Post-COVID symptoms of potential peripheral nervous and muscular origin.

Many patients report persistent symptoms attributable to dysfunction of the peripheral nervous and muscular systems after acute COVID-19. These symptoms may constitute part of the so-called post-acute COVID-19 syndrome (PACS), or may result from neuromuscular complications of hospitalisation in intensive care units (ICUs). This article provides an updated review of symptoms of potential neuromuscular origin in patients with PACS, differentiating symptoms according to muscle, peripheral nerve, or autonomic nervous system involvement, and analyses the forms of neuromuscular involvement in patients who were admitted to the ICU due to severe COVID-19.

Los pacientes que han padecido COVID-19 frecuentemente refieren síntomas persistentes atribuibles a disfunción del sistema nervioso periférico y muscular. Estos síntomas pueden formar parte del denominado síndrome COVID-19 post-agudo (post-acute COVID-19 syndrome o PACS) o pueden surgir como consecuencia de las complicaciones neuromusculares del ingreso en unidades de cuidados intensivos (UCI). En este manuscrito se realiza una revisión actualizada de los síntomas de potencial origen neuromuscular en pacientes afectos de PACS, diferenciándolos en función de su posible origen a nivel de músculo, nervio periférico o sistema nervioso autónomo, así como las formas de afectación neuromuscular en pacientes que precisaron ingreso en UCI por COVID-19 grave.

Nivolumab: «Tormenta inmune» en paciente con miastenia gravis previa / Nivolumab: An «Immune storm» in a patient with history of myasthenia gravis

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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.

Value of NMO-IgG determination at the time of presentation as CIS.

BACKGROUND: Despite the availability of diagnostic criteria, an overlap between neuromyelitis optica (NMO) and multiple sclerosis (MS) exists, particularly in the early stage of the disease. OBJECTIVE: To study the value of NMO-immunoglobulin G (IgG) determination in Caucasian patients with a first demyelinating episode who develop a relapsing form of optic neuritis or myelitis. METHODS: This study was based on a prospectively acquired cohort of patients regarded as having a clinically isolated syndrome (CIS) at the time of presentation. From this cohort, 2 different groups were selected: group 1 (NMO phenotype), consisting of a first attack involving the optic nerve or the spinal cord, and at least a second event affecting either topography, and group 2 (negative control group), consisting of a first attack involving the brainstem or the cerebral hemispheres and at least 1 relapse in any topography. Group 3 was composed of patients with NMO according to the 2006 revised diagnostic criteria. Serum NMO-IgG was determined by indirect immunofluorescence. RESULTS: A total of 3.1 of the group 1 patients were positive for NMO-IgG in comparison to 3.9% of group 2 and 44.5% of group 3, NMO. One of the positive patients in group 1 evolved to NMO. CONCLUSIONS: NMO-IgG determination is crucial in detecting patients who will develop NMO; however, its value as a routine test in cases presenting with symptoms of the type seen in MS is low, and should only be performed in those patients in which the initial diagnosis is not clear.

Chitinase 3-like 1 plasma levels are increased in patients with progressive forms of multiple sclerosis.

BACKGROUND: Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis. OBJECTIVE: The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNß) treatment on protein levels. METHODS: Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing-remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNß treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC. RESULTS: Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNß-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels. CONCLUSIONS: These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS.

Natalizumab para la esclerosis múltiple remitente-recurrente / Natalizumab for relapsing-remitting multiple sclerosis

Introducción: Natalizumab es un anticuerpo monoclonal inhibidor de la migración leucocitaria a través de la barrera hematoencefálica, autorizado para el tratamiento de la esclerosis múltiple remitente-recurrente. Objetivo: Realizar una revisión y actualización de los aspectos farmacológicos y terapéuticos de natalizumab, con especial énfasis en los datos de eficacia, efectividad y seguridad publicados más recientemente. Desarrollo: Varios ensayos clínicos aleatorizados en pacientes con formas recurrentes de esclerosis múltiple han demostrado que natalizumab reduce considerablemente la actividad clínica y radiológica de la enfermedad. El análisis post hoc de ensayos clínicos fase III y los resultados de estudios observacionales postautorización indican que natalizumab incrementa significativamente la proporción de pacientes con respuesta clínica y radiológica completa, y que es eficaz en aquellos con formas muy activas de esclerosis múltiple y con respuesta subóptima a otras terapias. Al igual que otros anticuerpos monoclonales, natalizumab puede causar reacciones de hipersensibilidad, siendo graves en el 1% de los pacientes. Otros efectos adversos de natalizumab son en general leves o poco frecuentes. No obstante, se han detectado varios casos de leucoencefalopatía multifocal progresiva en pacientes tratados con natalizumab en monoterapia. El riesgo de esta grave complicación parece incrementarse con el número de dosis recibidas. Conclusión: Natalizumab ha demostrado una relación beneficio-riesgo favorable en el tratamiento de la esclerosis múltiple remitente-recurrente. El riesgo potencial de leucoencefalopatía multifocal progresiva, sin embargo, obliga a la selección cuidadosa de los pacientes y a seguir protocolos de actuación específicos durante su administración (AU)

