Biomedical subjects
H Reichmann
Publications and source records attributed to H Reichmann.
Prion codon 129 homozygosity and sporadic inclusion body myositis.
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Cricopharyngeal achalasia is a common cause of dysphagia in patients with mtDNA deletions.
To assess dysphagia, the authors examined 12 patients with Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) deletion by videofluoroscopy and manometry. Cricopharyngeal achalasia was documented in nine of 12 patients (75%), whereas deglutitive coordination problems were found in one patient. Cricopharyngeal myotomy may be an effective treatment in selected cases with severe cricopharyngeal obstruction.
Intrathecal methylprednisolone for postherpetic neuralgia.
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Modafinil for excessive daytime sleepiness in myotonic dystrophy.
The authors conducted an open-label trial of modafinil for excessive daytime sleepiness in myotonic dystrophy. Eleven patients were evaluated: two were not treated because of obstructive sleep apnea, and nine received 200 to 400 mg modafinil/day for an average of 16.4 weeks. There were no major side effects. Average sleep latency as measured by the Multiple Sleep Latency Test increased from 7.3 to 22.7 minutes ( p = 0.00013), and average Epworth Sleepiness Scale score decreased from 13.25 to 7.75 (p = 0.01028). Modafinil shows evidence of effectiveness for excessive daytime somnolence in myotonic dystrophy and should be investigated further.
Subcutaneous microdialysis in mitochondrial cytopathy.
We present the results of subcutaneous microdialysis, a new minimally invasive biochemical monitoring technique, in mitochondrial cytopathy. We studied 6 ambulatory patients with mitochondrial cytopathy and 6 controls without mitochondrial disease using a subcutaneous probe for continuous microdialysis, and obtained measurements of lactate, pyruvate, and glucose from samples gathered at 30-60 min intervals during the day and at 3-h intervals at night. The lactate:pyruvate ratio (LPR) was calculated and related to disease severity and metabolic stress. Microdialysis was well tolerated. Controls had stable lactate and pyruvate values in the normal range and a low LPR (average values between 0.0114 and 0.0145). Patients had widely fluctuating lactate and pyruvate values, a higher average LPR between 0.0187 and 0.0724, and marked diurnal variation, especially in the severely affected patients. Increases in the LPR coincided with metabolic stress in individual cases. We conclude that subcutaneous microdialysis is well tolerated and enables continuous metabolic monitoring of patients with mitochondrial cytopathy. It has particular potential for use in the identification of metabolic risk factors and may help to assess the impact of therapeutic regimens.
Neurodegeneration-associated proteins and inflammation in sporadic inclusion-body myositis.
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[Proximal weakness and exercise-induced pain as initial symptom of oculopharyngeal muscular dystrophy].
A 54-year-old female patient presented with exercise-induced proximal muscle pain and weakness of the lower limbs. One year after the onset of these symptoms she developed bilateral ptosis and dysphagia. Molecular genetic analysis of the poly(A) binding protein 2 gene (PABP2) confirmed the presumptive diagnosis of oculopharyngeal muscular dystrophy (OPMD). Exercise-induced proximal muscle pain and weakness are rarely initial symptoms of OPMD. We discuss therapeutic options and present an overview of the relevant literature.
High-dose therapy with ropinirole in patients with Parkinson's disease.
Ropinirole is effective as mono- and combination therapy in PD. Previous studies have used a maximal dose of 24 mg/day; the present study assesses the effect of higher doses (up to 36 mg/day) on patients with motor fluctuations. Outcome measures were changes in the motor function score of the Unified Parkinson's Disease Rating Scale, the duration of dyskinesias and reductions in levodopa dose. 21/22 patients completed the study. The mean daily ropinirole dose at endpoint was 26.2 mg (SD, 4.43 mg, range 20-36 mg). Improvements in motor function (29%) and the duration of dyskinesias (45%) from baseline to endpoint were significant (p < 0.01 and p < 0.05, respectively). The mean levodopa dose fell by 32% during the study (from 599 mg to 409 mg; p = 0.007). Side effects were mild. High-dose ropinirole (20-36 mg/day) was well tolerated and conferred significant clinical benefit on patients with motor fluctuations.
Echo-enhanced transcranial color-coded duplexsonography to study collateral blood flow in patients with symptomatic obstructions of the internal carotid artery and limited acoustic bone windows.
