Classification of fine-motoric disturbances in Wilson's disease using artificial neural networks.

Patients suffering from Wilson's disease are divided into several types according clinical symptoms only at time of manifestation. Thereby two main subgroups exist: neurologic and non-neurologic types. After long-term therapy the neurological symptoms occurring in hepatolenticular degeneration may be improved but frequently with remaining fine-motoric disturbances which should be used for evaluation of the actual patient state. These disturbances are difficult to assess in an exact and objective manner by clinical examination. Therefore we measured fine-motoric passive and active abilities based on a standardized test set using the VSCOPE-system. The parallel evaluation of all fine-motoric data using an artificial neural network leads to a reclassification of these patients based on actual fine-motoric abilities but not reflecting the clinical classification at time of manifestation.

Investigation of fine-motor disturbances in Wilson's disease.

Patients suffering from Wilson's disease (WD) can be divided into two main subgroups: neurologic and nonneurologic WD. We measured passive and active fine-motor abilities of 37 WD patients and 24 randomly selected volunteers. The measurement was based on a standardized test set in a defined environment for detection of disturbed finemotor control. The set contains 5 tests comprising rest tremor, postural tremor, target tapping, forefinger tapping and spiral painting, reflecting different aspects of movement disorders. The tests showed significant differences between neurologic WD and volunteers, especially for tasks defining active control. In neurologic WD we found no differences between subgroups whereas for non-neurologic WD we often detected slight movement disorders. The detected movement disorders cam be interpreted as persistent disorders after long-term therapy.

Comparison of clinical types of Wilson's disease and glucose metabolism in extrapyramidal motor brain regions.

In Wilson's disease a disturbed glucose metabolism especially in striatal and cerebellar areas has been reported. This is correlated with the severity of extrapyramidal motor symptoms (EPS). These findings are only based on a small number of patients. Up to now it is unknown whether EPS are caused by various patterns of disturbed basal ganglia glucose metabolism. We investigated 37 patients and 9 normal volunteers to characterize the disturbed glucose metabolism in Wilson's disease more precisely. The glucose metabolism was determined in 5 cerebellar and cerebral areas (putamen, caput nuclei caudati, cerebellum, midbrain and thalamic area) by using (18)F-Fluorodesoxyglucose-Positron-Emission-Tomography ( [(18)F]FDG-PET). The database was evaluated by a cluster analysis. Additionally, the severity extrapyramidal motor symptoms were judged by a clinical score system. Three characteristic patterns of glucose metabolism in basal ganglia were obtained. Two of them may be assigned to patients with neurological symptoms whereas the third cluster corresponds to most patients without EPS or normal volunteers. The clusters can be identified by characteristic consumption rates in this 5 brain areas. The severity of EPS can not clearly be assigned to one of the clusters with disturbed glucose metabolism. However, the most severe cases are characterized by the lowest consumption in the striatal area. When there is marked improvement of EPS impaired glucose consumption reveals a persistent brain lesion. Finally, the neurological symptoms in Wilson's disease are caused by (at least) two different patterns of disturbed glucose metabolism in basal ganglia and cerebellum. The severity of EPS seems to be determined by a disturbed consumption in the striatal area.

Unusual triplet expansion associated with neurogenic changes in a family with oculopharyngeal muscular dystrophy.

The occasional observation of neurogenic features in oculopharyngeal muscular dystrophy (OPMD) is unclear both in nosological and in etiological respects. Studies are reported here of a family with autosomal-dominant OPMD involving seven members over three generations. In three of them muscle biopsies were performed. Two of the patients (a 45-year-old sister and a 57-year-old brother of the third generation) were studied in more detail and, in addition to the typical changes of OPMD, showed a neurogenic component both by electrophysiology and morphology. Molecular genetic investigations revealed a repeat unit of (GCG/GCA)13 in the first exon of the poly(A)binding-protein2 gene in both siblings. A possible association of this unusually long triplet repeat extension with the atypical phenotype is considered and has to be verified in other cases.

Neurological disease-associated autoantibodies against an unknown protein encoded by a RES4-22 homologous gene.

