Ultrasound, computed tomography and magnetic resonance imaging in myopathies: correlations with electromyography and histopathology.

Imaging of examinations by ultrasound (US), computerized tomography (CT) and low field magnetic resonance imaging (MRI) were compared with EMG and muscle biopsy findings in the same muscles of 33 patients with different neuromuscular diseases. None of the imaging methods revealed specific diagnostic details, but gave valuable information on the extent and distribution of muscle involvement. In myopathies all imaging modalities corresponded well with the EMG and histopathology findings, but in the neuropathies with minimal tissue destruction EMG was, understandably, more sensitive. The imaging characteristics of MR were as good as those of CT, but MRI has the advantage of not requiring ionizing radiation. US is the most economical method and it was found to be, despite its lower resolution, very informative in the hands of an experienced examiner, especially for the detection of fibrosis. The good agreement of histopathology with pathologic imaging and EMG findings implies that the accuracy of muscle biopsy increases, if its site is selected on the basis of imaging and/or EMG examination.

Debrisoquine oxidation in Parkinson's disease.

Variations in the activities of xenobiotic metabolizing liver enzymes may be involved in the pathophysiology of diseases, including Parkinson's disease. We therefore studied the activity of the debrisoquine metabolizing enzyme in 97 patients with newly diagnosed Parkinson's disease. The urine debrisoquine metabolic ratios (MR) of the patients were compared with a group of 176 healthy subjects. There were 4 poor metabolizers (4.1%) among the parkinsonians. This proportion did not differ from that found in the group of healthy subjects (51%). In contrast to earlier finding, the parkinsonian poor metabolizers (PM) had the onset of the disease later than the parkinsonian extensive metabolizers (EM). In the parkinsonian patients, it was observed that the excretion of debrisoquine and 4-OH-debrisoquine into urine correlated inversely with the actual age and age at disease onset. Our results indicate that in patients with Parkinson's disease, debrisoquine hydroxylation is comparable with healthy subjects.

X-linked myopathy with excessive autophagy: a new hereditary muscle disease.

We report on 3 brothers with a myopathy that also affected their maternal grandfather and great-uncle. Characteristic features are onset in early childhood, very slow progression, normal life expectancy, weakness of proximal limb muscles, especially in the legs, elevation of serum creatine kinase, and no cardiac or intellectual involvement. In biopsy material muscle fibers are almost never necrotic but show excessive autophagic activity and exocytosis of the phagocytosed material. We suggest that this family has an undescribed type of congenital myopathy, for which we propose the name X-linked myopathy with excessive autophagy.

Linkage studies in a new X-linked myopathy, suggesting exclusion of DMD locus and tentative assignment to distal Xq.

We here report linkage studies in a family suffering from a recently described hereditary muscle disease named X-linked myopathy with excessive autophagy (XMEA). Significant lod scores excluding linkage to the Duchenne-Becker muscular dystrophy locus were found. Several other loci on the short and long arms of the X chromosome produced negative lod scores, whereas probe DX13-7 defining locus DXS15 showed no recombinants and a lod score of z = 0.903 at theta = .0. Further studies should be done to determine whether the gene for XMEA is (1) located at Xq and (2) caused by a mutation of the Emery-Dreifuss muscular dystrophy gene, which has been assigned to the same region.

Minicore myopathy with dominant inheritance.

Minicore disease (multicore disease) is a benign myopathy characterized by segmental muscle fibre degeneration with disruption of myofibrils and loss of mitochondria. The disease is generally thought to occur either sporadically or follow an autosomal recessive mode of inheritance. We describe 2 patients, a mother and her son, with essentially non-progressive weakness of both proximal and distal muscles. Biopsies from both patients showed focal defects of oxidative enzyme activity as well as focal disturbances of cross-striation typical of minicore myopathy. Normal fibre type differentiation was lacking. Three other families reported in the literature suggest dominant inheritance of minicore myopathy or closely related disease.

Hereditary multi-infarct dementia.

This paper summarizes the clinical and genetic features of a disease occurring in 16 patients from the same extended family, which resembles the multi-infarct dementia described by Sourander and Wålinder [Acta neuropath. 39: 247-254, 1977]. This family has relapsing strokes with neuropsychiatric symptoms, and they affect relatively young adult individuals of both sexes. The entity of the disease is characterized by autosomal dominant transmission with late onset and by association with occlusive cerebrovascular infarcts in the white matter, which was also generally reduced. Both of these features can be seen in the CT scan. In 13 members of this family the diagnosis can be regarded as certain and in a further 3 cases as more or less probable.

Long-term responses of Parkinson's disease to levodopa therapy.

The long-term responses of Parkinson's disease to levodopa therapy were studied in the patient material followed-up for 9 years. Levodopa treatment alleviated the parkinsonian symptoms to a considerable degree and substantially improved the quality of life of the parkinsonian patients. However, after treatment for 2 to 3 years, a progressive deterioration of parkinsonian symptoms was observed accompanied by an increase in the incidence of dyskinesias, on-off phenomena, postural instability and dementia. An analysis of the mortality rates in the follow-up material of 349 patients showed that initially levodopa treatment decreased the excess mortality due to Parkinson's disease. The ratios of observed to expected deaths ranged from 1.10 to 1.67. However, during the ninth year of treatment the ratio increased to 1.95 almost reaching the values obtained in the first years of levodopa treatment. Thus it appears that levodopa has only a limited period of usefulness in the treatment of Parkinson's disease. Although levodopa very significantly improves parkinsonian symptoms, it does not arrest the pathological progress and modify the natural course of the disease.

Mortality of patients with Parkinson's disease treated with levodopa.

