedule 1 (3-month washout), 1, 2, and 3 g of IVMP were administered on the first, second, and third month respectively. In schedule 2 (2-month washout), 1 and 2 g of IVMP were administered on the first and second month respectively. A new DMT was started 10 days after the end of each schedule. Rebound was defined as at least one clinical relapse plus rebound activity on MRI (>5 gadolinium-enhanced lesions and a number of new/T2-enhanced and/or gadolinium-enhanced lesions greater than before initiation of NTZ) during washout or at 6 months after new DMT initiation (6M-DMT). Clinical and MRI evaluations were performed at 3, 6, 12, and 24 months after initiation of the new DMT. RESULTS: Fifty patients (68% women) were included, with a mean (SD) age of 37.76 (10.88) years and pre-NTZ annualized relapse rate (ARR) of 1.78 (1.04). During NTZ therapy, mean Expanded Disability Status Scale (EDSS) score was 3.7 (1.73) and ARR was 0.23 (0.39). The ARR (mean of both schedules) was 0.1 (0.71) during washout and 0.32 (0.84) at 6M-DMT. Rebound was observed in 10% of cases (n = 5), with no significant clinical or radiological differences (p>0.05) between the two IVMP schedules. Rebound was observed in younger patients and was associated with new MRI lesions and higher ARR at 3M-DMT and 6M-DMT respectively, with no difference in EDSS after 2 years of follow-up. Neither the ARR before NTZ initiation nor the choice of new DMT after NTZ discontinuation was associated with development of rebound effect. CONCLUSIONS: Both IVMP schedules were well tolerated during NTZ washout and rebound was observed in only 10% of cases. In our experience, administration of IVMP during NTZ washout could reduce the possibility of a rebound effect.

Multi-centre validation of a flow cytometry method to identify optimal responders to interferon-beta in multiple sclerosis.

BACKGROUND AND OBJECTIVES: Percentages of blood CD19+CD5+ B cells and CD8+perforin+ T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice. METHODS: Fourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values. RESULTS: After results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81-0.91) for CD19+CD5+ B cell and 0.89 (CI: 0.85-0.93) for CD8+ perforin+ T cell quantification; Spearman r was 0.92 (0.89-0.95; p <0.0001) and 0.92 (0.88-0.95; p <0.0001) respectively. All centres obtained z-scores≤0.5 for both biomarkers. CONCLUSION: Homogenous percentages of CD19+CD5+ B cells and CD8 perforin+ T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established.

Capillary leak syndrome in neuromyelitis optica treated with rituximab.

61-year-old woman with Neuromyelitis optica (NMO) diagnosis treated with rituximab was referred to our hospital with severe hypovolemic shock and anasarca. The laboratory findings showed marked hemoconcentration and a decrease in total serum protein. She developed a multiple organ failure and died three hours later. We diagnosed the patient as having capillary leak syndrome (CLS). CLS is a very rare condition caused by unexplained episodic capillary hyperpermeability, which can be idiopathic or secondary to some conditions like infection, malignant disease and some drugs like monoclonal antibodies. We reported the first CLS case in NMO patient treated with rituximab.

Clinical and radiological control of highly active relapsing-remitting multiple sclerosis with first-line natalizumab.

A 33-year-old man with gait instability, weakness of the left lower extremity, decreased visual acuity in the left eye, and urgency and urine incontinence was diagnosed of relapsing-remitting multiple sclerosis. He was treated with natalizumab (300 mg intravenously every 4 weeks) as first-line therapy, which reached at 6 months a favorable clinical evolution and dramatic radiological improvement (T2-weighted lesion load decreased by 50% and no gadolinium-enhancing T1 lesions) sustained over the course of 8 years. This clinical case shows the efficacy of natalizumab in a real-world setting and, particularly, the sustained effect of this drug in the long term as demonstrated by persistent radiological improvement. Natalizumab can be considered as the treatment of choice in relapsing-remitting multiple sclerosis forms presenting with two relapses and gadolinium-enhancing (Gd+) lesions.

Optic neuritis in pregnancy after Tdap vaccination: Report of two cases.

Two pregnant women developed one-eye blurring vision within three weeks after Tdap vaccination. Neurophtalmologic and MR examination confirmed an unilateral optic neuritis without evidence of underlying disease. Both patients had a full recovery, one after intravenous metilprednisolone. This is the first report of optic neuritis related with Tdap vaccination in pregnancy.

Predictors of burden and depression among caregivers of relapsing-remitting MS patients in Spain: MS Feeling study.