Screening a human small intestinal library with human serum yielded a clone which encoded a protein res4-22 the gene of which was highly homologous to a recently described gene located in the Huntington's disease locus. Autoantibodies against res4-22 (anti-res4-22), mainly of the immunoglobulin (Ig)A type, were detected in patients with neurological disorders at a higher frequency (18.4%) than in healthy blood donors (8.0%). In neurological patients with cerebral ischaemia anti-res4-22 was found significantly more often (47.4%) than in the total group of neurological patients. Anti-res4-22 positive sera showed significantly more frequently myelin staining in cerebellum and nerve sections than anti-res4-22 negative sera. Our findings demonstrate a new species of human autoantibodies against a newly described protein the function of which is still unknown.

[Contralateral and ipsilateral repetitive transcranial magnetic stimulation in Parkinson patients]. / Kontralaterale und ipsilaterale repetitive transkranielle Magnetstimulation bei Parkinson-Patienten.

In seven women and two men with Parkinson's disease, Hoehn and Yahr stage 1 or 2, the effect of repetitive transcranial magnetic stimulation (rTMS) was evaluated. Primary endpoint outcome measure was the changing of the motor items of the Unified Parkinson's Disease Rating Scale (subscale III of UP-DRS) 24 h after stimulation. Kinesiologic tests and writing samples were secondary outcome measures. After discontinuing all medication, stimulation was performed with 5 Hz at 90% of the motor threshold over the primary motor cortex of the more affected. There were 2250 stimuli applied, divided into 15 trains at intervals of 10 s. The identical treatment of the opposite side served as control treatment. Only treatment of the more affected side resulted in a significant improvement of the clinical symptoms of 46% as assessed by the UPDRS (p < 0.02). This effectiveness differed significantly from the control treatment (21%, p < 0.02). The kinesiological testing did not show any significant speeding of movements (p > 0.05). Some patients showed a normalisation of the previously disturbed handwriting specimen. These data confirm the previous observation that rTMS of primary motor regions leads to at least temporary clinical improvement of symptoms in patients with Parkinson's disease.

Filtration of cerebrospinal fluid for acute demyelinating neuropathy in systemic lupus erythematosus.

We report a patient with systemic lupus erythematosus complicated by an acute demyelinating neuropathy. Conventional therapy with intravenous immunoglobulins and immunoadsorption complemented by pulse methylprednisolone and cyclophosphamide failed. Institution of filtration of the cerebrospinal fluid was followed by a rapid improvement of the paresis.

[Clinical and fine motor therapy assessment in Wilson disease]. / Klinische und feinmotorische Therapiekontrolle bei Morbus Wilson.

At the time of diagnosis and after therapy, we examined 33 patients suffering from Wilson's disease. We applied a standardized diagnostic score system on the basis of clinical signs. Without observing any differences between pseudoparkinsonian and pseudosclerosis subtypes, patients with neurological symptoms significantly improved by 2.33 points. Patients with initially more severe symptoms showed the same improvement as less affected patients. Fine motor disturbances were evaluated using the V-scope system. Finger tapping and drawing a spiral were compared to values of a healthy control group (n = 52). Patients with neurological symptoms showed significantly decreased frequencies in both tests. The clinical score was related to frequencies in finger tapping but not in drawing a spiral. Therefore finger tapping can be used as an objective diagnostic tool to evaluate the severity of Wilson's disease, while spiral testing appears to be a sensitive screening tool.

Quantitative thermal perception testing in 225 children and juveniles.

Quantitative Thermotesting evaluates peripheral small nerve fiber function. The method of limits is a widely used algorithm of perception threshold determination. Normative data are needed to apply the method of limits in children and juveniles. In 225 healthy boys and girls, aged 7 to 17.9 years, warm and cold perception thresholds were established with the method of limits at the volar distal forearm, the thenar eminence, the lower medial calf, the lateral dorsal foot, and the cheek. A 1 degree C/s stimulus velocity, a 32 degrees C thermode baseline, and a 1.5-cm x 2.5-cm Thermotest stimulator were used. Accuracy of stimulus perception was studied by comparing the lowest to the highest response of five consecutive stimuli. The influence of different stimulator sizes on thresholds was tested at the lower calf and distal forearm with an additional 2.5-cm x 5.0-cm thermode. To determine the impact of the pretest skin temperature on thresholds, skin temperature was correlated with thresholds. Results showed good intratrial reproducibility of thresholds. The large thermode yielded lower thresholds than the small probe. Skin temperature had only minor influence on thresholds. The large probe should be used at body sites where it adjusts planely.