Introduction: Natalizumab is a monoclonal antibody that inhibits leukocyte migration across the blood-brain barrier and has been approved for the treatment of relapsing-remitting multiple sclerosis. Objective: To provide a review and update of the pharmacological and therapeutic characteristics of natalizumab, with special emphasis on the most recently published data on the efficacy, effectiveness and safety of this drug. Development: Several randomized clinical trials in patients with relapsing forms of multiple sclerosis have demonstrated that natalizumab substantially reduces clinical and radiological disease activity. Post hoc analysis of phase III clinical trials and the results of post-approval observational studies indicate that natalizumab significantly increases the proportion of patients with complete clinical and radiological response and is effective in patients with highly active forms of multiple sclerosis and suboptimal response to other treatments. Like other monoclonal antibodies, natalizumab can cause hypersensitivity reactions, which are severe in 1% of patients. Other adverse effects are generally mild or infrequent. Nevertheless, several cases of progressive multifocal leukoencephalopathy have been detected in patients treated with natalizumab monotherapy. The risk of this severe complication seems to increase with the number of doses administered. Conclusion: Natalizumab has a favorable risk-benefit ratio in the treatment of relapsing -remitting multiple sclerosis. However, because of the potential risk of progressive multifocal leukoencephalopathy, patients must be carefully selected and specific protocols must be followed during the drug's administration (AU)

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.

Ketanserin potentiates morphine-induced antinociception mediated by kappa-receptor activation.

How can we treat patients with reduced morphine doses without loosing the pain killing effect or morphine antinociceptive effects (MAE)? To address this question, we hypothesized that serotonin (5-HT2) receptor antagonism could enhance MAE mediated by kappa-opioid receptors. We pretreated mice with ketanserin, a 5-HT2 receptor antagonist, and measured the morphine dose required to observe analgesia. The morphine dose effective in 50% of animals (ED(50)) was reduced from 4.7 to 1.3mg/kg, and the morphine dose effective in 100% of animals (ED(max)) from 13.7 to 2.5mg/kg. Ketanserin has a similar enhancer effect when morphine, which has a dual role via mu and kappa receptors, was substituted by the antinociceptive spiradoline, a selective κ-opioid agonist. At a morphine dose of 3.5mg/kg, 30% of the mice showed antinociceptive behaviour, rising to 100% when ketanserin was co-administered and then reduced to 20% in the presence of nor-binaltorphimine, a kappa-opioid receptor antagonist. Our data strongly suggests a serotonergic inhibition of the kappa-opioid component of MAE and the possibility that this serotonergic inhibition could be reversed through 5-HT2 receptor antagonism.

Natalizumab for relapsing-remitting multiple sclerosis.

INTRODUCTION: Natalizumab is a monoclonal antibody that inhibits leukocyte migration across the blood-brain barrier and has been approved for the treatment of relapsing-remitting multiple sclerosis. OBJECTIVE: To provide a review and update of the pharmacological and therapeutic characteristics of natalizumab, with special emphasis on the most recently published data on the efficacy, effectiveness and safety of this drug. DEVELOPMENT: Several randomized clinical trials in patients with relapsing forms of multiple sclerosis have demonstrated that natalizumab substantially reduces clinical and radiological disease activity. Post hoc analysis of phase III clinical trials and the results of post-approval observational studies indicate that natalizumab significantly increases the proportion of patients with complete clinical and radiological response and is effective in patients with highly active forms of multiple sclerosis and suboptimal response to other treatments. Like other monoclonal antibodies, natalizumab can cause hypersensitivity reactions, which are severe in 1% of patients. Other adverse effects are generally mild or infrequent. Nevertheless, several cases of progressive multifocal leukoencephalopathy have been detected in patients treated with natalizumab monotherapy. The risk of this severe complication seems to increase with the number of doses administered. CONCLUSION: Natalizumab has a favorable risk-benefit ratio in the treatment of relapsing -remitting multiple sclerosis. However, because of the potential risk of progressive multifocal leukoencephalopathy, patients must be carefully selected and specific protocols must be followed during the drug's administration.

