Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial.

BACKGROUND: The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. METHODS: We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50-0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. FINDINGS: Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. INTERPRETATION: At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke.

[Argentine consensus on late-onset Pompe's disease]. / Consenso argentino sobre enfermedad de Pompe de inicio tardío.

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Consenso argentino sobre enfermedad de Pompe de inicio tardío / Argentine consensus on late-onset Pompe's disease

La enfermedad de Pompe (EP) es un desorden metabólico autosómico recesivo infrecuente, producido por la ausencia o deficiencia de la enzima lisosomal alfa-glucosidasa ácida en los tejidos de los individuos afectados. Se considera enfermedad de Pompe de inicio tardío (EPIT) en aquellos individuos de más de un año de edad al comienzo de los síntomas. El objetivo del presente consenso es el de actualizar las pautas y recomendaciones para un correcto tratamiento de los pacientes con EPIT, tomando como referencia los lineamientos del Consenso Argentino para el diagnóstico, seguimiento y tratamiento de la enfermedad de Pompe publicado en el año 2013. Se organizó un consenso que reunió profesionales con experiencia en la EP en las áreas de clínica médica, diagnóstico de laboratorio, neuropatología, neumonología, nutrición, neurología, enfermedades metabólicas, enfermedades neuromusculares y rehabilitación. Se realizó una actualización de la bibliografía sobre EPIT, con especial atención en las publicaciones relevantes de los últimos cuatro años. Los términos finales del documento fueron consensuados por todo el grupo de trabajo. Cada participante proporcionó su declaración de conflicto de intereses. El resultado es una actualización del último Consenso Argentino para la EP, con particular enfoque en su forma de comienzo tardío. Tratándose de una afección infrecuente, en la que los datos disponibles son limitados, las presentes recomendaciones deben ser consideradas como opinión de expertos.

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Epidermolysis bullosa simplex with muscular dystrophy associated with PLEC deletion mutation.

Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; OMIM #226670) is an autosomal recessive disorder characterized by neonatal blistering and later-onset muscle weakness.

Randomized Trial of Thymectomy in Myasthenia Gravis.

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations.

Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype-phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of phosphorylated ChAT of seven CHAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys, and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal stability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp, and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met, which is located far from both active and substrate-binding sites, produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes.

Adverse outcome of early recurrent ischemic stroke secondary to atrial fibrillation after repeated systemic thrombolysis.

Background. Recurrent ischemic stroke is associated with adverse neurological outcome in patients with atrial fibrillation. There is very scarce information regarding the neurological outcome of atrial fibrillation patients undergoing repeated systemic thrombolysis after early recurrent ischemic stroke. Clinical Case and Discussion. We describe a case of a 76-year-old woman with known paroxysmal atrial fibrillation who was admitted because of an acute right middle cerebral artery ischemic stroke and who underwent repeated systemic thrombolysis within 110 hours. The patient underwent systemic thrombolysis after the first ischemic stroke with almost complete neurological recovery. On the fourth day after treatment, an acute left middle cerebral artery ischemic stroke was diagnosed and she was treated with full-dose intravenous recombinant tissue plasminogen activator. A hemorrhagic transformation of the left middle cerebral artery infarction was noted on follow-up cranial computed tomographic scans. The patient did not recover from the second cerebrovascular event and died 25 days after admission. Conclusion. To the best of our knowledge, this is the second case reporting the adverse neurological outcome of a patient with diagnosis of atrial fibrillation undergoing repeated systemic thrombolysis after early recurrent ischemic stroke. Our report represents a contribution to the scarce available evidence suggesting that repeated systemic thrombolysis for recurrent ischemic stroke should be avoided.

Morvan syndrome: clinical and serological observations in 29 cases.