AIM: To assess potential predictors for burden and depression among caregivers of relapsing-remitting multiple sclerosis patients in Spain. Family functioning and social support were also assessed. PATIENTS & METHODS: Multicenter and cross-sectional study in relapsing-remitting multiple sclerosis adult patients and their respective informal caregivers (n = 180). Assessment performed: Zarit Scale (Burden), Center for Epidemiologic Studies Depression-7 Scale (depression), Family APGAR (Adaptation, Partnership, Growth, Affection, Resolve) Questionnaire (family functioning) and Duke UNC-11 Functional Social Support Questionnaire (social support). Multivariate logistic regression analysis assessed burden and depression predictors among caregivers. RESULTS: Caregivers suffered burden (19.4%) and depression (20.6%) and perceived poor social support (9.4%) and family dysfunction (10.6%). Burden predictors were patient's degree of disability, caregiver time and number of medications administered to patient. Depression predictors were patient's age and daily caregiving time. CONCLUSION: The factors reported here could help clinicians to identify caregiver groups particularly at risk of burden and depression for timely intervention.

Spasticity in multiple sclerosis and role of glatiramer acetate treatment.

INTRODUCTION: Spasticity is one of the most disabling and difficult-to-treat symptoms shown by patients with multiple sclerosis, who often show a suboptimal and unsatisfactory response to classic treatment and new available nonpharmacological alternatives. Due to the progressive nature of this condition, the early management should be essential to improve long-term outcomes. METHODS: We performed a narrative literature review of the contribution of spasticity to the burden of multiple sclerosis and the potential role of classic disease-modifying drugs. RESULTS: Added to the underlying pathophysiology of spasticity, certain external factors and drugs such as interferon may exacerbate the existing condition, hence their awareness is crucial as part of an effective management of spasticity. Furthermore, the evidence for the effectiveness of glatiramer acetate in preventing spasticity in naïve patients and in those switching from interferon should not be ignored. CONCLUSIONS: This literature review proposes the examination of spasticity and the influence of classic disease-modifying agents on the level of existing condition among the variables to be considered when deciding on therapy for multiple sclerosis in clinical practice.

[Oral treatments in multiple sclerosis]. / Tratamientos orales en esclerosis múltiple.

The development of new disease-modifying drugs (DMD) in relapsing-remitting multiple sclerosis (RRMS), which share the common denominator of oral administration, considerably improves patient expectations in terms of effectiveness, tolerability and treatment adherence compared with currently available drugs. However, the common route of administration of these drugs does not mean that they are equivalent, since the heading of "oral route" encompasses drugs with distinct indications and mechanisms of action, as well as heterogeneous results in terms of efficacy and safety, allowing treatment to be personalized according to the each patient' s characteristics. Currently, four oral DMD are available or in an advanced stage of clinical development: fingolimod, teriflunomide, dimethyl fumarate and laquinimod. In pivotal trials versus placebo, these molecules reduced the annualized rate of exacerbations versus placebo by 54%, 31%, 53% and 23%, respectively, the risk of progression of disability by 31%, 30%, 38% and 36%, and the number of active lesions showing contrast uptake on magnetic resonance imaging by 82%, 80%, 90% and 37%, respectively. Based on the risk/benefit ratio, fingolimod is indicated in patients with suboptimal response to initial DMD or in severe rapidly progressing RRMS, while the remaining drugs can be used as first-line options. Clinical experience with these treatments will provide new data on safety and effectiveness, which will be determinant when establishing therapeutic algorithms.

Plasma exchange for steroid-refractory relapses in multiple sclerosis: an observational, MRI pilot study.

BACKGROUND: Numerous studies have shown that plasma exchange (PE) is effective as second-line treatment of severe exacerbations of multiple sclerosis (MS) or other idiopathic inflammatory demyelinating diseases of the central nervous system that are nonresponsive to steroid therapy. OBJECTIVE: The goal of this study was to analyze the effect of PE on clinically active radiologic lesions in steroid-refractory relapses of MS and idiopathic inflammatory demyelinating diseases of the central nervous system. METHODS: This was a prospective, observational pilot study in which the primary end point was the degree of radiologic resolution of active lesions after PE. RESULTS: A total of 15 patients were included (median age, 36.9 years [age range, 21-67 years]; 60% women). Five (33.3%) of the 15 patients had relapsing-remitting MS, 2 (13.3%) had clinically isolated syndrome that presented with transverse myelitis, 2 (13.3%) had recurrent myelitis, 1 (6.7%) had transverse myelitis, 1 (6.7%) had longitudinally extensive transverse myelitis, 1 (6.7%) had acute disseminated encephalomyelitis, 1 (6.7%) had Baló's concentric sclerosis, and 2 (13.3%) had neuromyelitis optica. Mean increase on the expanded disability status scale scores due to relapses was 4.8 (2.53). After PE, 93.3% showed a marked to moderate clinical improvement, and 46.7% recovered their baseline expanded disability status scale score 3 months post-PE. On the post-PE MRI, 60% showed radiologic resolution (80% mass-effect lesions, 83.3% new-onset disease, and 100% neuromyelitis optica), 20% had partial resolution, and 20% no resolution. A significant relationship was not obtained between degree of resolution of radiologic lesions and the variables: clinical response to PE, new-onset disease, mass-effect lesions, number of PE sessions, and early initiation of PE. CONCLUSION: A marked to moderate clinical improvement post-PE accompanied by a lack of radiologic resolution of the active lesion is not indicative of poor prognosis.

