CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS.

OBJECTIVE: To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). METHODS: We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria. RESULTS: After a median follow-up of 50 months (IQR 25-82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma. CONCLUSIONS: Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.

Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (III).

The most significant data presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in France in October 2012, have been summarised in the fifth edition of the Post-ECTRIMS Experts Meeting, held in Madrid in October 2012. This led to the drafting of this review, which has been published in three parts. This third part of the Post-ECTRIMS review presents the findings from the latest studies conducted with disease-modifying treatments, more specifically with glatiramer acetate, laquinimod, ponesimod, BG-12, teriflunomide, daclizumab, natalizumab and secukinumab (AIN457). Likewise, we also address the reasons that justify the search for innovative treatments for multiple sclerosis, with antigen-specific therapy, cell therapy and therapy aimed at promoting remyelination being highlighted among other future therapeutic strategies. Access to new pharmacological agents and the complexity of the therapy of multiple sclerosis in the future will require new design strategies and directions in clinical trials, including the use of surrogate markers, new statistical applications, superiority, inferiority or equivalence clinical trials and adaptable designs.

TITLE: Revision de las novedades presentadas en el XXVIII Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (III).Los datos mas relevantes presentados en la XXVIII edicion del Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS), celebrado en octubre de 2012 en Francia, han sido resumidos en la quinta edicion de la Reunion de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2012, fruto de la cual nace esta revision que se publica en tres partes. Esta tercera parte de la revision Post-ECTRIMS expone los resultados de los ultimos estudios realizados con los tratamientos modificadores de la enfermedad, concretamente con acetato de glatiramero, laquinimod, ponesimod, BG-12, teriflunomida, daclizumab, natalizumab y secukinumab (AIN457). Asimismo, se abordan las razones que justifican la busqueda de tratamientos innovadores para la esclerosis multiple, destacando la terapia antigenoespecifica, la terapia celular y la terapia dirigida a promover la remielinizacion entre las futuras estrategias terapeuticas. La disponibilidad de nuevos farmacos y la complejidad de la futura terapia de la esclerosis multiple necesitan nuevas direcciones y estrategias de diseño en los ensayos clinicos, entre ellas el uso de marcadores subrogados, nuevas aplicaciones estadisticas, ensayos clinicos de superioridad, inferioridad o equivalencia, y diseños adaptables.

Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (I).

The most relevant data presented at the 28th edition of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in October 2012 in France, have been summarized in the fifth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2012. The present review summarizes the views and results of the meeting and is being published in three parts. This first part of the Post-ECTRIMS review addresses the incidence and prevalence of multiple sclerosis (MS), which has increased at the global level, largely due to the increased incidence in women because the risk of developing the disease is increased in females, with minimal concurrent effect on the progression of MS. Sexual dimorphism is evident in MS, and all evidence points to an interaction between hormonal, genetic, and environmental factors. The paediatric population represents an ideal group to study susceptibility factors to the disease, which is why collaborative studies designed to increase the patient samples are being considered, given its low prevalence. In this review, inflammatory and neurodegenerative phenomena involved in the pathogenesis of the disease and that have a cause-and-effect or shared relationship with the disease are being discussed. Current hypotheses suggest a phenomenon of compartmentalization, presumably inaccessible to current immunomodulatory therapy. Among the possible mechanisms involved in these processes of inflammation and demyelination, the role of Th17 cells, mitochondrial dysfunction, early disruption of astrocytic processes, and chronic hypoxia are discussed.

TITLE: Revision de las novedades presentadas en el XXVIII Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (I).Los datos mas relevantes presentados en la XXVIII edicion del Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS), celebrado en octubre de 2012 en Francia, se han resumido en la quinta edicion de la Reunion de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2012, fruto de la cual nace esta revision, que se publica en tres partes. Esta primera parte de la revision Post-ECTRIMS aborda la incidencia y prevalencia de la esclerosis multiple (EM), que, en el ambito mundial, ha aumentado a expensas de las mujeres, ya que el sexo femenino aumenta el riesgo de desarrollar la enfermedad, aunque no afecta de forma negativa a su evolucion. El dimorfismo sexual en la EM es evidente, y todo apunta a una interaccion entre factores hormonales, geneticos y medioambientales. La poblacion pediatrica representa un grupo idoneo para el estudio de factores de susceptibilidad a la enfermedad, razon por la que se estan planteando estudios colaborativos ideados para aumentar la muestra de pacientes, dada su baja prevalencia. En esta revision se discute sobre los fenomenos inflamatorios y de neurodegeneracion que intervienen en la patogenia de la enfermedad, y que probablemente esten relacionados, bien de forma compartida o como causa efecto. Las hipotesis actuales apuntan a un fenomeno de compartimentacion presumiblemente inaccesible a la terapia inmunomoduladora actual. Entre los posibles mecanismos involucrados en estos procesos de inflamacion y desmielinizacion se discute el papel de las celulas Th17, disfuncion mitocondrial, disrupcion precoz de procesos astrocitarios e hipoxia cronica.

Factors related with treatment adherence to interferon beta and glatiramer acetate therapy in multiple sclerosis.

BACKGROUND: Awareness of the factors influencing discontinuation of immunomodulatory drugs (IMD) treatment in multiple sclerosis (MS) can help to find approaches to patient management with the aim of establishing more specific indications and also attaining more optimal patient selection in future clinical trials. OBJECTIVE: To identify the causes that influence adhesion to IMD therapy within the clinical practice in a large cohort of patients with MS. PATIENTS AND METHODS: We have studied all MS patients who have initiated IMD in our hospital. All patients took part in training sessions where treatment expectations and side effects were explained and they received training in the administration technique. Reasons for stopping therapy were recorded during follow-up. RESULTS: We studied 632 MS patients (mean follow-up was 47.1 (28.7) months). At the time of analysis, 107/632 patients (17%) were no longer receiving IMD. Almost half of the patients who stopped IMD (52/107) did so within the first two years on therapy. Fifty-six patients stopped IMD because of lack of efficacy. Only 27 patients (4.3%) discontinued treatment for reasons other than inefficacy or side effects. The proportion of patients with secondary progressive MS that stopped IMD therapy was 30%, while only 13.5% of the patients with relapsing remitting MS stopped therapy (P < 0.0001). Expanded Disability Status Scale (EDSS) score at entry was the main factor that predicted interruption of therapy. CONCLUSIONS: The proportion of patients interrupting IMD in our centre is low, possibly due to individualized care. Higher EDSS, mainly in the first two years of treatment, is the main factor related with interruption. Close follow-up of these patients would be useful in avoiding early discontinuation of therapy.