OBJECTIVE: A study was undertaken to describe the clinical spectrum, voltage-gated potassium channel (VGKC) complex antibody specificities, and central nervous system localization of antibody binding in 29 patients diagnosed with Morvan syndrome (MoS). METHODS: Clinical data were collected using questionnaires. Radioimmunoassay, cell-based assays, and mouse brain immunohistochemistry were used to characterize the serum antibodies. RESULTS: Neuromyotonia (100%), neuropsychiatric features (insomnia 89.7%, confusion 65.5%, amnesia 55.6%, hallucinations 51.9%), dysautonomia (hyperhidrosis 86.2%, cardiovascular 48.3%), and neuropathic pain (62.1%) were the most common manifestations. A total of 93.1% of MoS patients were male. VGKC-complex antibodies were present in 23 of 29 (79%) MoS patients at referral; 24 of 27 available sera had CASPR2, LGI1, or both CASPR2 and LGI1 antibodies (3 also with contactin-2 antibodies). CASPR2 antibodies were generally higher titer than LGI1 antibodies. Tumors (41.4%), mainly thymomas, were associated with CASPR2 antibodies and a poor prognosis, whereas LGI1 antibodies were associated with serum hyponatremia. In brain tissue regions including the hypothalamus, raphe, and locus coeruleus, commercial antibodies to LGI1 bound to neuronal cell bodies including the antidiuretic hormone-secreting and orexin-secreting hypothalamic neurons, whereas CASPR2 commercial antibodies bound more often to the neuropil. MoS antibodies bound similarly, but there was evidence of additional antibodies in some sera that were not adsorbed by LGI1- or CASPR2-expressing cells and bound to mouse Caspr2(-/-) tissue. INTERPRETATION: MoS is clinically distinct from other VGKC-complex antibody-associated conditions, and usually is associated with high-titer CASPR2 antibodies, often accompanied by lower-titer LGI1 antibodies. CASPR2 and LGI1 antibodies bind to multiple brain regions, which helps to explain the multifocal clinical features of this disease, but other antibodies are likely to play a role in some patients and need to be characterized in future studies.

[Update on interventional treatment of acute ischemic stroke]. / Terapéuticas intervencionistas para el accidente cerebrovascular isquémico.

New options have been developed for the prevention and treatment of acute ischemic stroke in the last 20 years, such as carotid endarterectomy and intravenous thrombolysis with tissue plasminogen activator. Scientific evidence has supported their use in developed countries, while there is an evident delay in their use among emerging countries. Other promising modalities require the conclusion of ongoing randomized, controlled trials. Malignant middle or carotid cerebral artery infarction accounts for 10 to 15% ischemic strokes and constitutes a devastating event associated with high morbidity and mortality. Decompressive craniectomy seems to be an effective and safe approach for rapidly lowering intracranial pressure. Although randomized trials are lacking, there is enough evidence to support this surgical procedure in appropriately selected patients.

Miastenia gravis desencadenada por el uso de estatinas: presentación de once casos / Myasthenia gravis precipitated by statin use: presentation of eleven cases

Los inhibidores de 3-hidroxi-3 metil glutaril coenzima A reductasa (estatinas) son eficaces para el descenso de los nivelesde colesterol sérico y, consecuentemente, la prevención de la enfermedad isquémica cardíaca, cerebrovascular y vascularperiférica. Una de las principales limitaciones del uso de estas drogas es la aparición de sintomatología muscular como la elevación de la CK, mialgias, miositis o rabdomiolisis. La miastenia gravis (MG) es una enfermedad autoinmune caracterizada por la presencia de debilidad fluctuante de los músculos voluntarios. La enfermedad se desencadena por el ataque de anticuerpos dirigidos contra los receptores nicotínicosde acetilcolina (ACRA) localizados en la membrana del músculo a nivel de la unión neuromuscular. Existe un número interesante de fármacos que empeoran el curso de la enfermedad o que en algunos casos la "desenmascaran". Recientemente se publicaron casos de pacientes con MG que presentaron exacerbación de su enfermedad con laingesta de estatinas. Presentamos 11 pacientes que comenzaron con síntomas de MG luego de la toma de estas drogas. Seis recibieron atorvastatina (54.5%), tres simvastatina (27.3%) y dos rosuvastatina (18.2%).