Presentación tardía de una encefalopatía de Wernicke tras gastrectomía por adenocarcinoma gástrico: a propósito de un caso / Late presentation of wernicke's encephalopathy after gastrectomy in a patient with gastric adenocarcinoma: case report

La encefalopatía de Wernicke es una emergencia neurológica caracterizada por la tríada clínica clásica de oftalmoplejia, ataxia y alteración del estado mental, que conlleva alta morbimortalidad. Se debe a un déficit de la vitamina B1 (tiamina), que en su forma activa desempeña un papel esencial en el metabolismo de neuronas de áreas específicas del cerebro. Aunque el alcoholismo es la causa más frecuente de este déficit, se han descrito numerosos agentes que pueden alterar la biodisponibilidad o el metabolismo de la tiamina (1), entre las que cabe destacar la cirugía del tracto gastrointestinal, sobre todo tras cirugía bariátrica. Por lo general el cuadro se produce entre las semanas cuatro y doce tras la resección, pero excepcionalmente se han descrito casos que ocurren de forma tardía (años). Presentamos el caso de un paciente intervenido de gastrectomía por un adenocarcinoma antropilórico que desarrolló una encefalopatía de Wernicke a los ocho años de la resección quirúrgica.

Wernicke encephalopathy is a neurological emergency characterized by classic clinical triad of ophthalmoplegia, ataxia and disturbance of mental status, which carries high morbidity and mortality. It is caused by a deficiency of vitamin B1 (thiamine), which plays an essential role in the metabolism of neurons in specific brain areas. While alcoholism is the most common cause of this syndrome, numerous etiologies have been described that alter the bioavailability or metabolism of thiamine (1), among which are included gastrointestinal tract surgery, mainly bariatric surgery. Usually the onset occurs between week 4 and 12 after resection, but some cases have been rarely described to occur late (years). We report the case of a patient who underwent gastrectomy for a gastric adenocarcinoma who developed Wernicke encephalopathy after 8 years of surgical resection.

Encefalitis progresiva por anticuerpos anti-DPPX: un caso con buena respuesta al tratamiento con rituximab / Progressive encephalitis due to anti-DPPX antibodies: a case with good response to treatment with rituximab

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Prevalencia de la esclerosis múltiple en la Región de Murcia / Prevalence of multiple sclerosis in the Region of Murcia

Introducción. La esclerosis múltiple (EM) es una enfermedad inflamatoria desmielinizante del sistema nervioso central con patogenia inmunomediada. Recientes estudios indican un aumento de su prevalencia, y numerosos trabajos relacionan el virus de Epstein-Barr (VEB) con su etiología. Objetivo. Análisis de prevalencia de la EM en la Región de Murcia, incluyendo la descripción de las características clínicas en el momento del inicio de la enfermedad, y del estado serológico del VEB de los pacientes con EM. Pacientes y métodos. Estudio epidemiológico retrospectivo, tomando como muestra la población residente en el área sanitaria centro-oeste de la Región de Murcia (257.865 habitantes). Se analizan datos clínicos y serológicos extraídos de diferentes fuentes. Resultados. Prevalencia de la EM en la población estudiada: 88 casos/100.000 habitantes. Prevalencia de la EM junto con el síndrome desmielinizante aislado: 98,4 casos/100.000 habitantes. Incidencia media de la EM: 5,8 casos/100.000 habitantes/año. En el inicio de la EM, el 67,8% eran mujeres, el 81,9% presentaba un curso recurrente-remitente, la edad media era de 31,4 años, el sistema funcional más frecuentemente afectado era el sensitivo (45,1%), el inicio fue monofocal en el 55,4% y el grado de discapacidad en la Expanded Disability Status Scale era de 2,1 puntos. La seroprevalencia del VEB fue del 99,3%. La reactivación de la infección por VEB se relacionó con actividad clínica de EM en 10 pacientes (45,4%). Conclusiones. Actualmente, la prevalencia de la EM en la Región de Murcia es similar a la estimada en otras comunidades autónomas españolas. El estudio confirma la tendencia de incremento de prevalencia observada en las últimas décadas (AU)