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.

Antiviral immune response in patients with multiple sclerosis and healthy siblings.

The objective of this study was to determine the immune responses to candidate viral triggers of multiple sclerosis in patients and healthy siblings raised in the same family household. Virus antigen-specific IgG responses to Epstein-Barr virus-derived gene products as well as to human herpersvirus-6, human cytomegalovirus, and measles virus were evaluated in 25 multiple sclerosis patients and compared with 49 healthy full-siblings. IgG responses to the latent Epstein-Barr virus-encoded nuclear antigen-1 (EBNA1) were selectively increased in individuals with multiple sclerosis compared with their unaffected siblings. We conclude that elevated IgG responses towards EBNA1 are associated with the development of multiple sclerosis.

Clinical features of CIS of the brainstem/cerebellum of the kind seen in MS.

Recognition of multiple sclerosis (MS) attacks relies mostly on clinical assessment. However, their definition based on McDonald criteria refers mostly to timing and when dealing with clinical features is rather ambiguous: "...of the kind seen in multiple sclerosis." This is heightened in clinically isolated syndromes of the brainstem/cerebellum (CISB), where clinical manifestations can be manifold. This study aimed to describe the clinical features of patients with CISB to improve clinical recognition of patients with brainstem manifestations at the onset of their MS. To this end, we conducted a retrospective analysis of case notes of consecutively recruited patients with CISB assessed within 3 months of symptoms onset. Seventy-five patients were included. Most common brainstem-specific symptoms were: diplopia (68%), facial sensory symptoms (32%) and gait disturbance (31%). Adjusting for follow-up times, total number of symptoms and presence of other brainstem-specific symptoms, only the presence of facial sensory symptoms was predictive of (a lower risk of) conversion to clinically definite (CD) MS (Odds ratio: 0.086; p = 0.007). Neither the total number of brainstem-specific, non brainstem-specific nor the sum of both predicted conversion to CDMS. Results indicate that diplopia, facial sensory symptoms and gait disturbance occur in more than 30% of patients with CISB. Facial sensory symptoms are less associated with conversion to CDMS.

Do multimodal evoked potentials add information to MRI in clinically isolated syndromes?

The role of multimodal evoked potentials (MMEPs) in establishing multiple sclerosis (MS) diagnosis and prognosis has diminished nowadays. The objective of this article is to evaluate whether MMEPs add information to MRI in identifying patients with higher risk of relapse or development of disability after a clinically isolated syndrome (CIS). Patients who underwent visual, somato-sensory and brainstem auditory evoked potentials (EPs) were identified from a cohort of consecutive CIS. Patients also underwent brain MRI within 3 months of first attack. We analysed time to second attack and to Expanded Disability Status Scale (EDSS) score of 3.0 according to number of Barkhof criteria and number of abnormal MMEPs. A complete study was performed in 245 patients who were followed for a mean of 76.4 months (interquartile range: 61 to 96). Seventy-one patients (29%) had the three EPs normal, 115 patients (47%) had one abnormal EP; 40 patients (16%) had two; and 19 patients (8%) had three abnormal EPs. Baseline MRI determined the risk for converting to clinically definite MS and correlated with disability according to previous studies. EPs individually did not modify the risk of conversion or disability. However, the presence of three abnormal EPs increased the risk of reaching moderate disability (hazard ratio 7.0; 1.4-34.9) independently of baseline MRI. In conclusion, in the presence of three abnormal EPs could help identify CIS patients with a higher risk of developing disability, independently of MRI findings. However, the utility of MMEPs is limited by the low percentage of CIS patients having the three abnormal at baseline.

Plasma exchange for acute attacks of CNS demyelination: Predictors of improvement at 6 months.

BACKGROUND: Plasma exchange (PE) is used to treat severe episodes of CNS demyelination unresponsive to corticosteroids. Predictors of long-term response are not well known. METHODS: We retrospectively reviewed the medical records of 41 patients consecutively treated by PE between January 1995 and July 2007. The primary outcome was improvement at 6 months after PE defined as decrease of >or=1 point in the Expanded Disability Status Scale (EDSS) score for patients with EDSS or=8.0 or improvement of more than 2 lines in the visual acuity chart for patients with optic neuritis (ON). RESULTS: Twenty-five patients (61%) were women, and the median age was 33 years (range 14-57 years). Twenty-three (56%) had multiple sclerosis, 2 (5%) had clinically isolated syndrome, 2 (5%) had Marburg disease, 7 (17%) had acute disseminated encephalomyelitis, 4 (10%) had neuromyelitis optica, 2 (5%) had idiopathic ON, and 1 (2%) had idiopathic transverse myelitis. The median EDSS score before the attack was 1.0 (range 0-6.5). At PE onset, the median EDSS score was 7.0 (range 3.0-9.5). Sixteen patients (39%) improved at discharge, and 26 (63%) improved at 6 months. In the multivariate analysis, early initiation of PE (odds ratio [OR] 6.29, 95% confidence interval [CI] 1.18-52.96) and improvement at discharge (OR 7.32, 95% CI 1.21-44.38) were significantly associated with response at 6 months. CONCLUSIONS: Plasma exchange (PE) was associated with clinical improvement in 63% of patients at 6 months. Early initiation of PE and improvement at discharge were predictors of this response. Twelve patients (48%) who did not improve early did so during follow-up.

