Zotepine in levodopa-induced Psychosis.
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Aged↗
Biomedical subjects
T Klockgether
Publications and source records attributed to T Klockgether.
Fixation instability and oculomotor abnormalities in Friedreich's ataxia.
Eye movements were studied in 13 patients with Friedreich's ataxia and correlated with MRI findings to investigate whether oculomotor abnormalities can be traced to cerebellar disturbances in this disease. One of the most prominent eye signs was fixation instability (square-wave jerks, SWJ.). Besides SWJ the patients showed various combinations of cerebellar, vestibular and brain-stem oculomotor signs. Our patients did not comprise a homogeneous group with regard to their oculomotor findings. There was no correlation between the severity of any of the so-called cerebellar oculomotor disturbances and the number of SWJ. We tried to correlate the extent of oculomotor disturbances with floccular atrophy and atrophy of the dorsal vermis on MRI in seven of the patients. None of the oculomotor features (including SWJ) correlated with flocculus or dorsal vermis size. Furthermore, floccular and vermal measurements on MRI were normal. Accordingly, we think it unlikely that the oculomotor disturbances, including SWJ, are attributable to cerebellar pathology per se.
Adult↗
[Classification and diagnosis of degenerative ataxias].
The degenerative ataxias comprise a wide spectrum of neurodegenerative diseases with varying clinical characteristics and heterogeneous neuropathology. Traditionally, classification of these diseases has been based on neuropathological criteria. Recently, however, clinical and genetic classifications have gained wide acceptance. These classifications distinguish between hereditary and non-hereditary ataxias. According to their mode of inheritance, the hereditary ataxias are further subdivided into autosomal-recessive and autosomal-dominant ataxias. The non-hereditary ataxias are divided into symptomatic ataxias with an identified cause and idiopathic ataxia with unknown cause. Diagnostic criteria based on history, clinical presentation and a number of laboratory tests have been defined for each category. More extensive ancillary tests are necessary to identify or exclude symptomatic causes of ataxia. Recent molecular genetic research has led to the identification of a number of gene loci and mutations responsible for certain types of hereditary ataxia.
Chromosome Aberrations↗
Autosomal dominant familial spastic paraplegia: reduction of the FSP1 candidate region on chromosome 14q to 7 cM and locus heterogeneity.
Three large pedigrees of German descent with autosomal dominant "pure" familial spastic paraplegia (FSP) were characterized clinically and genetically. Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1), were performed. In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation. In pedigrees D and S, the gene locus could be excluded from the whole FSP1 region, confirming the locus heterogeneity of autosomal dominant FSP.
Alleles↗
Tremorlytic activity of budipine: a quantitative study with long-term tremor recordings.
The tremorlytic activity of the novel antiparkinson agent budipine was quantified in an open trial. Eleven patients with Parkinson's disease (PD) were treated with individual doses of budipine added to stable conventional antiparkinsonian medication. Tremor activity was measured using long-term electromyogram (EMG) recordings. Tremor intensity was reduced by 25%, tremor occurrence by 34%, and conventional "Unified Parkinson's Disease Rating Scale" (UPDRS) scores improved by 20% with this medication. There were two dropouts because of side effects. One dropout appeared not to be related to budipine. Apart from those, the drug was well tolerated by all patients. We conclude that budipine is an effective and well-tolerated tremorlytic drug and that the method of long-term EMG recording is suitable for tremor quantification in clinical studies.
Adult↗
NMDA-mediated toxicity to striatal neurons is not reversed by 7-nitroindazole, an inhibitor of neuronal nitric oxide synthase.
L-glutamate itself and compounds activating glutamate receptor subtypes such as N-methyl-D-aspartate (NMDA) can produce excitotoxic lesions similar to neuronal cell damage following ischemia, traumatic brain injury or as seen in human neurodegenerative disorders. Competitive and non-competitive NMDA-receptor antagonists have neuroprotective properties in a number of in-vitro and in-vivo models for these disorders. The discovery of nitric oxide (NO) in the central nervous system (CNS) and the demonstration of the link between glutamate receptor activation and NO formation led to the hypothesis that NMDA toxicity may be mediated by NO because of its ability to promote free radical generation. Three isoforms of nitric oxide synthase (NOS) have been described, one of which is expressed constitutively in neuronal tissues (nNOS) and is perferentially inhibited by 7-nitroindazole (7-NI). One day after intrastriatal injection of NMDA, systemic pretreatment of rats with 7-NI had no effect on lesion volumes. It is concluded that formation of NO subsequent to NMDA receptor stimulation is not critically involved in excitotoxicity seen in this model.
Animals↗
Visual control of arm movement in Parkinson's disease.
