Myasthenia gravis: descriptive analysis of life-threatening events in a recent nationwide registry.

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) may become life-threatening if patients have respiratory insufficiency or dysphagia. This study aimed to determine the incidence, demographic characteristics, risk factors, response to treatment and outcome of these life-threatening events (LTEs) in a recent, population-based sample of MG patients. METHODS: A retrospective analysis of MG patients who presented with an LTE between 2000 and 2013 was performed. Participants were identified from a neuromuscular diseases registry in Spain that includes 648 patients with MG (NMD-ES). RESULTS: Sixty-two (9.56%) patients had an LTE. Thirty-two were classified as class V according to the MG Foundation of America, and 30 as class IVB. Fifty per cent were previously diagnosed with MG and median duration of the disease before the LTE was 24 months (3-406). The most common related factor was infection (n = 18). All patients received intravenous human immunoglobulin; 11 had a second infusion and six had plasma exchange. Median time to feeding tube removal was 13 days (1-434). Median time to weaning from ventilation was 12 days (3-176), and it was significantly shorter in late onset MG (≥50 years) (P = 0.019). LTEs improved <2 weeks in 55.8% but did not improve until after 1 month in 20% of patients. Four patients died. No other factors influenced mortality or duration of LTEs. CONCLUSIONS: The percentage of LTEs in MG patients was low, particularly amongst those previously diagnosed and treated for the disease. The significant percentage of treatment-resistant LTEs indicates that more effective treatment approaches are needed for this vulnerable sub-population.

Identification and biochemical characterization of the novel mutation m.8839G>C in the mitochondrial ATP6 gene associated with NARP syndrome.

Mutations in the ATP6 gene are reported to be associated with Leber hereditary optic neuropathy, bilateral striatal necrosis, coronary atherosclerosis risk and neuropathy, ataxia and retinitis pigmentosa (NARP)/maternally inherited Leigh syndromes. Here, we present a patient with NARP syndrome, in whom a previously undescribed mutation was detected in the ATP6 gene: m.8839G>C. Several observations support the concept that m.8839G>C is pathogenically involved in the clinical phenotype of this patient: (1) the mutation was heteroplasmic in muscle; (2) mutation load was higher in the symptomatic patient than in the asymptomatic carriers; (3) cybrids carrying this mutation presented lower cell proliferation, increased mitochondrial DNA (mtDNA) copy number, increased steady-state OxPhos protein levels and decreased mitochondrial membrane potential with respect to isogenic wild-type cybrids; (4) this change was not observed in 2959 human mtDNAs from different mitochondrial haplogroups; (5) the affected amino acid was conserved in all the ATP6 sequences analyzed; and (6) using in silico prediction, the mutation was classified as 'probably damaging'. However, measurement of ATP synthesis showed no differences between wild-type and mutated cybrids. Thus, we suggest that m.8839G>C may lower the efficiency between proton translocation within F0 and F1 rotation, required for ATP synthesis. Further experiments are needed to fully characterize the molecular mechanisms involved in m.8839G>C pathogenicity.

[Guillain-Barre syndrome and IVIg: does early initiation of treatment influence the mean hospital stay?]. / Síndrome de Guillain-Barré e IVIg: ¿influye la instauración precoz del tratamiento en la estancia media hospitalaria?

INTRODUCTION: Treatment with intravenous immunoglobin (IVIg) in the first two weeks of hospitalization has proven efficiency for shortening recovery time of patients with Guillain- Barré syndrome (GBS). The goal of the study is to determine if early treatment with IVIg in the first days after onset of symptoms has a significant effect on shortening average length of hospital stay. METHODS: We examined retrospectively the records of 69 patients with GBS. Group A (9 patients) received no treatment with IVIg, Group B (31 patients) received treatment on the sixth day or thereafter and Group C (29 patients) received treatment in the first five days from symptoms onset. RESULTS: Mean duration of hospitalisation time for Group A was 47.4 days, for Group B it was 32.4 days and for Group C, 21.3 days (p < 0.001). In summary, treatment with IVIg in the first five days after the onset of GBS symptoms reduces the length of hospitalisation by 11 days. Given the retrospective nature of our study, these findings should be confirmed in a prospective, randomised, multicentric study.