Genetic association between polymorphisms in the BTG1 gene and multiple sclerosis.

In the present study, we investigated the B-cell translocation gene 1 (BTG1) as a candidate for multiple sclerosis (MS) susceptibility. BTG1 is a member of a family of genes involved in the apoptotic process. We genotyped two SNPs of the BTG1 gene (rs731652 and rs12694) in 550 MS patients and 548 controls. For SNP rs731652, significant associations with relapse-onset MS were found at the allele and genotype levels when compared with controls. We identified a risk haplotype associated with relapse-onset MS. These findings support the hypothesis that BTG1 polymorphisms may influence genetic predisposition for MS, especially in relapse-onset MS patients.

Measures in the first year of therapy predict the response to interferon beta in MS.

BACKGROUND AND OBJECTIVE: Several criteria for treatment response to interferon beta (IFNbeta) have been proposed, although there is no consensus among different investigators. Hence, the aim of this study was to investigate magnetic resonance imaging (MRI) and clinical predictors of response during the first 12 months of therapy. METHODS: This is a prospective and longitudinal study of relapsing-remitting multiple sclerosis (RRMS) patients treated with IFNbeta. Patients were classified based on the presence of new lesions on MRI, relapses, confirmed disability increase, or combinations of all these variables after 1 year of therapy. Regression analysis was performed in order to identify variables of response after a follow-up of 3 years. RESULTS: We included 222 RRMS patients. The logistic model demonstrated that only the combination of new active lesions on MRI with the presence of relapses (OR 4.4; 95% CI 1.6-12.5) or disability progression (Odds Ratio (OR) 7.1; 95% Confidence Interval (CI) 1.6-33.9), or both (OR 6.5; 95% CI 1.9-23.4) achieved significant values to identify those patients with a poor outcome. CONCLUSIONS: In RRMS patients treated with IFNbeta, the combination of measures of disease activity and the presence of new active lesions on MRI may have a prognostic value for identifying patients with disease activity in the second and third year of therapy.

Encefalomielitis aguda diseminada: estudio de factores implicados en un posible desarrollo hacia una esclerosis múltiple / Acute disseminated encephalomyelitis: study of factors involved in a possible development towards multiple sclerosis

La encefalomielitis aguda diseminada (EAD) es una entidad infrecuente que cursa con inflamación y desmielinizacióndel sistema nervioso central (SNC). Ocurre típicamente tras una infección vírica o una vacunación y es más frecuente en niños. El pronóstico inmediato y a largo plazo seconsidera bueno (20% de secuelas). Aunque es típicamentemonofásica, puede presentar varios brotes. El principal diagnóstico diferencial, especialmente al inicio, se establece con la esclerosis múltiple (EM), enfermedad inflamatoriadesmielinizante crónica del SNC de peor pronóstico. Tradicionalmentese consideraba que el 10% de pacientes con EAD evolucionaban a EM. Series recientes apuntan un mayorporcentaje (alrededor del 30%) de evolución a EM. Hay descritos patrones de riesgo para desarrollar EM cuando sepresentan en pacientes con EAD, como presencia de bandas oligoclonales en el líquido cefalorraquídeo, lesiones periventriculares y perpendiculares al cuerpo calloso en la resonanciamagnética (RM) craneal inicial o aparición de nuevas lesiones en las RM de control. Los objetivos de nuestro estudio fueron: a) describir una serie de 29 pacientes (22 niños y adultos) ingresados en nuestro centro entre 1990 y 2005 con diagnóstico al alta de EAD; b) estudiar aquellos patronesde riesgo descritos para conversión a EM, y c) comparar las poblaciones pediátrica y adulta de nuestra serie. Tras un período medio de seguimiento de 54 meses (55 meses parala población pediátrica y 50,3 para la adulta), 6 niños (27%) y ningún adulto desarrollaron una EM. Los patrones de riesgo para evolucionar a EM predijeron dicha conversión con mayor precisión entre los niños que entre los adultos. Ocho pacientes (6 niños y 2 adultos) presentaron secuelas (AU)