Histologic evidence for a toxic polyneuropathy due to exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a considerable environmental hazard in industrial societies. Its toxic effects on animals and humans are numerous, but little is known about its neurotoxicity. We studied the neurotoxic effects of TCDD in 80 male, adult Wistar rats. The substance was dissolved in corn oil and a single dose injected intraperitoneally (8.8 micrograms, 6.6 micrograms, 4.4 micrograms or 2.2 micrograms/kg). Neurophysiological examinations proved a dose-related, statistically significant slowing of sensory and motor conduction velocities. Ten months after the application of TCDD peripheral nerves showed a progressive, and proximally accentuated neuropathy. The extent of changes, however, differed remarkably between individual animals. Our data indicate that TCDD caused a toxic polyneuropathy in rats.

Electrophysiologic evidence for a toxic polyneuropathy in rats after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

At present, experimental data on the neurotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin are still lacking. Therefore, electrophysiologic studies were performed in 80 adult, male Han/Wistar rats intraperitoneally injected with a single, low dose of TCDD (8.8, 6.6, 4.4 or 2.2 micrograms/kg) dissolved in corn oil. 20 control animals received corn oil only. The typical 'wasting syndrome' of high-dose TCDD-intoxication was therefore not observed. Motor and sensory nerve conduction velocities in the right sciatic nerve showed dose-dependent and statistically significant slowing in TCDD-exposed rats as compared to controls. Spontaneous activity in the flexor digitorum muscle of the right hind paw and in tail muscles could be seen in the electromyogram of TCDD-group 1 (100%), group 2 (93%), groups 3 and 4 (87% each). This was significantly less frequent in the controls (21%). These findings give electrophysiologic evidence for a toxic polyneuropathy in rats after a single, low dose of TCDD.

Cryptogenetic polyneuropathies: an out-patient follow-up study.

An out-patient follow-up study of 41 patients suffering from cryptogenetic PNP was performed: 19 (46%) had a symmetric-paretic; 15 (37%) a symmetric-sensory, 4 (10%) an asymmetric type polyneuropathy and 3 (7%) presented with mononeuropathia multiplex; 12 of 41 (29%) unclassified PNP could be clarified. Of the remaining 29 unsolved cases, 14 (48%) formed a homogeneous subgroup sharing specific criteria: primary, axonal type degeneration; slowly progressing clinical course reaching a plateau; low disability status; onset between the age of 45-65. We concluded that out-patient re-evaluation of cryptogenetic PNP yields improved diagnosis. Hereditary and immune-mediated PNP exhibit specific diagnostic problems and account for a large portion of the cryptogenetic PNP.

Postoperative effects and value of sural nerve biopsies: a retrospective study.

In order to compare the adverse effects with the benefits for the characterization of neuropathies after complete sural nerve biopsy, 56 out of 80 patients were examined postoperatively. Preoperatively, sensory deficits were reported by 30 patients (53%), paresthesia and dysesthesia by 18 (32%), and pain by 16 (28%). Twenty-one months after biopsy on the average, persistent loss of sensation was found in 52 patients (93%), persistent paresthesia and dysesthesia in 17 (30%) patients each, and persistent pain in 14 (25%) patients. Pain and paresthesia showed better postoperative improvement than the other sensory symptoms. 15 cases (27%) were diagnosed by histology alone. In 21 cases (37%), nonspecific histological findings contributed valuable diagnostic information. The remaining 20 cases (36%) continued to be unclear despite histology. Demyelinating or mixed-type neuropathies did not yield better results than purely axonal forms. We conclude that sural nerve biopsy is a valuable diagnostic tool, but its side-effects require careful selection of fully informed patients.

[Disseminated polyneuropathy after coma]. / Disseminierte Polyneuropathie nach Koma.