Síndrome de Guillain-Barré e IVIg: ¿influye la instauración precoz del tratamiento en la estancia media hospitalaria? / Guillain-Barre síndrome and IVIg: does early initiation of treatment influence the mean hospital stay?

Introducción. El tratamiento con inmunoglobinas (IVIg) administradas en las 2 primeras semanas del inicio de la clínica se ha demostrado eficaz para acortar el tiempo de recuperación de pacientes Guillain-Barré (GBS). El objetivo del trabajo consiste en averiguar si la administración precoz de IVIg en los primeros días del inicio de los síntomas influye de forma significativa en el acortamiento de la estancia media hospitalaria. Métodos. Se revisaron retrospectivamente 69 pacientes con GBS. El Grupo A (9 pacientes) no recibió tratamiento con IVIg, el grupo B (31 pacientes) recibió el tratamiento a partir del sexto día y el grupo C (29 pacientes) recibió el tratamiento en los 5 primeros días. Resultados. La estancia media para el Grupo A fue de 47,4 días; Grupo B, 32,4 días, y Grupo C, 21, 3 días (p < 0,001). En conclusión, la administración de IVIg en los primeros 5 días desde el inicio de los síntomas de un GBS acorta la estancia media hospitalaria en 11 días. Dado el carácter retrospectivo de nuestro trabajo, sería necesario realizar un estudio prospectivo, aleatorizado y multicéntrico para confirmar estos resultados (AU)

Introduction: Treatment with intravenous immunoglobin (IVIg) in the first two weeks of hospitalization has proven efficiency for shortening recovery time of patients with Guillain- Barré syndrome (GBS). The goal of the study is to determine if early treatment with IVIg in the first days after onset of symptoms has a significant effect on shortening average length of hospital stay. Methods: We examined retrospectively the records of 69 patients with GBS. Group A (9 patients) received no treatment with IVIg, Group B (31 patients) received treatment on the sixth day or thereafter and Group C (29 patients) received treatment in the first five days from symptoms onset. Results: Mean duration of hospitalisation time for Group A was 47.4 days, for Group B it was 32.4 days and for Group C, 21.3 days (p < 0.001). In summary, treatment with IVIg in the first five days after the onset of GBS symptoms reduces the length of hospitalisation by 11 days. Given the retrospective nature of our study, these findings should be confirmed in a prospective, randomised, multicentric study (AU)

[Survey on the current situation of the young neurologists in Spain: analysis of their current working stability and degree of social protection]. / Encuesta sobre la situación actual de los neurólogos jóvenes en España: análisis de la estabilidad laboral y de la protección social.

INTRODUCTION: The aims of this study were to evaluate the working stability and degree of social protection of the Spanish young neurologists, and to know their opinion about their own situation. METHODS: The 343 neurologists that became specialists in Spain between 2000 and 2004 were asked to participate in two consecutive surveys. The first, conducted online, included questions about the availability to change the place of work and the opinion about the situation of young neurologists, and obtained 66 answers. The second was a telephonic and online survey, answered by 217 neurologists, whose questions referred to: places of neurological education and work, type of working contract, and degree of social protection (estimated by the percentage of worked time during which they paid Social Security contributions). RESULTS: Sixty-three per cent (136/217) of the Spanish young neurologists had an unstable job. The most frequent unstable working contracts were: eventual (n=65; 31%), on-call contracts (n=54; 25%) and grants (n=53; 24%). Forty-eight per cent of the neurologists who ended their specialization in 2000 still remained working-unstable. The mean percentage of worked time with full social protection was 71.01+/-36.74%. Less than a half (n=101; 46%) had social protection during the entire worked time, 60 (28.6%) were socially protected during <50% of the worked time, and 23 (11%) never had social protection. A direct relationship was observed 68 between working instability and lower social protection (p=0.0002). The working situation of the Spanish young neurologists was seen as problematic by 97% of the 66 participants in the first survey. CONCLUSIONS: The current situation of the Spanish young neurologists, attending their working stability and degree of social protection, seems precarious and problematic. Urgent actions should be taken by the Administration to improve it.