Acute disseminated encephalomyelitis (ADEM) is an uncommon disease characterized by inflammation anddemyelination of the central nervous system (CNS). It typically occurs after a viral infection or vaccination andis more frequent in children. Its immediate and longtermprognosis is expected to be good (20% of cases with sequelae). Although ADEM is typically monophasic, occasional relapses may occur. Differential diagnosis, mostly in the early phases, is established with multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS that may have worse prognosis. Traditionally it has been believed that 10% of ADEM patientsdevelop MS. However, this percentage could be higher according to several recently published clinical series.Some clinical and paraclinical patterns are considered to confer risk of developing MS when present in ADEM patients. Our study has aimed to: a) describe a series of 29 patients (22 children and 9 adults) admitted in ourhospital and diagnosed of ADEM between 1990 and 2005; b) study those patients considered to have riskpatterns of developing MS, and c) compare the child and adult populations of our series. After a median 55 monthfollow-up, 6 children (27%) and no adults developed MS. In our series, risk patterns for developing MS predictedconversion to MS more accurately in children than in adults. Eight patients (6 children and 2 adults) had sequelae, cognitive in 6 of them. Our work supportsthat also observed in recent publications: that both conversionto MS or presence of sequelae after an episode of ADEM are more frequent than traditionally considered (AU)

[Acute disseminated encephalomyelitis: study of factors involved in a possible development towards multiple sclerosis]. / Encefalomielitis aguda diseminada: estudio de factores implicados en un posible desarrollo hacia una esclerosis múltiple.

Acute disseminated encephalomyelitis (ADEM) is an uncommon disease characterized by inflammation and demyelination of the central nervous system (CNS). It typically occurs after a viral infection or vaccination and is more frequent in children. Its immediate and longterm prognosis is expected to be good (20% of cases with sequelae). Although ADEM is typically monophasic, occasional relapses may occur. Differential diagnosis, mostly in the early phases, is established with multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS that may have worse prognosis. Traditionally it has been believed that 10% of ADEM patients develop MS. However, this percentage could be higher according to several recently published clinical series. Some clinical and paraclinical patterns are considered to confer risk of developing MS when present in ADEM patients. Our study has aimed to: a) describe a series of 29 patients (22 children and 9 adults) admitted in our hospital and diagnosed of ADEM between 1990 and 2005; b) study those patients considered to have risk patterns of developing MS, and c) compare the child and adult populations of our series. After a median 55 month follow-up, 6 children (27%) and no adults developed MS. In our series, risk patterns for developing MS predicted conversion to MS more accurately in children than in adults. Eight patients (6 children and 2 adults) had sequelae, cognitive in 6 of them. Our work supports that also observed in recent publications: that both conversion to MS or presence of sequelae after an episode of ADEM are more frequent than traditionally considered.

[Natalizumab in the treatment of multiple sclerosis]. / Natalizumab en el tratamiento de la esclerosis multiple.

AIM: To review and update the mechanism of action of natalizumab and its efficacy in the treatment of multiple sclerosis (MS). DEVELOPMENT: Natalizumab, an anti-alfa-4 integrin monoclonal humanized antibody, binds to lymphocyte surface receptors to prevent transmigration of lymphocytes to areas of inflammation into the brain tissue. Furthermore, natalizumab appears to reduce T-cell activation following their infiltration of the brain parenchyma and may contribute to T-cell apoptosis in these tissues. Two large two-year, multicenter phase III trials (AFFIRM and SENTINEL) have been completed and demonstrate previously unseen efficacy in preventing MS relapses and disease progression. Natalizumab reduced the rate of clinical relapse at one year by 68 and 54% respectively in these trials (p < 0.001). Moreover, natalizumab reduced significantly the risk of sustained progression of disability by 42 and 24% respectively. Based on results from the AFFIRM study, the adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 vs. 21%) and allergic reaction (9 vs. 4%). There was a low incidence (< 1%) of serious systemic hypersensitivity reactions described as anaphylactoid or anaphylactic, and they appear to be effectively managed by post-treatment observation and by timely and appropriate medical treatment. In the SENTINEL study, two cases of progressive multifocal leukoencephalopathy (PML), one of which was fatal, were diagnosed in natalizumab plus interferon beta-1a treated patients. CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing MS. In spite of their low risk of adverse reactions, patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML, and natalizumab use must be restricted to the indicated patients.