Patients with Parkinson's disease (PD) are more dependent on visual information during movements than normals. To investigate the mechanisms underlying deterioration of movement under nonvisual conditions, we studied two-dimensional pointing movements to randomly occurring targets. The experimental design allowed us to systematically manipulate visual feedback during the movement by removing vision of the target, of the moving hand, or of both. Execution of pointing movements in PD deviated most severely from that of normals when PD patients moved without vision of their own moving hand. Under this condition, undershooting of the target appeared, and movements were particularly slow. In contrast, with complete vision or when only vision of the target was occluded, pointing movements of PD patients were accurate and faster. PD patients had no difficulties selecting the correct movement direction. Reaction times were longer in PD patients irrespective of the availability of visual feedback. Our findings suggest that the ability of PD patients to use nonvisual feedback during execution of arm movements is impaired.
Adult↗
Oculomotor abnormalities and MRI findings in idiopathic cerebellar ataxia.
Extensive oculomotor testing and quantitative MRI evaluation was performed in seven patients with idiopathic cerebellar ataxia without extracerebellar symptoms (IDCA-C) and in ten patients with additional extracerebellar symptoms (IDCA-P). The most severe oculomotor deficits were disturbed smooth pursuit, optokinetic nystagmus and suppression of the vestibulo-ocular reflex (VOR). The symptoms correlated well and consistently with the amount of atrophy of the flocculus and the dorsal vermis. These correlations, however, were not specific, and deficits also correlated with the amount of atrophy of other cerebellar structures. No correlation was found between saccade velocity and brainstem atrophy or between saccade metrics and atrophy of the dorsal vermis. Although patients with IDCA-P had more severe oculomotor deficits than patients with IDCA-C, the pattern of the oculomotor disturbances was the same for both groups. Thus, eye movement analysis alone is not sufficient to distinguish between patients with pure cerebellar ataxia and those with additional extracerebellar symptoms.
Adult↗
New medical and surgical treatments for Parkinson's disease.
This article reviews new medical and surgical treatments for Parkinson's disease (PD). Catechol-O-methyl-transferase (COMT) inhibitors supplement the variety of antiparkinsonian drugs interacting with the dopaminergic system. Clinical studies show that COMT inhibitors prolong the action of levodopa in patients with the "wearing off" phenomenon. The atypical antipsychotic drug clozapine is the treatment of choice for the alleviation of levodopa-induced psychosis. Clozapine also has beneficial effects on tremor and levodopa-induced dyskinesias. Thus, COMT inhibitors and clozapine provide new opportunities for the treatment of patients with longstanding PD and fluctuating responses to levodopa. Experimental evidence in animals suggests that glutamate antagonists have symptomatic and neuroprotective actions in PD. At present, however, only weak antiglutamatergic drugs that have low specificity, such as memantine, amantadine, and budipine are available for clinical studies. Neurotrophic factors, in particular ciliary neurotrophic factor and glial cell line-derived neurotrophic factor, are among the most promising new approaches for neuroprotection in PD. Problems of bioavailability, however, thus far preclude their use in patients. An improved understanding of the pathophysiology of parkinsonism has led to a renaissance of stereotaxic surgery. The subthalamic nucleus is a potential new target for surgical intervention. Ventroposterior pallidotomy has been shown to improve not only rigidity and tremor, but also akinesia. The techniques for thalamic interventions have been refined by introducing chronic thalamic stimulation. Future transplantation approaches to PD will focus on the use of genetically modified cells carrying genes for dopamine-synthesizing enzymes or neurotrophic factors. Animal studies show the feasibility of in vivo gene transfer for the treatment of PD.
Animals↗
Absence of SCA1 mutation in idiopathic cerebellar ataxia.
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Adult↗
Assessing tremor severity with long-term tremor recordings.
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Circadian Rhythm↗
Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT.
Sixteen patients with a clinical diagnosis of probable multiple system atrophy (MSA) were examined clinically by MRI and by 123I-iodobenzamide single photon emission computed tomography (IBZM-SPECT). The clinical records of another 16 patients were also analysed retrospectively. On the basis of their clinical presentation, patients were subdivided into those with prominent parkinsonism (MSA-P, n = 11) and those with prominent cerebellar ataxia (MSA-C, n = 21). Autonomic symptoms were present in all patients and preceded the onset of motor symptoms in 63% of patients. Calculated median lifetime and the median time to become wheelchair bound after onset of disease were significantly shorter for MSA-P than for MSA-C (lifetime: 4.0 v 9.1 years; wheelchair: 3.1 vs 5.0 years) suggesting a better prognosis for cerebellar patients. A significant loss of striatal dopamine receptors (below 2 SD threshold) was detected by IBZM-SPECT in 63% of the patients (56% below 2.5 SD threshold). There was no difference between patients with MSA-C and those with MSA-P in the proportion with significant receptor loss and the extent of dopamine receptor loss. Planimetric MRI evaluation showed cerebellar and brainstem atrophy in both groups. Atrophy was more pronounced in patients with MSA-C than in those with MSA-P. Pontocerebellar hyperintensities and putaminal hypointensities on T2 weighted MRI were found in both groups. Pontocerebellar signal abnormalities were more pronounced in MSA-C than in MSA-P, whereas the rating scores for area but not for intensity of putaminal abnormalities were higher in MSA-P. MRI and IBZM-SPECT provide in vivo evidence for combined basal ganglia and pontocerebellar involvement in almost all patients in this series.