Encuesta sobre la situación actual de los neurólogos jóvenes en España: análisis de la estabilidad laboral y de la protección social / Survey on the current situation of the young neurologists in Spain: analysis of their current working stability and degree of social protection

Introducción. No existen estudios que hayan analizado la problemática laboral de los neurólogos jóvenes. Este trabajo tuvo como objetivos evaluar la estabilidad laboral y grado de protección social de los neurólogos jóvenes en España y conocer la visión que éstos tienen sobre su propia situación. Métodos. Sobre una muestra total de 343 neurólogos que acabaron su formación especializada en España entre 2000 y 2004 se realizaron dos encuestas consecutivas (electrónica y electrónica más telefónica], obteniéndose datos de 66 y de 217 neurólogos, respectivamente. En la primera se preguntó por la disponibilidad de desplazamiento en caso de contrato inestable y por la impresión sobre la situación de la neurología joven. La segunda versó sobre los lugares de formación y trabajo actual, la estabilidad laboral y la protección social (porcentaje del tiempo trabajado cotizado a la Seguridad Social). Resultados. El 63 % (136/217) de los neurólogos encuestados se encontraba en situación laboral inestable. Los tipos de contrato inestable más frecuentes fueron: contratos eventuales (n = 65; 31 %), contratos de guardias (n = 54; 25%) Y becas (n=53; 24%). Un 48% de los neurólogos titulados en 2000 permanecía en situación laboral inestable. El porcentaje medio de tiempo cotizado a la Seguridad Social fue de 71,01 :t36,74%. Menos de la mitad (46%) de los encuesta dos cotizó el 100% del tiempo trabajado, un 28,6% cotizó durante menos del 50% y un 11 % no cotizó nunca. Se observó una relación directa entre inestabilidad laboral y mayor desprotección social (p=0,0002). En la otra encuesta, el 97% de los 66 encuestados consideró que la situación actual de la neurología joven se podía calificar de problemática. Conclusiones. La situación actual de los neurólogos jóvenes en España, en lo que se refiere a estabilidad laboral y protección social, es muy precaria y problemática. Dada la creciente demanda social de la neurología es necesaria una planificación adecuada de las necesidades y los recursos por parte de la Administración para mejorar la situación laboral de los neurólogos jóvenes

Introduction. The aims of this study were to evaluate the working stability and degree of social protection of the Spanish young neurologists, and to know their opinion about their own situation. Methods. The 343 neurologists that became specialists in Spain between 2000 and 2004 were asked to participate in two consecutive surveys. The first, conducted online, included questions about the availability to change the place of work and the opinion about the situation of young neurologists, and obtained 66 answers. The second was a telephonic and online survey, answered by 217 neurologists, whose questions referred to: places of neurological education and work, type of working contract, and degree of social protection (estimated by the percentage of worked time during which they paid Social Security contributions). Results. Sixty-three per cent (136/217) of the Spanish young neurologists had an unstable job. The most frequent unstable working contracts were: eventual (n=65; 31 %), on-call contracts (n=54; 25%) and grants (n = 53; 24 %). Forty-eight per cent of the neurologists who ended their specialization in 2000 still remained working-unstable. The mean percentage of worked time with full social protection was 71.01 :t36.74%. Less than a half (n = 10 1; 46 %) had social protection during the entire worked time, 60 (28,6 %) were socially protected during < 50% of the worked time, and 23 (11 %) never had social protection. A direct relationship was observed between working instability and lower social protection (p = 0.0002). The working situation of the Spanish young neurologists was seen as problematic by 97 % of the 66 participants in the first survey. Conclusions. The current situation of the Spanish young neurologists, attending their working stability and degree of social protection, seems precarious and problematic. Urgent actions should be taken by the Administration to improve it