The effect of levodopa on the mortality of patients with Parkinson's disease was investigated in 349 patients treated with levodopa or levodopa combined with decarboxylase inhibitor during 1969-1975 inclusive. During the study period, 61 patients died. The expected mortality was 32.99 resulting in a ratio of actual to expected deaths of 1.85. The excess mortality was accounted for by patients with a severe disease at entry and especially, by the less favorable effect of levodopa treatment than in the living patients. In comparison with the prelevodopa era, the reduction of mortality and the increase of life expectancy of patients with Parkinson's disease during levodopa treatment possibly reflect the decrease of the early mortality due to Parkinson's disease.

Brain dopamine turnover and the relief of parkinsonism.

The relationship between dopamine receptor activation and the relief of parkinsonian clinical features was studied in 40 patients with Parkinson's disease. Treatment with dopamine receptor agonists, piribedil or bromocriptine, decreased significantly both the basal level and probenecid-induced accumulations of homovanillic acid (HVA) in the CSF. But there were no changes in the concentrations of 5-hydroxyindole acetic acid (5-HIAA). Correlation analyses showed that patients who improved with both the dopamine agonists used had significantly lower probenecid response of HVA in the CSF and a less severe disease condition than those without beneficial effect. This relationship between dopamine receptor activation and improvement of parkinsonian disability suggests that the therapeutic efficacy of dopamine receptor agonists depends on the functional capacity of brain dopaminergic mechanisms.

Brain dopamine turnover and the relief of parkinsonism.

Levodopa alone or combined with a decarboxylase inhibitor elevated the concentration of homovanillic acid (HVA) in the cerebrospinal fluid (CSF). This increase correlated significantly with the dose of the drug but not with the clinical improvement, although some correlations with clinical side effects were evident. Nevertheless, the concentrations of HVA in the CSF during combined treatment were considerably lower than with therapeutically equivalent doses of levodopa alone. Obviously, a part of the HVA found in the CSF during levodopa treatment originates from the capillary walls. Treatment with dopamine receptor agonists, Piribedil or Bromocriptine decreased significantly both the basal level and probenecid- induced accumulations of HVA and CSF. But there were no changes in concentrations of 5-hydroxyindoleacetic acid (5-HIAA). Correlation analyses showed that patients who improved with both dopamine agonists used had significantly lower probenecid response of HVA in the CSF and less severe disease than those without beneficial effect. This relationship between dopamine receptor activation and improvement of parkinsonian disability suggests that the therapeutic efficacy of dopamine receptor agonists depends on the functional capacity of brain dopaminergic mechanisms.

Dopaminergic agonist effects on Parkinsonian clinical features and brain monamine metabolism.

The effect of a new dopaminergic agonist, piribedil, was studied in 16 patients with Parkinson's disease and compared with placebo and L-DOPA. Piribedil appeared to have a moderate therapeutic effect that was significantly less than that of L-DOPA. Tremor appeared to be the main clinical feature to benefit. Nausea, vomiting, and somnolence were most frequent during the buildup of treatment and confusion and hallucinations during long-term treatment. Piribedil caused a significant decrease in probenecid-induced accumulation of HVA in the CSF, suggesting reduced turnover of endogenous dopamine in the brain. There was a significant relationship between dopamine receptor activation by piribedil and improvement of parkinsonian disability.

Interaction between dopamine and phospholipids. Studies of the substantia nigra in Parkinson disease patients.

Interaction between dopamine and phospholipids was studied in the substantia nigra of ten patients with Parkinson disease and nine control subjects. There were no differences in the total content of phospholipids. However, in parkinsonian patients without previous levodopa treatment, the amount of sphingomyelin was increased and the amount of phosphatidylethanolamine and phosphatidylcholine decreased. Levodopa treatment corrected these values to the level of controls, whereas the amount of phosphatidylserine was decreased. It is concluded that changes in phospholipids are reflections of the deficiency of dopamine and loss of dopaminergic neurons in the substantia nigra of patients with Parkinson disease.

Urinary excretion of monoamines and their metabolites in patients with Parkinson's disease. Response to long-term treatment with levodopa alone or in combination with a dopa decarboxylase inhibitor and clinical correlations.

Urinary excretion of DA, DOPAC, 3-MT, HVA, NMA, MA, VMA and 5-HIAA were studied in 33 parkinsonian patients treated with 1.5-7.5 g of levodopa daily for up to six months and in 30 patients receiving levodopa (800-1,000 mg) combined with a dopa decarboxylase inhibitor, benserazide (200-250 mg). Basal urinary excretions were within normal limits except for that of 3-MT which was significantly lower in parkinsonian patients as compared to controls. Levodopa induced an increase of about 400 fold in urinary DA; DOPAC was increased about 300 fold, 3-MT only about 70 fold, but HVA about 300 fold. Urinary NMA and MA did not change but VMA was increased significantly. On the other hand, urinary 5-HIAA was significantly decreased. The amounts of excreted DA and its subsequent metabolities were increased with the continuation of treatment, suggesting inductive phenomena in enzyme systems. During combined treatment with levodopa and benserazide urinary DA was increased, but only to about one tenth the extent seen with levodopa alone. The excretion of DOPAC was about one 20th, of 3-MT about one fourth and of HVA one 25th that seen during levodopa treatment. No signs of enzyme induction were seen. NMA was lowered significantly but MA remained unchanged. VMA was increased and significantly more than during therapy with levodopa alone. 5-HIAA was again significantly decreased and the decrease was significantly greater than that seen with levodopa alone. Some statistically significant correlations were seen between the excretions of NMA, MA and VMA and cardiovascular side effects, indicating an affection on the NA-ergic system by levodopa treatment. Significant correlation between 5-HIAA excretion and clinical improvement of tremor during levodopa treatment may suggest that participation of 5-HT in the mechanism of tremor.