We prospectively evaluated 30 consecutive patients with echo-enhanced transcranial color-coded duplexsonography (TCCD) and correlative transfemoral digital subtraction angiography to assess the diagnostic efficacy of echo-enhanced TCCD for evaluation of collateral pathways through the circle of Willis in patients with limited acoustic bone windows and critical symptomatic carotid disease. Echo-enhanced TCCD detected collateral blood flow through the anterior communicating artery in 16 of 18 patients (sensitivity 89%, 95% CI 65-99%) and was false positive in one out of 12 patients without collateral flow (specificity 92%, 95% CI 59-100%). For the posterior communicating artery, sensitivity was 11/14 (79%, 95% CI 49-95%) and specificity was 15/16 (94%, 95% CI 70-100%). Echo-enhanced TCCD enables to study collateral blood flow through the communicating arteries of the circle of Willis with high sensitivity and specificity in patients with obstructions of the internal carotid artery and limited acoustic bone windows.
Chronic alcohol consumption and cerebral indices of oxidative stress: is there a link?
BACKGROUND: It is still difficult to define the biochemical mechanisms that cause alterations in neuronal function and plasticity and neuronal cell loss in the brains of alcohol-dependent patients. METHODS: To evaluate the extent of cerebral alcohol-induced oxidative stress ex vivo, we investigated the levels of glutathione (GSH), its oxidation product glutathione disulfide (GSSG, produced by GSH-peroxidases), and the activities of catalase and superoxide dismutases (SOD). In addition, selected brain regions from up to 22 subjects (versus controls) were studied post mortem to compare the amount of oxidized DNA-base 8-hydroxy-2'-deoxyguanosine (8-OHdG) with levels of deoxyguanosine (dG) in mitochondrial and nuclear DNA. RESULTS: The most prominent findings showed significantly decreased GSH/(GSH+2GSSG) molar redox (oxidation-reduction) ratios in the corpus mamillare and cerebellum, which appeared due to an increase in GSSG caused by chronic alcohol intake. Catalase activity was increased in only the frontal cortex, whereas decreased catalase activity was found in the corpus callosum. In contrast, neither copper-zinc-superoxide dismutase (CuZnSOD) and manganese-superoxide dismutase (MnSOD) activities nor 8-OHdG/dG molar ratios were altered, although a tendency toward higher OHdG/dG ratios in temporal and parietal cortex from alcohol-dependent patients could be detected when mitochondrial DNA was analyzed selectively. CONCLUSIONS: We propose that decreased brain GSH/(GSH+2GSSG) molar redox (oxidation-reduction) ratios in alcohol-dependent patients may reflect neural impairment due to increased peroxide production after chronic alcohol consumption. However, future experiments, investigating the activities of enzymes and cofactors involved in GSH synthesis and metabolism in the human brain, will have to validate the specificity of these results for oxidative stress.
Neural degeneration in Parkinson's disease.
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Mitochondrial dysfunction--a pathogenetic factor in Parkinson's disease.
The cause of Parkinson's disease is still unknown. Nonetheless, there are some generally accepted hypotheses with respect to the cascade of dopaminergic cell degeneration. One of the factors is a decrease in respiratory chain complex I activity. This enzyme abnormality is only found in substantia nigra pars compacta. It is not currently known whether this is due to a genetic abnormality of the nuclear or mitochondrial genome or to an exo- or endotoxin. To date, no specific abnormality of the mitochondrial genome has been detected, although ageing leads to deletions in up to 5% of all mitochondrial genome molecules in the brain. There is controversy whether this complex I defect is also detectable in muscle or blood cells. It is our conviction that the considerable overlap between blood cells from normal controls and patients with Parkinson's disease means that such measurements are not distinctive for the two conditions. A decrease in complex I activity in postmitotic cells may be one of the crucial factors for cell death.
Long-term treatment with dopamine agonists in idiopathic Parkinson's disease.
Long-term treatment studies with any antiparkinsonian drug are rather limited. Especially, double-blind, randomized and multicenter studies do not exist except for some rare exceptions. Nonetheless, such studies are mandatory to prove certain therapy regimens. This overview reports on the comparison between dopamine agonists and levodopa. There are open studies comparing bromocriptine, lisuride, pergolide with levodopa which demonstrate that the use of dopamine agonists in monotherapy or combination with levodopa decreases the percentage of patients who develop dyskinesias compared to levodopa only. A long-term study was performed with cabergoline (3 years) which was extended in an open trial for another 2 years and which underlined the above mentioned observation. In a very recent study, ropinirole was compared with levodopa. This double-blind study spans 5 years and shows that about 30% of patients were able to stay for 5 years on ropinirole monotherapy, that withdrawal rate was not higher in the dopamine agonist group and that the side effects were similar in the levodopa and the ropinirole group. The major finding of this study was a very low dyskinesia rate when treating patients with ropinirol alone. Thus, this study underlines our therapy concept which advocates the early use of dopamine agonists in IPS.