[Chloroquine-induced myopathy and neuropathy: progressive tetraparesis with areflexia that simulates a polyradiculoneuropathy. Two case reports]. / Miopatía y neuropatía inducida por cloroquina: tetraparesia progresiva con arreflexia que simula una polirradiculoneuropatía. A propósito de dos casos.

INTRODUCTION: Chloroquine is a drug that is widely used in rheumatology and occasionally prescribed in dermatology. From a neurotoxicological point of view, chloroquine can have effects on the peripheral nerves, muscles, neuromuscular junctions and the central nervous system. In this study we analyse the clinical, neurophysiological and anatomopathological findings in two patients with chloroquine induced neuromyopathy, which took the form of a polyradiculoneuropathy. CASE REPORTS: Case 1: a 75 year old female with rheumatoid arthritis treated with daily doses of 250 mg of chloroquine for four years. The patient visited because of several months history of predominantly proximal progressive tetraparesis with areflexia. Analytical tests and lumbar puncture were normal. Electromyogram (EMG): proximal myopathic and distal neuropathic patterns. Muscular biopsy: vacuolar myopathy with accumulations of phagolysosomes, lipids, lipofuscin, myelinic curvilinear bodies. Case 2: a 74 year old female with arthropathy treated with daily doses of 250 mg of chloroquine for nine months. The patient presented a progressive proximal paraparesis with generalised areflexia. Analytical tests and lumbar puncture were normal. EMG: mixed sensory motor polyneuropathy, myogenic pattern with high frequency discharges in the iliac psoas and a neurogenic pattern in the distal muscles. Muscular biopsy: vacuolar myopathy suggesting a myopathy due to chloroquine. After stopping treatment with this drug the patients progressed favourably. CONCLUSION: Chloroquine can induce a clinical pattern that suggests a polyradiculoneuropathy. It is important to establish a history of having taken this drug. If this is indeed the case, then an electromyographic study of the most proximal muscles should be performed in order to detect a myogenic pattern and the same exploration should be applied to the distal muscles to reveal a neurogenic pattern. The final diagnosis will be established by muscular biopsy.

Miopatía y neuropatía inducida por cloroquina: tetraparesia progresiva con arreflexia que simula una polirradiculoneuropatía. A propósito de dos casos / Chloroquine-induced myopathy and neuropathy: progressive tetraparesis with areflexia that simulates a polyradiculoneuropathy. Two case reports

Introducción. La cloroquina es un fármaco ampliamente utilizado en reumatología y, ocasionalmente, en dermatología. Desde el punto de vista neurotoxicológico, la cloroquina puede afectar a los nervios periféricos, a los músculos, a la unión neuromuscular y al sistema nervioso central. En el presente trabajo se analizan los hallazgos clínicos, neurofisiológicos y anatomopatológicos de dos pacientes con una neuromiopatía inducida por cloroquina, que se manifestaron como una polirradiculoneuropatía. Casos clínicos. Caso 1. Mujer de 75 años con artritis reumatoide tratada con cloroquina 250 mg/día durante cuatro años. Consultó por tetraparesia progresiva de predominio proximal de meses de evolución con arreflexia. Las pruebas analíticas y la punción lumbar fueron normales. Electromiograma (EMG): patrones miopáticos proximales y neuropáticos distales. Biopsia muscular: miopatía vacuolar con acúmulo de fagolisosomas, lípidos, lipofucsina, cuerpos mielínicos y curvilíneos. Caso 2. Mujer de 74 años con artropatía tratada con cloroquina 250 mg/día durante nueve meses. Presentó una paraparesia proximal progresiva con arreflexia universal. Las pruebas analíticas y la punción lumbar fueron normales. EMG: polineuropatia mixta sensitivomotora, patrón miógeno con descargas de alta frecuencia en psoas ilíaco y patrón neurógeno en los músculos distales. Biopsia muscular: miopatía vacuolar sugestiva de miopatía por cloroquina. Tras la retirada de la medicación presentaron una evolución favorable de la clínica. Conclusión. La cloroquina puede inducir un cuadro clínico sugestivo de polirradiculoneuropatía. Es importante interrogar sobre el antecedente de ingesta del fármaco. En caso positivo tiene interés el estudio electromiográfico de los músculos más proximales para detectar patrón miógeno y de los músculos distales para evidenciar patrón neurógeno. La biopsia muscular establecerá el diagnóstico definitivo (AU)

