Significant clinical worsening after natalizumab withdrawal: Predictive factors.

We aimed to single out multiple sclerosis (MS) cases with poor outcome after natalizumab withdrawal and to identify predictive variables. We ascertained 47 withdrawals, and compared their pre- and post-natalizumab periods. We objectively defined significant clinical worsening after natalizumab withdrawal as a 2-step increase in Expanded Disability Status Scale (EDSS). We performed regression models. As a group, post-natalizumab annualized relapse rate (ARR) was lower in the post-natalizumab period, and there were no differences in the mean number of gadolinium (Gd)-enhancing lesions between pre- and post-natalizumab magnetic resonance imaging (MRI). Corticosteroid treatment did not change the outcomes. Eight patients (19%) presented significant clinical worsening after natalizumab withdrawal, which was predicted by a higher baseline EDSS and a 1-step EDSS increase while on natalizumab.

Clinical evaluation of rituximab treatment for neuromyelitis optica.

INTRODUCTION: Neuromyelitis optica is an inflammatory and usually relapsing demyelinating autoimmune disease of the central nervous system that targets the optic nerves and spinal cord. Rituximab has been used for different neurological diseases that are probably immune-mediated or involving humoural immunity. The objective of this study is to evaluate the efficacy and safety of rituximab as treatment for neuromyelitis optica in a tertiary hospital. METHODS: Retrospective study of patients with neuromyelitis optica treated with rituximab 1000mg on days 1 and 15, repeated every 6 to 8 months. We recorded EDSS score, relapse rate, overall condition, CD19+ count, presence of anti-NMO antibodies, and possible adverse reactions. RESULTS: Six patients were treated; all were women with a median age of 46 years (range, 38-58). Anti-NMO antibodies were detected in 3 patients (50%). Baseline EDSS was 4 (range 2.0-5.5). Two patients had previously been treated with an immunomodulatory drug. Median time from the first rituximab infusion to first relapse was 3.7 years (range 1.7-6.9). Two patients had infusion reactions after the first dose of rituximab. Four patients remained relapse-free and their EDSS score did not progress during rituximab treatment, one patient showed no clinical improvement, and one patient could not be evaluated. CONCLUSION: Rituximab can be considered an attractive therapeutic alternative for patients with neuromyelitis optica as there are no approved treatments for this disease. Further studies with rituximab are needed to establish the role of this drug in treating neuromyelitis optica.

Clinical experiences with cannabinoids in spasticity management in multiple sclerosis.

INTRODUCTION: Spasticity is a common symptom among patients with multiple sclerosis (MS). This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS. METHODS: Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression. RESULTS: Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age 47.8 years (25.6-76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1). CONCLUSIONS: THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile.

Clinical impact of early brain atrophy in clinically isolated syndromes.

BACKGROUND: The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged. OBJECTIVES: We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS. METHODS: We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions. RESULTS: The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (- 0.65% versus + 0.059%; p < 0.001). PBVC decreases below - 0.817% independently predicted shorter times to a second attack. CONCLUSIONS: Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS.

NFL during acute spinal cord lesions in MS: a hurdle for the detection of inflammatory activity.

INTRODUCTION: Levels of neuro-filament light chain (NFL) correlate with clinical and radiological activity in multiple sclerosis (MS) and have been used as a surrogate biomarker of axonal destruction related to inflammatory activity. The main objective of this work is to explore the specific contribution of acute inflammation within the spinal cord to the elevation of NFL levels. PATIENTS AND METHODS: MS patients with a baseline study of NFL at diagnosis of the disease and a brain and spinal cord MRI scan were selected. Patients were classified according to the presence, number and location of gadolinium enhancing lesion (GEL) and the relationship between NFL levels and both brain and spinal cord GEL were explored. RESULTS: Seventy-seven patients were selected. NFL levels were significantly higher in patients with only one GEL restricted to the brain than those without GEL (1702 pg/ml vs 722.7 pg/mL, p = 0.03) and correlated with number. However, no differences were seen among patients with GEL limited to the spinal cord and those without GEL (735.2 pg/ml vs 722.7 pg/mL). CONCLUSION: Our study reaffirms the value of NFL levels in monitoring asymptomatic inflammatory activity in the brain measured by GEL. However, NFL concentration is not as useful when only inflammatory activity occurs in the spinal cord.

Daclizumab in multiple sclerosis. / Daclizumab en la esclerosis multiple.

