ABSTRACT
BACKGROUND AND PURPOSE: The efficacy and safety of the neuroprotective drug clomethiazole was tested in a double blind placebo controlled trial in patients with a clinical diagnosis of acute hemispheric stroke. METHODS: Patients with symptom onset of /=60 points on the Barthel Index) at 90 days. RESULTS: A total of 1360 patients were included. In the main efficacy analysis (n=1353), 56.1% of patients taking clomethiazole and 54.8% of placebo patients reached relative functional independence. The difference was not statistically significant. An analysis of the effect of time since onset of symptoms showed no difference between the treatment groups. Clomethiazole was generally well tolerated and appeared safe in the population studied. Sedation was the most common adverse event, leading to treatment withdrawal that occurred in 15.6% of clomethiazole-treated patients compared with 4.2% of placebo-treated patients. In a subgroup classified before randomization as having total anterior circulation syndrome (TACS) (n=545, or 40% of all randomized patients), the percentage of those reaching relative functional independence was 40.8% on clomethiazole and 29.8% on placebo, a difference of approximately 11 percentage units. TACS patients have clinical symptoms suggesting a "large" stroke. CONCLUSIONS: Clomethiazole had no adverse or beneficial effect on long-term outcome for all patients but produced sedation. The hypothesis that clomethiazole is effective in patients with large strokes will be tested in a further study.
Subject(s)
Cerebrovascular Disorders/drug therapy , Chlormethiazole/administration & dosage , Neuroprotective Agents/administration & dosage , Acute Disease , Adult , Aged , Aged, 80 and over , Brain Ischemia/drug therapy , Brain Ischemia/mortality , Cerebrovascular Disorders/mortality , Chlormethiazole/adverse effects , Female , Humans , Incidence , Male , Middle Aged , Neuroprotective Agents/adverse effects , Placebos , Survival AnalysisABSTRACT
Three patients are reported with a neurological disorder in which hypokinesia and rigidity were the most prominent clinical signs. On CT scan and MRI, two were found to have bilateral lesions in the striatum, mainly in the putamen, and the third had bilateral lesions in the posterior limb of the internal capsule. Laboratory investigations suggested abnormal pyruvate metabolism in all three cases, which was confirmed to skeletal muscle in two cases. In the third the cause was a NADH dehydrogenase defect. The signs and symptoms, the bilateral striatal lesions in two of the patients, and the abnormal pyruvate metabolism justify a classification of mitochondrial encephalomyopathy, resembling Leigh syndrome. This diagnosis must be considered for infants and children presenting with Parkinsonian signs, and mitochondrial energy metabolism should be investigated.
Subject(s)
Brain Diseases, Metabolic/diagnosis , Leigh Disease/diagnosis , Mitochondria, Muscle/physiology , Neuromuscular Diseases/diagnosis , Adolescent , Atrophy , Brain/pathology , Child , Child Development , Follow-Up Studies , Humans , Leigh Disease/physiopathology , Magnetic Resonance Imaging , Male , Neuromuscular Diseases/physiopathology , Pyruvates/blood , Pyruvic Acid , Synaptic Transmission , Tomography, X-Ray ComputedABSTRACT
A 16 year old girl showed delayed psychomotor development. In infancy, exercise intolerance, cerebellar signs, deteriorated with increasing intercurrent infections, and disturbances of breathing and cardiac rhythm became manifest. From the age of 7 years there was chronic progressive psychomotor deterioration, with hypotonia, a bilateral pyramidal and cerebellar syndrome, and mild epilepsy. CSF pyruvate and lactate levels were elevated, and lactate content was elevated in the urine. There was an abnormally high rise of lactate levels on moderate exercise and an abnormal response to pyruvate loading. Quadriceps muscle biopsies obtained at age 10 and 16 years showed ragged-red fibres, and a decreased cytochrome c oxidase activity and cytochrome aa3 content. Cytochrome c oxidase activity in fibroblasts was normal. Clinical signs and symptoms in association with a disturbance of mitochondrial energy metabolism led us to diagnosis of probable Leigh syndrome.
Subject(s)
Brain Diseases, Metabolic/pathology , Cytochrome-c Oxidase Deficiency , Leigh Disease/pathology , Mitochondria, Muscle/ultrastructure , Adolescent , Biopsy , Energy Metabolism , Female , Humans , Muscles/pathologyABSTRACT
A 17-year-old patient had a progressive hypokinetic-rigid syndrome and several other signs and symptoms that indicated central nervous system involvement. Biochemical studies revealed a reduced form of nicotinamide-adenine dinucleotide dehydrogenase deficiency in skeletal muscle. Clinical signs and symptoms, and their association with an established defect of energy metabolism, led us to classify this disorder as a mitochondrial encephalomyopathy of Leigh's type.
Subject(s)
Brain Diseases, Metabolic/enzymology , Cytochrome Reductases/deficiency , Leigh Disease/enzymology , Mitochondria, Muscle/enzymology , Muscular Diseases/enzymology , NADH Dehydrogenase/deficiency , Adolescent , Energy Metabolism , Humans , Leigh Disease/physiopathology , Male , Muscular Diseases/physiopathologyABSTRACT
Four siblings with Leigh's syndrome are described. The diagnosis was confirmed by pathological examination in one case. Chemical and biochemical investigations of serum and urine revealed no abnormalities of pyruvate metabolism, but all patients had marked elevations of CSF pyruvate and lactate concentrations. In three of the siblings, [1-14C]pyruvate oxidation rates were normal in fibroblasts and leucocytes. In one patients, extensive biochemical and histochemical studies of liver and muscle tissue revealed no mitochondrial dysfunction. A defect of oxidative metabolism restricted to brain seems probable.