An acute polyneuropathy developed during intensive-care treatment of three young men who had sustained severe multiple traumas and of one woman with bacterial meningoencephalitis. In the first case there was a predominantly distal paraparesis of the legs; in the second, flaccid neurological deficits occurred particularly in the areas of the left ulnar, peroneal and tibial nerves combined with paralysis of cranial nerves IX, X and XII. A symmetrical sensorimotor polyneuropathy with tetraplegia and cranial nerve deficits occurred in the third case, and an asymmetrical sensorimotor polyneuropathy in the female patient. In all four patients electrophysiological tests demonstrated the pattern of neurogenic damage. All patients had respiratory failure, malnutrition, septic fevers and acute renal failure requiring haemodialysis for two to five weeks. It is assumed that the polyneuropathy was of multifactorial genesis.

Peripheral nerve disorders in Lyme-Borreliosis. Nerve biopsy studies from eight cases.

Clinical, cerebrospinal fluid and nerve biopsy findings from eight patients with peripheral nervous system complications of Lyme-Borreliosis are reported. Five cases showed the typical features of the Garin-Bujadoux-Bannwarth syndrome (meningoradiculoneuritis), one patient had a multiple mononeuritis associated with acrodermatitis chronica atrophicans Herxheimer. Two cases could not be classified under these diagnostic categories. In all patients we observed a prompt relief of signs and symptoms after antibiotic treatment. Nerve biopsy studies showed gross infiltrations of epineurial vasa nervorum and small infiltrations around endoneurial capillaries. The infiltrations consisted of lymphocytes, histiocytes and plasma cells. We did not find necrotizing changes of the vessel walls, but thrombosis and recanalization was observed in some epineurial vessels. Seven biopsies showed a significant loss of myelinated axons due to axonal degeneration. Only in one biopsy did we observe segmental demyelination next to axonal degeneration. We conclude that the PNS complications of Lyme-Borreliosis in early and late stages of the disease are angiopathic due to vasculitis of the vasa nervorum and primarily caused by axonal degeneration.

Differentiation in the medulloblastoma. A histological and immunohistochemical study.

The histological and immunohistological features of medulloblastomas were investigated in patients participating in an ongoing cooperative study of the Societé International d'Oncologie Pédiatrique (SIOP). Of 51 neoplasms, four were the classic desmoplastic variant. In regard to the histological features used to grade neoplasms, considerable inter- and intratumoral variation was observed. The neoplasms with the most pleomorphic and coarsely structured nuclei tended to be neuroblastic, whereas the most delicate and uniform nuclei were found in the desmoplastic neoplasms. Twenty-one of the cases exhibited neuroblastic differentiation in the form of neuroblastic rosettes. Of these, three also contained neoplastic ganglion cells. Of the five medulloblastomas that were calcified, four contained neuroblastic rosettes in accord with the tendency for calcification in neuroblastic neoplasms. In many of the neuroblastic neoplasms, islands of markedly neuron-specific enolase (NSE)-positive cells were seen. Although the limited specificity of this marker enzyme is recognized, we believe that this focal intense staining could indicate neuronal differentiation somewhat more advanced than in small NSE-positive islands of reduced cellularity, many of which were strongly positive. The nuclei in these island were usually larger and more vesicular than those in the surrounding densely cellular areas. These features and the frequent association with Homer-Wright rosettes suggest that these foci represent a form of neuronal differentiation. Astrocytic differentiation was more difficult to define and required the use of staining for glial fibrillary acidic protein (GFAP). Six neoplasms contained GFAP-positive cells that were clearly neoplastic. Many others contained scattered reactive astrocytes and dispersed cells whose neoplastic versus reactive nature could not be defined.(ABSTRACT TRUNCATED AT 250 WORDS)

Methylation versus ethylation of DNA in target and nontarget tissues of Fischer 344 rats treated with N-nitrosomethylethylamine.