INTRODUCTION: Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The present review addresses how the drug was developed, the known mechanism of action of the drug and the up-to-date data of efficacy and safety. DEVELOPMENT: Daclizumab has shown superiority in prevention of relapses against placebo and low-dose interferon beta-1a at a level that puts it on par with the rest of current first-line drugs. The effect on the progression of the disease and on neurodegeneration parameters, however, is not clear. On the other hand, it presents safety problems (mainly risk of autoimmunity phenomena including fulminant hepatopathy and encephalitis) that have supposed eventually its withdrawn from marketing. Daclizumab introduces a new mechanism of action through the blocking of a key interleukin in immune regulation and its effect on a population of cells with regulatory ability, such as the NK CD56(bright) cells. CONCLUSIONS: Daclizumab has shown efficacy in slowing the inflammatory process of multiple sclerosis, although the appearance of potentially serious side effects has not allowed its use to significantly impact current clinical practice. The development of new drugs in multiple sclerosis must be contingent on maintaining or improving the risk-benefit profile with respect to those already in use.

TITLE: Daclizumab en la esclerosis multiple.Introduccion. El daclizumab es un anticuerpo monoclonal dirigido contra la subunidad CD25 del receptor de la interleucina-2, investigado como terapia modificadora de la evolucion de la enfermedad en la esclerosis multiple. La presente revision aborda como se desarrollo el farmaco, cual es su mecanismo de accion conocido y los datos que se han obtenido hasta la fecha acerca de su eficacia y seguridad. Desarrollo. El daclizumab ha mostrado superioridad en prevencion de brotes frente a placebo e interferon beta-1a de baja dosis en un nivel que lo situa a la par del resto de farmacos de primera linea actuales. El efecto sobre la progresion de la enfermedad y sobre parametros de neurodegeneracion, no obstante, no esta aclarado. Por otro lado, presenta problemas de seguridad (riesgo de reacciones autoinmunes que incluyen hepatopatia fulminante y encefalitis) que han supuesto finalmente su retirada del mercado. El daclizumab introduce un nuevo mecanismo de accion a traves del bloqueo de una interleucina clave en la regulacion inmune y por su efecto sobre una poblacion de celulas con capacidad reguladora, como son las celulas NK CD56(bright). Conclusiones. El daclizumab ha demostrado eficacia para frenar el proceso inflamatorio de la esclerosis multiple, aunque la aparicion de efectos secundarios potencialmente graves no ha permitido que su uso impacte de manera significativa en la practica clinica actual. El desarrollo de nuevos farmacos en la esclerosis multiple debe estar supeditado a mantener o mejorar el perfil riesgo-beneficio respecto a los ya en uso.

Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: a hospital-based study.

INTRODUCTION: Rituximab is considered as a potential therapeutic option in relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). OBJECTIVE: To investigate the effectiveness and safety of rituximab in MS. PATIENTS AND METHODS: Observational study of effectiveness (clinical and radiological) and safety of rituximab in RRMS and PMS. RESULTS: A total of 90 rituximab-treated patients were collected: 31 RRMS and 59 PMS All patients had an active disease despite standard treatment. The annualized relapse rate (ARR) the year before rituximab was 0.86, 53.3% of patients had gadolinium enhanced lesion, and mean Expanded Disability Status Scale (EDSS) had increased from 4.2 to 4.9. During treatment, the ARR was reduced an 88.4% (p < 0.001). A significant decrease of EDSS to 4.6 was observed (p = 0.01) after 1 year of treatment, which remained stable during the second year in both groups. There was no evidence of disease activity in 70% of total sample, 74.2% of RRMS, and 67% of the PMS patients. Infusion-related symptoms were the most prevalent side effect (18.8%) and most were mild. Three thrombotic events were detected. CONCLUSION: Rituximab could be an effective and safe treatment in aggressive RRMS. Some selected PMS patients could also benefit from this treatment.

[Treatment of relapsing-remitting multiple sclerosis with fingolimod in routine clinical practice]. / Tratamiento de la esclerosis multiple remitente recurrente con fingolimod en la practica clinica habitual.

INTRODUCTION: Fingolimod is a selective immunosuppressant that targets the S1P receptor, and is indicated in the treatment of aggressive relapsing-remitting multiple sclerosis (RRMS) and following treatment failure with first-order drugs. AIM: To investigate the safety and effectiveness of fingolimod under the conditions of routine clinical practice. PATIENTS AND METHODS: We conducted an observational study with prospective follow-up of patients with RRMS who received fingolimod from January 2011 until February 2014. Data assessed were the annualised relapse rate (ARR), disability measured by the Expanded Disability Status Scale (EDSS), magnetic resonance activity and the appearance of side effects. RESULTS: Our sample consisted of 122 patients, 79.5% of them females and with a mean age of 26.8 years. They were classified, according to the last treatment received, as being: naive (aggressive RRMS; n = 17), previous treatment failure (n = 67) and withdrawal of natalizumab due to risk of progressive multifocal leukoencephalopathy (n = 38). After a mean follow-up of 29.9 ± 15.9 months, the ARR and the appearance of new lesions with gadolinium enhancement were reduced in both the naive and the previous treatment failure groups. There were no differences between the various subgroups as regards the progression of EDSS or the time elapsed until the first attack or treatment failure. The risk of treatment failure is higher with a baseline EDSS > 3 (hazard ratio: 4.24; p = 0.001) and presence of IgM oligoclonal bands (hazard ratio: 2.45; p < 0.022). CONCLUSIONS: Fingolimod is an effective and well-tolerated drug under conditions of routine clinical practice. Having a baseline EDSS > 3 and IgM oligoclonal bands is predictive of a poor response to fingolimod.