Chloroquine is a drug that is widely used in rheumatology and occasionally prescribed in dermatology. From a neurotoxicological point of view, chloroquine can have effects on the peripheral nerves, muscles, neuromuscular junctions and the central nervous system. In this study we analyse the clinical, neurophysiological and anatomopathological findings in two patients with chloroquine-induced neuromyopathy, which took the form of a polyradiculoneuropathy. Case reports. Case 1: a 75-year-old female with rheumatoid arthritis treated with daily doses of 250 mg of chloroquine for four years. The patient visited because of several months’ history of predominantly proximal progressive tetraparesis with areflexia. Analytical tests and lumbar puncture were normal. Electromyogram (EMG): proximal myopathic and distal neuropathic patterns. Muscular biopsy: vacuolar myopathy with accumulations of phagolysosomes, lipids, lipofuscin, myelinic curvilinear bodies. Case 2: a 74-year-old female with arthropathy treated with daily doses of 250 mg of chloroquine for nine months. The patient presented a progressive proximal paraparesis with generalised areflexia. Analytical tests and lumbar puncture were normal. EMG: mixed sensory-motor polyneuropathy, myogenic pattern with high frequency discharges in the iliac psoas and a neurogenic pattern in the distal muscles. Muscular biopsy: vacuolar myopathy suggesting a myopathy due to chloroquine. After stopping treatment with this drug the patients progressed favourably. Conclusion. Chloroquine can induce a clinical pattern that suggests a polyradiculoneuropathy. It is important to establish a history of having taken this drug. If this is indeed the case, then an electromyographic study of the most proximal muscles should be performed in order to detect a myogenic pattern and the same exploration should be applied to the distal muscles to reveal a neurogenic pattern. The final diagnosis will be established by muscular biopsy (AU)

Neuropatía por vasculitis necrotizante: estudio anatomoclínicoy neurofisiológico y evolución terapéutica de 26 pacientes / Neuropathy due to necrotizing vasculitis: a study of the anatomoclinical and neurophysiological characteristics, and those of the clinical course, of the disorder in 26 patients