Workshop IV: drug treatment guidelines for the long-term management of Parkinson's disease.
An attempt was made to establish a decision algorithm for the treatment of idiopathic Parkinson's disease at various stages and in different subgroups such as akinetic-rigid or tremor dominance type. We suggest treating young patients with selegiline and a dopamine agonist. In the tremor dominance type we use either budipine or a dopamine agonist. Due to levodopa-induced dyskinesia, we try to avoid levodopa in the early stages of the disease and use it only later in more advanced situations in a combination therapy with dopamine agonists. Since IPS is not only based upon dopamine deficiency but also on resulting glutamatergic overstimulation, we advocate the use of a glutamate antagonist such as amantadine or budipine. Catechol-O-methyl inhibitors are very helpful when wearing-off occurs. Anticholinergics are only used in the early stages of tremor-dominant IPS because we fear enhancing the risk of dementia.
[Molecular diagnosis of hereditary neurologic diseases. Position paper].
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[1st long-term double-blind study of effectiveness and dyskinesia prevention of ropinirol].
Psychiatric symptoms and motor fluctuations are frequently occurring late sequelae of long-term therapy with L-dopa. Up to 80% of patients on L-dopa therapy suffer from disturbing dyskinesias, with onset during the first few years after beginning treatment. In particular, younger and middle-aged patients with idiopathic parkinsonian syndrome may develop dyskinesias in the early years of L-dopa therapy. We propose that these particular patient groups should initially be treated with a dopamine agonist--if possible in monotherapy but at least in a dopamine agonist-dominated combination therapy with L-dopa. In this paper, we discuss the reasons for these recommendations, which are based on the findings of the first double-blinded study in which L-dopa was compared with ropinirole, a nonergot dopamine agonist, over a 5-year period. The main results of this study are as follows: At least 1/3 of patients in the ropinirole group could be treated with the dopamine agonist in monotherapy over 5 years. Treatment in the ropinirole group was as effective as in the L-dopa group. Despite equal effectiveness of both drugs, the incidence of dyskinesias was considerably lower with ropinirole (5%) than with L-dopa (36%). The long-term experience gained in this 5-year study support our recommendations to use dopamine agonists early and as the preferred drug of choice in the treatment of Parkinson's disease.
Bromal-derived tetrahydro-beta-carbolines as neurotoxic agents: chemistry, impairment of the dopamine metabolism, and inhibitory effects on mitochondrial respiration.
The mammalian alkaloids tryptoline (1) and eleagnine (2) as well as the highly halogenated (X = F, Cl, Br) tetrahydro-beta-carbolines (THbetaCs) 3-5, structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 6), were found to have a common feature of inducing a severe impairment of the nigrostriatal dopamine metabolism and inhibiting complex I of the mitochondrial respiratory chain highly selectively. Within the series of compounds tested, 1-tribromomethyl-1,2,3,4-tetrahydro-beta-carboline ('TaBro', 5), which was prepared in high yields from the biogenic amine tryptamine ('Ta', 7) and the unnatural aldehyde bromal ('Bro', 8) by a Pictet-Spengler cyclization reaction, turned out to be the most potent toxin in vitro and in vivo. As demonstrated by voltammetric measurements on rats, for all the THbetaCs 1-5 investigated, intranigral application of a single dose of 10 microg resulted in a significant reduction of the dopaminergic activity in the striatum, with the strongest effect being observed for TaBro (5). Using rat brain homogenates, again 5 (IC50 = 200 microM) as well as its dehydrohalogenation product 11 (IC50 = 150 microM) exhibited the most pronounced inhibitory potential on mitochondrial respiration. The halogen-free THbetaCs 1 and 2 as well as the MPTP metabolite 1-methyl-4-phenylpyridinium ion (MPP+), by contrast, showed only a moderate inhibition at concentrations in the millimolar range (e.g. for MPP+: IC50 = 3.5 mM). For an elucidation of the role of hydrophobic portion in the inhibitory action against complex I activity, several N-acyl derivatives (15-21) of 5 were synthesized and tested. An X-ray diffraction study on the 3-dimensional structure of trifluoroacetylated highly halogenated THbetaCs (12-14) revealed the tetrahydropyrido part to adopt a nearly planarized half-chair conformation. Because of the steric demand of the trihalogenmethyl moiety (CF3 < CCl3 < CBr3), the N-substituent is dramatically pushed out of that ring 'plane'.