TITLE: Tratamiento de la esclerosis multiple remitente recurrente con fingolimod en la practica clinica habitual.Introduccion. El fingolimod es un inmunosupresor selectivo dirigido contra el receptor SP-1, indicado en el tratamiento de la esclerosis multiple remitente recurrente (EMRR) agresiva y tras el fracaso del tratamiento con farmacos de primera linea. Objetivo. Investigar la seguridad y efectividad del fingolimod en condiciones de practica clinica habitual. Pacientes y metodos. Estudio observacional con seguimiento prospectivo de pacientes con EMRR que recibieron fingolimod desde enero de 2011 hasta febrero de 2014. Se evaluo la tasa anual de brotes (TAB), la discapacidad medida por la escala expandida del estado de discapacidad (EDSS), la actividad en la resonancia magnetica y la aparicion de efectos adversos. Resultados. Incluimos 122 pacientes, el 79,5% mujeres y con una edad media de 26,8 antilde;os. Se clasificaron segun el ultimo tratamiento recibido en: naive (EMRR agresiva; n = 17), fracaso a terapias previas (n = 67) y retirada de natalizumab por riesgo de leucoencefalopatia multifocal progresiva (n = 38). Tras un seguimiento medio de 29,9 ± 15,9 meses, se redujo de forma significativa la TAB y la aparicion de nuevas lesiones con realce de gadolinio en el grupo naive y el de fracaso a terapias previas. No ha habido diferencias en la evolucion de la EDSS ni en el tiempo hasta el primer brote o el fracaso terapeutico entre los diferentes subgrupos. El riesgo a fracaso terapeutico es mayor con la EDSS basal > 3 (hazard ratio: 4,24; p = 0,001) y presencia de bandas oligoclonales IgM (hazard ratio: 2,45; p < 0,022). Conclusiones. El fingolimod es un farmaco eficaz y seguro en la EMRR en condiciones de practica clinica habitual. Tener una EDSS basal > 3 y bandas oligoclonales IgM predice una mala respuesta al fingolimod.

Incidence of and risk factors for neurologic complications after heart transplantation.

INTRODUCTION: Following heart transplantation (HT), neurologic complications occur in 50% to 70% of patients, mostly in the perioperative period. The objective of our study was to analyze the frequency and impact of factors related to the development of neurological complications after HT. MATERIALS AND METHODS: HT patients with survival greater than 1 month (November 1987 to May 2003) were included. Heart-lung transplants, retransplants, and pediatric patients were excluded. Neurologic complications were defined as a neurologic event requiring hospitalization or detected in the hospital. Groups included ischemic or hemorrhagic stroke, seizures, neurotoxicity or other complications (e.g., infections, headaches, Alzheimer's). RESULTS: We assessed 322 HT patients (87.6% men, 12.4% women) and grouped them according to the presence of neurologic complications during follow-up. There were no differences in the baseline characteristics between the two groups. Of patients the patients studied, 13.7% suffered a neurologic complication: ischemic stroke (3.5%), neurotoxicity (2.9%), seizures (1.9%), and other complications (1.6%). Only two cases of hemorrhagic stroke (0.6%) were observed. Associations with pretransplant risk factors included seizures with diabetes mellitus (OR, 6.54; 95% CI, 1.28 to 33.6, P = .024), seizures with renal failure (OR, 5.95; 95% CI, 1.03 to 34.3; P = .046), and ischemic stroke with prior valvular disease (OR, 4.96, 95% CI, 1.22 to 20.1; P = .045). Associations with pretransplant risk factors were neurologic complications with the number of infections (OR, 1.35, 95% CI, 1.05 to 1.73; P = .02). No differences were found in survival of patients with neurologic complications. CONCLUSIONS: The incidence of neurologic complications in our series was 13.7%. The most frequent neurologic complication was ischemic stroke. Valvular disease as the underlying disease was associated with ischemic stroke. Diabetes mellitus and renal failure were associated with seizures. The number of posttransplant infections was associated with neurologic complications. There were no differences in survival of patients with neurologic complications.

Peripheral nerve hyperexcitability: a clinical and immunologic study of 38 patients.