Introducción. La neuropatía periférica suele ser uno de los síntomas iniciales de las vasculitis necrotizantes y el diagnóstico temprano es fundamental para el pronóstico. Objetivo. Determinar qué parámetros son útiles para el diagnóstico precoz y elección del tejido para realizar la biopsia. Pacientes y métodos. Se han analizado los datos clínicos, biológicos, electromiográficos y anatomopatológicos de 26 pacientes afectos de vasculitis necrotizante y con neuropatía periférica. Resultados. 12 pacientes padecían una panarteritis nodosa, 3 una enfermedad de Churg-Strauss, 2 Wegener, 2 lupus eritematoso diseminado, 1 sarcoidosis y 1 paciente macroglobulinemia de Waldeström. 15 pacientes padecían multineuritis y el resto una polineuropatía mixta distal, siendo en tres casos simétrica. En 5 pacientes la biopsia fue negativa. La biopsia del nervio sural fue positiva para el diagnóstico en un 20 por ciento de los casos, pero si se realizaba en un nervio neurofisiológicamente afectado aumentaba el rendimiento al 61 por ciento. La biopsia del músculo gemelo incrementaba la rentabilidad hasta el 73 por ciento si se detectaban anomalías electromiográficas en él. Conclusiones. El estudio neurofisiológico es imprescindible para detectar alteraciones en pacientes con la sospecha clínica de vasculitis necrotizante, aun en casos aparentemente libres de neuropatía. Se recomienda la biopsia del músculo gemelo como primera elección si las neurografías de los nervios surales son normales. Si la neurografía del nervio sural está alterada, la biopsia de nervio sería de primera elección y la biopsia de músculo sería la segunda. En caso de negatividad de ambas biopsias, debe considerarse la biopsia renal como tercer procedimiento diagnóstico (AU)

[Neuropathy due to necrotizing vasculitis: a study of the clinical anatomy, neurophysiological characteristics, and clinical course of the disorder in 27 patients]. / Neuropatía por vasculitis necrotizante: estudio anatomoclínico, neurofisiológico y evolución terapéutica de 26 pacientes.

INTRODUCTION: Peripheral neuropathy is usually one of the initial symptoms of necrotizing vasculitis. Early diagnosis is essential for good prognosis. OBJECTIVE: To determine which parameters are useful for early diagnosis and selection of tissue for biopsy. PATIENTS AND METHODS: We analyzed the clinical, biological, electromyographic and anatomopathological characteristics of 26 patients with necrotizing vasculitis and peripheral neuropathy. RESULTS: Twelve patients had panarteritis nodosa, three Churg Strauss syndrome, two Wegener s syndrome, two disseminated lupus erythematosis, one sarcoidosis and one Walderstrom s macroglobulinemia. Fifteen patients had multineuritis and the remainder distal mixed polyneuropathy which was symmetrical in three cases. In five cases biopsy was normal. Sural nerve biopsy showed the diagnosis to be correct in 20% of the patients. However, when this was done on a neurophysiologically affected nerve, the tissue was seen to be altered in 61%. Biopsy of the gastrocnemius increased the degree of usefulness to 73% when electromyographic anomalies were detected in this muscle. CONCLUSIONS: Neurophysiological study is essential for detection of alterations in patients clinically suspected of having necrotizing vasculitis, even in cases where there is apparently no neuropathy. We recommend biopsy of the gastrocnemius muscle as the first choice in cases where sural nerve neurography is found to be normal. If the sural nerve is not normal, it is the site of choice for biopsy, and muscle biopsy is the site of second choice. When both biopsies are normal, renal biopsy should be considered to establish the diagnosis, as a third alternative.

[Mitochondrial encephalomyelitis, lactic acidosis and cerebrovascular accidents (MELAS) in pediatric age with the A3243G mutation in the tRNALeu(UUR) gene of mitochondrial DNA]. / Encefalomiopatía mitocondrial, acidosis láctica y accidentes cerebrovasculares (MELAS) en edad pediátrica con la mutación A3243G en el gen del ARNtLeu(UUR) del ADN mitocondrial.