Subject(s)
Brain Diseases, Metabolic/metabolism , Brain/metabolism , Leigh Disease/metabolism , Pyruvates/metabolism , Adolescent , Adult , Female , Humans , Lactates/metabolism , Leigh Disease/genetics , Malates/metabolism , Male , Mitochondria, Liver/enzymology , Mitochondria, Muscle/enzymology , Oxidation-Reduction , Pedigree , Pyruvic AcidABSTRACT
Diagnosis of defective pyruvate metabolism can present difficulties in clinical practice. In search of a diagnostic procedure that can give a clear indication of a disturbance of pyruvate metabolism, we have developed an intravenous pyruvate loading test. The loading test was applied to 9 patients with Leigh syndrome. Results and characteristics are described. The test proved to be a sensitive procedure to detect disturbances in pyruvate oxidation. The intravenous pyruvate loading test can be a useful tool in the diagnosis of mitochondrial (encephalo) myopathies.
Subject(s)
Brain Diseases, Metabolic/physiopathology , Leigh Disease/physiopathology , Pyruvates , Cells, Cultured , Citric Acid Cycle , Fibroblasts/metabolism , Humans , Leigh Disease/metabolism , Oxidation-Reduction , Pyruvates/metabolism , Pyruvic AcidABSTRACT
Results of a literature survey of 173 patients with Leigh syndrome are presented, with emphasis on signs and symptoms in relation to age at onset, contributions of technical investigations to the diagnosis, pathophysiology, genetic considerations and therapeutic aspects. Based on this study we are of the opinion that it is possible to come to a diagnosis of "most probable Leigh syndrome" durante vitamin on the combination of clinical signs and symptoms, autosomal recessive mode of inheritance, association with a defect of energy metabolism, and CT or MRI abnormalities.
Subject(s)
Brain Diseases, Metabolic/pathology , Leigh Disease/pathology , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Leigh Disease/metabolism , Leigh Disease/physiopathology , MaleABSTRACT
Several disorders of oxidative metabolism have been described in association with subacute necrotizing encephalomyelopathy (SNE) or Leigh syndrome. We present an eight-year-old girl with a mild spastic paraparesis and clinical deterioration on intercurrent infections. One sib died of SNE proven by autopsy. Biochemical examination of muscle tissue points to a disturbance in the process of oxidative phosphorylation due to a disturbed oxidation of NADH. The biochemical disorders associated with SNE are reviewed. The relation of SNE to the concepts of encephalomyopathy and mitochondriopathy is discussed.
Subject(s)
Brain Diseases, Metabolic/metabolism , Cytochromes/metabolism , Electron Transport Complex IV/metabolism , Leigh Disease/metabolism , Liver/metabolism , Malates/metabolism , Muscles/metabolism , Pyruvates/metabolism , Biopsy , Carbon Radioisotopes , Child, Preschool , Female , Humans , Leigh Disease/genetics , Leigh Disease/pathology , Liver/pathology , Male , Muscles/pathology , Oxidation-Reduction , PedigreeABSTRACT
We performed neurophysiological studies in 12 patients with the Leigh syndrome (6 pathologically confirmed and 6 clinically diagnosed). The results are compared with data derived from a literature survey of 173 Leigh syndrome patients. We found no positive contribution of neurophysiological studies towards the diagnosis of the Leigh syndrome.
Subject(s)
Brain Diseases, Metabolic/diagnosis , Electrodiagnosis , Leigh Disease/diagnosis , Brain Stem/physiopathology , Electroencephalography , Electromyography , Evoked Potentials, Auditory , Evoked Potentials, Somatosensory , Evoked Potentials, Visual , HumansABSTRACT
We studied a 17-year-old girl with subacute necrotizing encephalomyelopathy (Leigh syndrome). Lactate and pyruvate levels were increased in serum and cerebrospinal fluid. The oxidation rates of all substrates tested, i.e. pyruvate in liver, and pyruvate, malate and 2-oxoglutarate in muscle, were decreased, as was the production of adenosine triphosphate plus creatine phosphate. Cytochrome content was normal. The data imply a defect in oxidative phosphorylation, outside the cytochrome region.
Subject(s)
Brain Diseases, Metabolic/enzymology , Ketoglutaric Acids/metabolism , Leigh Disease/enzymology , Liver/enzymology , Malates/metabolism , Muscles/enzymology , Pyruvates/metabolism , Adolescent , Brain/pathology , Enzymes/metabolism , Female , Humans , Lactates/metabolism , Lactic Acid , Leigh Disease/genetics , Leigh Disease/pathology , Oxidation-Reduction , Phosphorylation , Pyruvic Acid , Spinal Cord/pathologyABSTRACT
Two patients with Moya-Moya syndrome are reported. The first patient has a trisomy 21 and is to our knowledge the third patient reported with the association of Down's syndrome and Moya-Moya. The second patient also demonstrates the typical Moya-Moya picture in angiography. Angiographic follow-up is demonstrated. The presenting age and symptoms, the symptoms in the course of the disease and the prognosis of 120 non-mongoloid cases of Moya-Moya are reviewed.