OBJECTIVE: We studied a case series of peripheral nerve hyperexcitability (PNH) aiming to describe clinical characteristics, immunologic and cancer associations, antibodies against neuronal antigens (voltage-gated potassium channel antibodies [VGKC-Abs] and other), and muscle biopsy findings. METHODS: Patients presenting with clinical and electrophysiologic signs of PNH were selected. We studied clinical and electrophysiologic features; a panel of non-neuronal organ-specific antibodies, immunofluorescence on rat nervous tissues, and radioimmunoprecipitation for VGKC-Abs; and muscle biopsies. RESULTS: Thirty-eight patients were included. After the exclusion of 6 cases with axonopathy of known origin, patients were subdivided according to the presence of electrophysiologic findings of motor axonopathy and association with cancer: axonopathic-PNH (group A: 12 patients), isolated nonparaneoplastic PNH (group B: 16 patients), and isolated paraneoplastic PNH (3 with thymoma and myasthenia gravis, 1 with thyroid carcinoma). PNH clinical features were similar in groups A and B. We found an overall high prevalence of clinical autoimmunity (33% of group A and 63% of group B) and systemic non-neuronal autoantibodies (42% of group A and 75% of group B). However, VGKC-Abs were only positive in 2 patients of group B. Ten patients underwent muscle biopsy, which showed inflammatory changes in 2 cases and nonspecific myopathic features in 8. CONCLUSIONS: PNH is a heterogeneous disorder involving the peripheral nerves in patients with a high propensity for developing autoimmunity. Associated muscle diseases are frequent in the form of myositis, myasthenia gravis, or nonspecific myopathic pathologic findings. VGKC-Abs were uncommon in this series.

An observational study of the effectiveness and safety of natalizumab in the treatment of multiple sclerosis.

AIM: To analyse the safety and effectiveness of natalizumab in the treatment of multiple sclerosis in a real clinical practice setting and according to the approved indications. PATIENTS AND METHODS: All patients with multiple sclerosis treated with natalizumab in our centre were evaluated. The clinical and radiological disease activity during the first year of treatment was analyzed in patients who received at least 12 doses of the drug. The data regarding moderate and severe adverse events in the entire study sample was also evaluated. RESULTS: A total of 112 patients were included in the study, of which 110 had been previously treated with other drugs and 76 had received at least 12 doses of natalizumab. In this group, the annualized relapse rate was reduced by 89% compared to the preceding year and 80% of patients were free from relapses after one year of treatment. Nine percent of patients exhibited 3-month confirmed disability progression. At month 12, the mean number of gadolinium-enhancing lesions on brain MRI was decreased by 99% compared to the pre-treatment MRI. During the first year of treatment, 76% of patients remained free from clinical activity and 33% remained free from both clinical and radiological disease activity. Twenty-nine percent of patients had at least one moderate or severe adverse event, which led to treatment discontinuation in 6%. Four percent of patients experienced immediate hypersensitivity reactions. CONCLUSION: This study suggests that natalizumab is effective in reducing disease activity in patients with relapsing multiple sclerosis and inadequate response to other therapies, with a favorable risk-benefit ratio.

Brainstem lesions in clinically isolated syndromes.

BACKGROUND: Number of baseline lesions has been shown to predict future attacks and disability in clinically isolated syndromes (CIS). OBJECTIVE: To investigate the role of baseline infratentorial lesions in long-term prognosis. METHODS: Subjects were included in a prospective cohort of patients with CIS. Patients underwent brain MRI within 3 months after CIS onset. Number and location of lesions at baseline were prospectively studied. Retrospective scan analysis was conducted to specifically look at number and location of infratentorial lesions. We analyzed the time to a second attack and to reach EDSS 3.0. RESULTS: We included 246 patients with CIS followed for a median of 7.7 years. Patients with infratentorial lesions had both a higher risk of conversion (71.4% vs 29.6%; hazard ratio [HR] 3.3; 95% confidence interval [CI] 2.2-4.8; p < 0.001) and of developing disability (32.5% vs 12.4%; HR 2.4; 95% CI 1.3-4.3; p = 0.003). Presence of at least one cerebellar lesion was associated with an increased risk of conversion (HR 2.4; 95% CI 1.3-4.5; p = 0.007). Presence of at least one brainstem lesion increased both the risk of conversion (HR 2.9; 95% CI 1.7-5.0; p < 0.001) and disability (HR 2.5; 95% CI 1.1-5.4; p = 0.026). Broken down into number of lesions, the presence of infratentorial lesions increased both the risk of conversion (83% vs 61%) (HR 22.3; 95% CI 9.7-51.1; p < 0.001) and of reaching EDSS 3.0 (40% vs 19%) (HR 3.2; 95% CI 1.3-7.4; p = 0.008) only in patients with 9 or more lesions. CONCLUSIONS: Presence of infratentorial lesions increases the risk for disability. Brainstem rather than cerebellar lesions may be responsible for poor prognosis.