Shortening the time to the diagnosis of amyotrophic lateral sclerosis: role of the neurologist.

Early diagnosis is particularly relevant in the diagnosis of amyotrophic lateral sclerosis (ALS) as new therapies, which may have a direct impact on the outcome of the disease, are being developed. Many ALS patients go to non-neurological specialists rather than neurologists for their first consultation. Neurologists specialized in the field of neuromuscular diseases therefore have a duty to help general neurologists and other non-neurological specialists to recognize the disease. This may be achieved by disseminating the El Escorial/Airlie House clinical and electrophysiological criteria for the diagnosis of ALS as well as by emphasizing that ALS is a manageable condition. Neurologists should collaborate better with patient organizations as well as reinforce public awareness of ALS.

Current treatment pathways in ALS: a South American perspective.

This article presents the findings relating to the South American subgroup of 60 patients in an international survey of the current diagnosis and treatment of patients with amyotrophic lateral sclerosis (ALS). The mean time between first symptoms and first consultation with a physician was 3.7 months, and mean delay in seeing a neurologist was then 5.6 months, giving a mean time from symptom onset to confirmation of diagnosis of 16.6 months. The time to confirmation of diagnosis was much longer for patients with symptoms of limb onset (17.5 months) than for those with bulbar onset (10.0 months). Cases with symptoms of upper-limb onset were diagnosed more rapidly (14.9 months) than those with symptoms of lower-limb onset (21.8 months). The diagnosis was confirmed in 48% of cases within 15 months of symptom onset, and a further 27% were diagnosed within 15-24 months; 47% of cases were confirmed within 4 months of consulation with a neurologist and a further 17% within 4-6 months. The first physician seen was the general practitioner in 47% of cases overall. When the neurologist was the first physician seen (27% of patients in Brazil, 0% in Argentina), diagnosis was achieved within 14 months in 88% of cases. EMG was performed in almost all patients. MRI and CT were widely used, which may cause delays. Announcement of the diagnosis was made immediately to 75% of patients overall. Riluzole was prescribed for 23% of patients in Brazil and for 67% of patients in Argentina.

Uptake of immunoglobulin G from amyotrophic lateral sclerosis patients by motor nerve terminals in mice.

Clinical and experimental evidence support an autoimmune etiopathogenesis for amyotrophic lateral sclerosis (ALS). We have shown that local application of ALS-IgG onto nerve terminals induces dysfunction in transmission at the neuromuscular junction. It has been established that IgG and other circulating serum proteins can be taken up by motor nerve terminals, being immunolocalized in the soma where they accumulate following retrograde axonal transport. In the present study, we investigated the presence of human ALS and control IgG in the soma of mouse motoneurons. IgG was applied onto motor nerve terminals of mice by subcutaneous injections on the left levator auris longus muscle which is innervated by a branch of the facial nerve. After several injections, sections of the brainstem containing the facial nuclei were immunoprocessed to detect human IgG. For all IgG tested, motoneuron labeling was significantly more intense in the facial nucleus ipsilateral to the site of injection. In ALS-IgG-treated animals, ipsilateral labeling was significantly stronger than that found on the ipsilateral side of control IgG-treated animals. Our results are compatible with the concept that motoneurons preferentially take up, transport and/or accumulate ALS-IgG. Uptake of pathogenic antibodies by motoneuron terminals may play a role in the pathogenesis of motoneuron disease.

Duchenne muscular dystrophy and myotonic dystrophy in the same patient.

We report on the first patient identified with myotonic dystrophy and Duchenne muscular dystrophy (DMD). The family of the propositus had a strong history of myotonic dystrophy, and there was an intrafamilial pathological expansion of the responsible CTG repeat between the mildly affected mother (160 repeats; normal 27 repeats) and her more severely affected son (650 repeats), and his sister (650 repeats). The propositus was an isolated case of Duchenne muscular dystrophy with marked dystrophin deficiency in muscle biopsy. The patient was still ambulatory post age 16. Myotonic dystrophy could interfere to some extent with the progression of Duchenne dystrophy. However, other interpretations are possible. Twelve percent of dystrophin revertant fibers as observed by immunohistochemistry could be sufficient to ameliorate typical DMD clinical severity, or the patient may present a somatic mosaic. The pathophysiological interactions of these two unlinked disorders are discussed at the clinical and histopathological levels.

Steroids in Duchenne muscular dystrophy--deflazacort trial.

We conducted a double blind controlled trial in 28 Duchenne muscular dystrophy (DMD) patients with Deflazacort (DF), an oxazoline derivative of prednisolone which reduces its side-effects. Myometric muscle strength measurements, Scott Score and timed tests showed statistically significant improvement for the treated group (P less than 0.05). Side-effects after 9 months of treatment included mild cushingoid appearance in four patients (28%) and moderate in only one (7%), increased appetite in seven (50%), increased body hair in four (28%), irritability and hyperactivity in three (21%). Increased body weight was not prominent and was controlled with dietary measures. No patient had to be withdrawn from medication. More research and long-term follow-up are needed in order to establish the mechanism of improvement and the consequences of long-term steroid administration in DMD. In this regard DF appears as an alternative to prednisone preserving its benefits but with fewer side-effects.

Ca-dependent slow action potentials in human skeletal muscle.