Introduction. Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system with immunemediated pathogenesis. Recent research points to an increase in its prevalence, and a number of studies relate EpsteinBarr virus (EBV) with its aetiology. Aims. This study seeks to analyse the prevalence of MS in the Region of Murcia, and includes a description of the clinical characteristics at the time of onset of the disease, and of the EBV serological status of patients with MS. Patients and methods. We conducted a retrospective epidemiological study based on a sample consisting of the population living within the central-west healthcare area of the Region of Murcia (257,865 inhabitants). Clinical and serological data extracted from different sources were analysed. Results. Prevalence of MS in the population under study: 88 cases/100,000 inhabitants. Prevalence of MS together with isolated demyelinating syndrome: 98.4 cases/100,000 inhabitants. Mean incidence of MS: 5.8 cases/100,000 inhabitants/ year. At the onset of MS, 67.8% were females, 81.9% presented a relapsing-remitting course, the mean age was 31.4 years, the sensory system was the most frequently compromised (45.1%), onset was monofocal in 55.4% and the degree of disability on the Expanded Disability Status Scale was 2.1 points. The seroprevalence of EBV was 99.3%. The reactivation of EBV infection was related to the clinical activity of MS in 10 patients (45.4%). Conclusions. Currently, the prevalence of MS in the Region of Murcia is similar to that estimated in other Spanish autonomous regions. The study confirms the trend of increased prevalence observed over the last few decades (AU)

Tratamientos orales en esclerosis múltiple / Oral treatments in multiple sclerosis

La aparición de nuevas opciones terapéuticas modificadoras del curso de la enfermedad (MCE) en esclerosis múltiple recurrente-remitente (EMRR), con el denominador común de la vía oral de administración, mejora considerablemente las expectativas de los pacientes en términos de efectividad, tolerancia y adherencia al tratamiento frente a los fármacos disponibles en la actualidad. Que estos fármacos compartan la vía de administración no implica que sean equivalentes entre sí, ya que bajo el epígrafe "vía oral" se engloban fármacos con diferentes indicaciones, distintos mecanismos de acción y resultados heterogéneos en cuanto a eficacia y seguridad, que permiten personalizar el tratamiento en función de las características individuales de cada paciente. En la actualidad hay 4 tratamientos MCE orales disponibles o en avanzado estado de desarrollo clínico: fingolimod, teriflunomida, dimetilfumarato y laquinimod. En los ensayos pivotales frente a placebo, estas moléculas redujeron la tasa anualizada de brotes frente a placebo en un 54, 31, 53 y 23%, respectivamente, el riesgo de progresión de la discapacidad en un 31, 30, 38 y 36%, y el número de lesiones activas captantes de contraste en resonancia magnética en un 82, 80, 90 y 37%, respectivamente. El balance riesgo/beneficio sienta la indicación de fingolimod en casos de respuesta subóptima al tratamiento MCE inicialmente instaurado o en formas de EMRR grave de rápida evolución, mientras que el resto de moléculas pueden utilizarse como primera opción de tratamiento. La experiencia clínica con estos tratamientos aportará nuevos datos de efectividad y seguridad, que serán determinantes a la hora de establecer nuevos algoritmos terapéuticos (AU)

The development of new disease-modifying drugs (DMD) in relapsing-remitting multiple sclerosis (RRMS), which share the common denominator of oral administration, considerably improves patient expectations in terms of effectiveness, tolerability and treatment adherence compared with currently available drugs. However, the common route of administration of these drugs does not mean that they are equivalent, since the heading of "oral route" encompasses drugs with distinct indications and mechanisms of action, as well as heterogeneous results in terms of efficacy and safety, allowing treatment to be personalized according to the each patient’ s characteristics. Currently, four oral DMD are available or in an advanced stage of clinical development: fingolimod, teriflunomide, dimethyl fumarate and laquinimod. In pivotal trials versus placebo, these molecules reduced the annualized rate of exacerbations versus placebo by 54%, 31%, 53% and 23%, respectively, the risk of progression of disability by 31%, 30%, 38% and 36%, and the number of active lesions showing contrast uptake on magnetic resonance imaging by 82%, 80%, 90% and 37%, respectively. Based on the risk/benefit ratio, fingolimod is indicated in patients with suboptimal response to initial DMD or in severe rapidly progressing RRMS, while the remaining drugs can be used as first-line options. Clinical experience with these treatments will provide new data on safety and effectiveness, which will be determinant when establishing therapeutic algorithms (AU)