OBJECTIVES: To evaluate three patients with the mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) diagnosed in childhood, with particular reference to the initial symptoms and clinical evolution during the first stage at a pediatric age, and to compare them with other studies on the subject. PATIENTS AND METHODS: Two boys and a girl of 10, 11 and 13 years had tests on lactate, pyruvate and aminoacids in biological fluids under basal conditions and also functional tests and enzyme activity assay of the mitochondrial respiratory chain of a muscle biopsy. We also analysed the particular DNA mutations related to MELAS in different tissues from these patients and in lymphocytes from members of the mothers' families who could be tested. RESULTS: The patients fulfilled the clinical criteria for the MELAS syndrome. Neuroimaging showed cerebrovascular accidents. Neurophysiological studies showed myopathy in one patient and neuroaxonal neuropathy in another. In two cases ophthalmological study showed retinitis pigmentaria and during cerebrovascular accidents transient phenomena of homonymous hemianopsia and cortical blindness were seen. In all patients muscle biopsy showed ragged red fibres and the biochemical study showed an enzyme deficit in the respiratory mitochondrial chain. On molecular genetic study of the mitochondrial DNA (mtDNA) there was a particular mutation A3243G on the tRNA(Leu) in all patients and some members of the mothers' families. CONCLUSIONS: In children with frequent episodes of migraine headaches, vomiting, refractory epilepsy and fatigue the presence of a mitochondrial disease should be suspected. On detection of mtDNA mutations MELAS may be diagnosed even without all the clinical criteria which characterise this syndrome.

Encefalomiopatía mitocondrial, acidosis lácticay accidentes cerebrovasculares (MELAS) en edad pediátricacon la mutación A3243G en el gen del ARNtLeu(UUR)del ADN mitocondrial / Mitochondrial encephalomyopathy, lactic acidosis and cerebrovascular accidents (MELAS) in children with the A3243G mutation of the tRNA(Leu)(UUR) gene of DNA mitochondria

Objetivos. Evaluar tres pacientes afectos de síndrome de encefalopatía mitocondrial, acidosis láctica y accidentes cerebrovasculares (MELAS) con diagnóstico en la infancia; en especial, los síntomas iniciales y la evolución clínica durante los primeros estadios en edad pediátrica, y compararlos con los descritos en otros estudios publicados sobre el tema. Pacientes y métodos. Dos varones y una mujer de 10, 11 y 13 años, a quienes se realizaron determinaciones de lactato, piruvato y aminoácidos en fluidos biológicos en condiciones basales, así como, tras pruebas funcionales y de las actividades enzimáticas de la cadena respiratoria mitocondrial, en biopsia muscular. Se analizaron también las mutaciones puntuales del ADN relacionadas con MELAS en diferentes tejidos de los pacientes y en linfocitos de sus familiares de línea materna disponibles. Resultados. Los enfermos cumplían los criterios clínicos de síndrome de MELAS. La neuroimagen demostró los accidentes cerebrovasculares. Los estudios neurofisiológicos mostraron en un paciente una miopatía y en otro una neuropatía neuroaxonal. En dos casos, el estudio oftalmológico reveló una retinitis pigmentaria y, en el transcurso de los accidentes cerebrovasculares, se observaron fenómenos transitorios de hemianopsia homónima y ceguera cortical. La biopsia muscular mostró en todos los enfermos fibras rojo rasgadas y el estudio bioquímico, un déficit enzimático de la cadena respiratoria mitocondrial. El estudio genético molecular del ADN mitocondrial (ADNmt) detectó la presencia de la mutación puntual A3243G del gen del ARNtLeu en todos los pacientes y en algunos familiares de línea materna. Conclusiones. En niños con episodios frecuentes de cefalea migrañosa, vómitos, epilepsia rebelde y fatiga debemos sospechar una enfermedad mitocondrial. Con la detección de mutaciones de ADNmt, el diagnóstico de MELAS puede realizarse sin que hayan aparecido aún todos los criterios clínicos que caracterizan este síndrome (AU)

[Diagnostic strategy for mitochondrial diseases]. / Estrategia diagnóstica de las enfermedades mitocondriales.