3-hydroxi-3 metyl glutaryl coenzyme A reductase inhibitors, also known as statins, are effective in reducing plasmaticcholesterol and thus preventing cardiac, cerebral, and peripheral vascular ischemia. One of the main reasons that limit their use is the potential for muscular disorders, such as the increase of plasmatic CK, myalgia, myositis, and rhabdomyolysis. Myasthenia gravis (MG) is an autoimmune disease characterized by the presence of fluctuating voluntary muscle weakness. It is triggered by antibodies directed against nicotinic acetylcholine receptors (AChR) located at the neuromuscular junction, within the muscle membrane. A number of drugs may either unmask the disease or worsen it when installed. Recent publications have reported on cases of MG who aggravated their condition with the intake of statins. Here, we report on eleven patients who presented symptoms of MG after medication with statins. Six patients received atorvastatin (54.5%), three simvastatin (27.3%), and two rosuvastatin (18.2%).

Compromisso respiratorio en el sindrome de Guillain Barré / Respiratory failure associated with Guillian Barré syndrome

El compromiso severo de los músculos respiratorios en el Guillain Barré se observa en alrededor del 25 por ciento de los pacientes. Para evaluar las características y la evolución de este grupo se revisaron las historias clínicas de los pacientes que ingresaron a nuestro Hospital entre enero del 87 y diciembre del 96. De los 44 pacientes con compromiso respiratorio, el 70.5 por ciento requiró ARM (asistencia respiratoria mecánica). La edad fue de 34.0 + 14.1 años. El 70.5 por ciento era de sexo masculino. El tiempo entre el inicio de síntomas y el comienzo de la ARM fue de 9.4 + 8.0 días. El tiempo de ARM fue mayor en los pacientes con menos de 48 hs de evolución de la enfermedad (2 100 + 2 076 vs 934 + 735 hs p < 0.05). Todos los pacientes presentaron, el 43 tenía disautonomía y el 55 por ciento compromiso de pares craneanos. El 24 por ciento presentó serología positiva para citomegalovirus. La capacidad vital previa a la ARM fue de 1 050 + 378 ml. El tiempo de ventilación mecánica fue de 1 224 + 1 208 hs. Dos de las pacientes que sobreviveron superaron los 6 meses de ARM. La mortalidad fue del 18 por ciento. La edad fue mayor en los fallecidos (44.9 + 17.5 vs 31.9 + 12.5, p < 0.02). La capacidad vital de egreso fue de 2 837 + 1 080 ml. En nuestro grupo se evidenció alto porcentaje de ARM, predominancia del sexo masculino, mayor tiempo de ARM en pacientes con evolución más rápida y tiempo de ARM prolongado. La mortalidad se relacionó con mayor edad, sepsi, barotrauma y disautonomía severa. (AU)

Compromisso respiratorio en el sindrome de Guillain Barré / Respiratory failure associated with Guillian Barré syndrome

El compromiso severo de los músculos respiratorios en el Guillain Barré se observa en alrededor del 25 por ciento de los pacientes. Para evaluar las características y la evolución de este grupo se revisaron las historias clínicas de los pacientes que ingresaron a nuestro Hospital entre enero del '87 y diciembre del '96. De los 44 pacientes con compromiso respiratorio, el 70.5 por ciento requiró ARM (asistencia respiratoria mecánica). La edad fue de 34.0 + 14.1 años. El 70.5 por ciento era de sexo masculino. El tiempo entre el inicio de síntomas y el comienzo de la ARM fue de 9.4 + 8.0 días. El tiempo de ARM fue mayor en los pacientes con menos de 48 hs de evolución de la enfermedad (2 100 + 2 076 vs 934 + 735 hs p < 0.05). Todos los pacientes presentaron, el 43 tenía disautonomía y el 55 por ciento compromiso de pares craneanos. El 24 por ciento presentó serología positiva para citomegalovirus. La capacidad vital pre'via a la ARM fue de 1 050 + 378 ml. El tiempo de ventilación mecánica fue de 1 224 + 1 208 hs. Dos de las pacientes que sobreviveron superaron los 6 meses de ARM. La mortalidad fue del 18 por ciento. La edad fue mayor en los fallecidos (44.9 + 17.5 vs 31.9 + 12.5, p < 0.02). La capacidad vital de egreso fue de 2 837 + 1 080 ml. En nuestro grupo se evidenció alto porcentaje de ARM, predominancia del sexo masculino, mayor tiempo de ARM en pacientes con evolución más rápida y tiempo de ARM prolongado. La mortalidad se relacionó con mayor edad, sepsi, barotrauma y disautonomía severa.