Bioactivation of N-nitrosomethylethylamine can be initiated by hydroxylation of either the methyl or ethyl moiety leading to an ethylating or methylating intermediate, respectively. This study was designed to determine which of these metabolic pathways predominates in vivo and to what extent DNA is alkylated in the target and nontarget tissues. Adult male Fischer 344 rats received a single i.p. or p.o. dose (4.4 mg/kg, 0.05 mmol/kg) of N-nitrosomethylethylamine, 14C-labeled in either the methyl or ethyl group (survival time, 4 h). DNA was analyzed by Sephasorb-HP chromatography following acid hydrolysis in 0.1 M HCl. Concentrations of 7-methylguanine in hepatic DNA were 170-200 times higher than those of 7-ethylguanine. This is approximately 2.6 times the 7-methylguanine:7-ethylguanine ratio of 68, observed when DNA is reacted in vitro with equimolar amounts of the direct alkylating agents N-nitrosomethylurea and N-nitrosoethylurea, suggesting that hydroxylation at the alpha-position of the ethyl group of N-nitrosomethylethylamine proceeds at about 2.6 times the rate as at the methyl group. Concentrations of 7-methylguanine in liver were approximately 15 times higher than in kidney, 100 times higher than in esophagus, and 200 times higher than in lung. Addition of ethanol to the drinking water (5%) caused a slight interorgan shift in metabolism with a decrease in the 7-methylguanine ratio for liver:esophagus by 50% and an increase in the 7-methylguanine ratio for liver:kidney by 40%.

Progressive myoclonic epilepsy (Unverricht type) with atypical Lafora bodies. Case report.

A patient with advanced progressive myoclonic epilepsy (Unverricht type) with Lafora bodies is presented. Although the clinical history and symptoms were classical, the regional distribution of the cerebral involvement differed from the classical picture: the corpora mamillaria, the nucleus subthalamicus, and the nucleus ruber, which are normally reported to be spared, contained multiple Lafora bodies, whereas the lateral geniculate body, which is usually involved, was intact. The number of inclusions per cell, up to 25, was extremely high and correlated with the marked cortical atrophy and the prolonged clinical course. Using electron microscopy, type I and type II Lafora bodies were found, but the latter lacked the typical filamentous ultrastructure in the peripheral zone. The lack of visceral Lafora bodies in this case suggests that liver, muscle, and skin biopsies, which are widely used for the diagnosis, may lead to false negative results and cannot always replace a stereotactic brain biopsy. The differential diagnosis on polyglucosan bodies is emphasized.

Antigenic heterogeneity of human anaplastic gliomas and glioma-derived cell lines defined by monoclonal antibodies.

The antigenic heterogeneity of human neuroectodermal tumors defined by both murine and human monoclonal antibodies (MAs) is reported; no patterns of reactivity defining degree of anaplasia, in vitro morphology, or immunogen used were apparent. We investigated the reactivity of 20 distinct murine MAs defining markers of glioma-associated or predominantly lymphoid distribution for 13 human glioma-derived (HGL) cell lines and frozen sections of 19 human glioblastoma multiforme (GBM) and six astrocytomas (AST). Methods included radioimmunoassay, immunofluorescence, immunohistochemistry, and absorption analysis. Two markers, HLA-A,B and human Thy-1, exhibited no deviation; all HGL cell lines tested bound high levels of specific MA. Individual HGL cell line reactivity with the MA panel ranged from 30 to 70%. HGL cell lines (7/13) which reacted with greater than or equal to 50% of the antiglioma MAs had the highest (30-70%) positive reactivity rates with the anti-lymphoid marker MA panel; complex antigenicity in one system correlated with multiple antigens in the other. Within the anti-lymphoid marker MA panel, subpopulations of 4/13 HGL cell lines were clearly positive for the HLA-DR (Ia) antigens; another 3/13 HGL cell lines were strongly positive for common acute lymphocytic leukemia antigen (CALLA). With the exception of Thymocyte 1 antigen (Thy-1), reactivity for early and mature T-cell markers was infrequent and sporadic. Lymphoid marker expression by HGL cell lines is highly heterogeneous, ranging from few (Thy-1 and HLA-A,B) to complex expression of Ia, T-cell, and lymphoid tumor markers. GBM and AST tissues were antigenically less complex; for each of 6/8 anti-glioma MA, 70-100% of GBM and 66-100% of AST were positive. Two MAs were highly reactive (7/10, 8/9) with GBM sections and minimally so (1/6) with AST. Antigenic expression in gliomas is complex and heterogeneous; however, clear differences in lymphoid marker expression, the identification of widely and rarely expressed glioma-associated antigens, and the potential of immunologic differentiation between GBM and AST by large panels of MAs will serve to reduce the complexity and may be of potential diagnostic or prognostic significance.