OBJECTIVE: The variability of both phenotypic and genotypic expression in mitochondrial diseases makes clinical diagnosis difficult, which is essential to establish therapy, aid in genetic counselling or for performing prenatal diagnosis. We have therefore proposed a strategy to help determine correct diagnosis of these alterations, in an attempt to rationalize the number of tests and, whenever possible, avoid tissue biopsy and minimize the size of the biopsy when indicated. DEVELOPMENT: Based on mitochondrial metabolism and molecular bases, as well as their alterations, a preliminary metabolic examination is carried out including at least one study of cytoplasmatic (lactate/pyruvate) and mitochondrial oxide reduction (hydroxibutirate/acetoacetate) in basal conditions or, if required, following glucose overload or an effort test. Metabolic study, in addition to clinical exploration, are the screening tests used to determine the need for tissue biopsy in which biochemical (pyruvate dehydrogenase, free and total carnitine, beta oxidation enzymes and respiratory chain complexes), genetic (mitochondrial DNA or nuclear alterations) and histologic tests are carried out to confirm diagnosis. CONCLUSIONS: a) Metabolic exploration may discard mitochondrial disease and many cases, avoid the use of an invasive procedure such as tissue biopsy. b) Biochemical study of tissue biopsy is the only useful key in the confirming of the diagnosis when no mitochondrial and/or nuclear DNA are observed.

Brain pyruvate oxidation in experimental thiamin-deficiency encephalopathy.

Pyrithiamine-induced thiamin deficiency has been used in rat as an experimental form of Wernicke-Korsakoff encephalopathy, a disease associated with chronic alcoholism. Although the main etiological factor is known to be the lack of thiamin, the biochemical mechanisms involved in the pathogenesis remain unclear. Thiamin-dependent enzymes were studied in brain mitochondria: alpha-ketoglutarate dehydrogenase activity exhibited 40% reduction, whereas pyruvate dehydrogenase did not change significantly. Polarographic recordings of mitochondrial respiration revealed a decreased State 3, when using pyruvate/malate, alpha-ketoglutarate or glutamine as a substrate, but the respiration rates remained unchanged with glutamate or succinate. This fall in pyruvate oxidation may be due to the impairment of alpha-ketoglutarate dehydrogenase, which follows pyruvate dehydrogenase in the metabolic pathway. A time course of lactate concentration showed dramatic increases in thalamus, mid brain, hypothalamus and colliculli, consistent with the anatomopathological findings. No increases were found before the onset of neurological symptoms.

Central nervous system disease in Sjögren's syndrome.

Our prospective study consisted of a general and neurological evaluation in 48 patients (41 females, 7 males; mean age: 58.2 years) with primary Sjögren's syndrome (PSS). We performed serologic studies and cranial magnetic resonance imaging (MRI). Main extraglandular features were arthralgias and non-erosive arthritis (37.5%). Raynaud (21%) and pulmonary fibrosis (12.5%). Antinuclear antibodies were positive in 42.5% and anti-SS-A (Ro) in 20%. Migraine (52%), neuropsychiatric disease (29%) and a past history of focal acute neurological deficits (23%), were the central nervous system (CNS) manifestations more frequently observed. Cranial MRI examination detected hyperintense small subcortical lesions in 51.3% of patients and in 36.6% of age and sex matched controls (P < 0.001). CNS disease was not serious concerning vital prognosis, but produced significant morbidity in some patients. Late onset "migraine-like" episodes with prolonged sensoromotor deficits and coexisting neuropsychiatric disease emerged as a characteristic clinical spectrum in those patients diagnosed in a neurological setting. Cranial MRI was frequently abnormal, but findings were not specific. Neurologic manifestations reminiscent of multiple sclerosis were rarely seen.

Assay of succinate dehydrogenase activity by a colorimetric-continuous method using iodonitrotetrazolium chloride as electron acceptor.

A spectrophotometric assay method for determining succinate dehydrogenase activity is described in which iodonitrotetrazolium chloride is used as a final electron acceptor. The enzyme activity is determined by measuring the formation of formazan due to the tetrazolium salt reduction. The assay is continuous, rapid, simple, and sensitive, and may be used in the determination of enzyme activity either in tissue homogenates or as a marker of the mitochondrial fraction in cell fractionation procedures.