Slow Ca-action potentials (CaAP) were studied in normal human skeletal muscle fibers obtained during surgery (fibers with both ends cut). Control studies also were carried out with intact as well as cut rat skeletal muscle fibers. Experiments were performed in hypertonic Cl-free saline with 10 or 84 mM Ca and K-channel blockers; muscles were preincubated in a saline containing Cs and tetraethylammonium. A current-clamp technique with two intracellular microelectrodes was used. In human muscle, 14.5% of the fibers showed fully developed CaAPs, 21% displayed nonregenerative Ca responses, and 64.5% showed only passive responses; CaAPs were never observed in 10 mM Ca. In rat muscle, nearly 90% of the fibers showed CaAPs, which were not affected by the cut-end condition. Human and rat muscle fibers had similar membrane potential and conductance in the resting state. In human muscle (22-32 degrees C, 84 mM Ca), the threshold and peak potential during a CaAP were +26 +/- 6 mV and +70 +/- 3 mV, respectively, and the duration measured at threshold level was 1.7 +/- 0.5 sec. In rat muscle, the duration was four times longer. During a CaAP, membrane conductance was assumed to be a leak conductance in parallel with a Ca and a K conductance. In human muscle (22-32 degrees C, 84 mM Ca, 40 micron fiber diameter), values were 0.4 +/- 0.1 microS, 1.1 +/- 0.7 microS, and 0.9 +/- 0.4 microS, respectively. Rat muscle (22-24 degrees C, 84 mM Ca) showed leak and K conductances similar to those found in human fibers. Ca-conductance in rat muscle was double the values obtained in human muscle fibers.

Type I striated muscular fiber hypotrophy with central nuclei.

Las enfermedades neuromusculares son frecuente causa de hipotonia en la infancia. Entre las enfermedades neuromusculares congenitas, se destaca la hipotrofia tipo I con nucleos centrales. Se presenta un paciente de 7 1/2 anos, con una historia de hipotonia y retardo motor, afectado de esta enfermedad. El EMG revelo potenciales de corta duracion.La biopsia muscular demostro la presencia de hipotrofia de fibras tipo I con un alto porcentaje de nucleos centrales. Un defecto en la maduracion de las fibras tipo I secundario a un deficit metabolico o trofico de las motoneuronas tipo I, podria ser el mecanismo patogenico. La presencia o ausencia de areas claras centrales alrededor de los nucleos podria explicarse por la incidencia del corte y por el estado madurativo de la fibra en el momento de la biopsia. La heterogeneidad genetica, clinica e incluso histopatologica de los casos de la literatura sugieren la posibilidad de que existan muchas variantes de la misma entidad

Histoquimica de los musculos extraoculares humanos. / Histochemistry of the human extraocular muscles

Los musculos extraoculares constituyen uno de los sistemas mas organizados de la economia por tener caracteristicas electrofisiologicas farmacologicas y ultraestructurales que las diferencian de los nucleos esqueleticos.Sin embargo, los estudios histoquimicos realizados son escasos. Se estudian los rectos laterales y mediales de 6 pacientes enucleados por enfermedad intrabulbar. Las caracteristicas histoquimicas de las fibras musculares, permiten diferenciar 3 tipos: atigradas, granulares y lisas que se dispone en forma concentrica. Se ponen de manifiesto las diferenciais en la estructura e histoquimica de los MEO con los esqueleticos. Muchas de las imagenes histoquimicas normales en los MEO, son consideradas patologicas en musculos esqueleticos, debiendose tener entonces precaucion en la interpretacion de los resultados

Type I striated muscular fiber hypotrophy with central nuclei.

Las enfermedades neuromusculares son frecuente causa de hipotonia en la infancia. Entre las enfermedades neuromusculares congenitas, se destaca la hipotrofia tipo I con nucleos centrales. Se presenta un paciente de 7 1/2 anos, con una historia de hipotonia y retardo motor, afectado de esta enfermedad. El EMG revelo potenciales de corta duracion.La biopsia muscular demostro la presencia de hipotrofia de fibras tipo I con un alto porcentaje de nucleos centrales. Un defecto en la maduracion de las fibras tipo I secundario a un deficit metabolico o trofico de las motoneuronas tipo I, podria ser el mecanismo patogenico. La presencia o ausencia de areas claras centrales alrededor de los nucleos podria explicarse por la incidencia del corte y por el estado madurativo de la fibra en el momento de la biopsia. La heterogeneidad genetica, clinica e incluso histopatologica de los casos de la literatura sugieren la posibilidad de que existan muchas variantes de la misma entidad

Histoquimica de los musculos extraoculares humanos. / Histochemistry of the human extraocular muscles

Los musculos extraoculares constituyen uno de los sistemas mas organizados de la economia por tener caracteristicas electrofisiologicas farmacologicas y ultraestructurales que las diferencian de los nucleos esqueleticos.Sin embargo, los estudios histoquimicos realizados son escasos. Se estudian los rectos laterales y mediales de 6 pacientes enucleados por enfermedad intrabulbar. Las caracteristicas histoquimicas de las fibras musculares, permiten diferenciar 3 tipos: atigradas, granulares y lisas que se dispone en forma concentrica. Se ponen de manifiesto las diferenciais en la estructura e histoquimica de los MEO con los esqueleticos. Muchas de las imagenes histoquimicas normales en los MEO, son consideradas patologicas en musculos esqueleticos, debiendose tener entonces precaucion en la interpretacion de los resultados