Adult↗
Mitochondrial gene mutations and diabetes mellitus.
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DNA, Mitochondrial↗
Late-onset Friedreich's ataxia. Molecular genetics, clinical neurophysiology, and magnetic resonance imaging.
OBJECTIVE--To clarify the nosological classification of late-onset Friedreich's ataxia (LOFA), ie, patients who have later onset of Friedreich's ataxia (FRDA), often after 25 years of age. DESIGN--Comparison of clinical examination data, nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging of a family with LOFA with a group of patients with FRDA. Genetic linkage analysis was performed in the family with LOFA. SETTING--Referral center. PATIENTS--Thirteen patients satisfied classic diagnostic criteria of FRDA, and three patients from one family satisfied all diagnostic criteria of FRDA but with disease onset after 25 years. RESULTS--Results of nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging in patients with LOFA closely corresponded to observations made in patients with FRDA. In addition, genetic linkage analysis using markers tightly linked to the FRDA locus on chromosome 9 showed that all affected members of the LOFA family, but not their unaffected siblings, had inherited identical paternal and maternal genotypes. CONCLUSIONS--Data suggest that LOFA may also result from mutation within the FRDA locus.
Adolescent↗
Toward an understanding of the role of glutamate in experimental parkinsonism: agonist-sensitive sites in the basal ganglia.
Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease. However, the mechanisms by which activation of glutamate receptors produce parkinsonism are unknown. Therefore, we examined whether the glutamate agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate produce parkinsonism in rats after microapplication into different subregions of the basal ganglia. Electromyographic activity was used as a measure of parkinsonian rigidity. We found that in the rostral striatum, excitation mediated by NMDA but not by non-NMDA receptors led to parkinsonism. In the substantia nigra pars reticulata, internal pallidal segment/entopeduncular nucleus, and subthalamic nucleus, activation of AMPA/kainate and metabotropic receptors but not of NMDA receptors led to parkinsonian rigidity. Rigidity occurred also in animals bearing ibotenate-induced lesions of the posterior part of the striatum and of the external pallidal segment, but not in animals with lesions of the anterior striatum, subthalamic nucleus, internal pallidal segment/entopeduncular nucleus, or substantia nigra pars reticulata. These observations suggest that the activation of glutamate receptor subtypes in the basal ganglia may be differentially involved in the expression of parkinsonian symptoms.
Animals↗
Cerebellar encephalitis in adults.
We examined 11 adult patients with cerebellar encephalitis (CE) during the acute phase of the disease and at least 12 months later. Five patients were aged between 23 and 31 years, 3 patients between 43 and 44 years and 3 patients between 60 and 64 years. Serological tests gave evidence of Epstein-Barr virus infection in 4 of the 5 young patients. Two patients had serological evidence of varicella-zoster virus reactivation, whereas the serological findings were negative in all other cases. All patients in the younger and middle age groups recovered within 3-30 weeks after onset of CE. If at all, they had only minor cerebellar deficits at the follow-up examination. Magnetic resonance imaging (MRI) examination performed at the follow-up examination was normal in all of them. In contrast, 2 of 3 patients older than 60 years had persistent cerebellar ataxia following CE. In these patients, MRI revealed infratentorial atrophy. Our data show that the clinical spectrum of CE in adults is wider than assumed so far. In addition to typical cases of CE in young male patients with good recovery, CE may also occur in older patients and give rise to persistent cerebellar ataxia.
Adult↗
The antiparkinsonian agent budipine is an N-methyl-D-aspartate antagonist.
Budipine (1-t-butyl-4,4-diphenylpiperidine) is a novel antiparkinsonian agent. Its clinical efficacy has been proven in double-blind placebo-controlled trials. The mechanism of action of budipine, however, is unknown. Budipine selectively increased the threshold of N-methyl-D-aspartate (NMDA)-induced seizures in mice. Similar to known specific NMDA antagonist, budipine depressed polysynaptic spinal reflexes in mice, but had no consistent effect on spinal monosynaptic reflexes. In receptor binding experiments, budipine displaced thienylcyclohexylpiperidyl-3,4-[3H]-(n) ([3H]-TCP) from its binding site with an IC50 of 36 microM suggesting that budopine acts as a non-competitive NMDA antagonist with moderate receptor affinity. It is concluded that the newly discovered NMDA antagonistic action of budipine is at least partly responsible for its antiparkinsonian activity. Our findings are additional evidence for the hypothesis that NMDA antagonists may be useful in the treatment of Parkinson's disease (PD).
Amino Acids↗
Combination therapy for PD.
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Antiparkinson Agents↗