Oculomotor abnormalities in diseases of the basal ganglia

Disorders of eye movements have been described in diseases of the basal ganglia for over a century. Recent neurophysiological and clinical work has greatly clarified the oculomotor role of these structures: their major involvement appears to be in the generation of "voluntary" saccades, and in the suppression of "reflex" saccades. The observed abnormalities of saccadic eye movements in Huntington's (HD) and Parkinson's (PD) diseases conform very well to predictions based on a combination of known disease pathology and recent neurophysiological work. This is not quite the case for other types of eye movement, such as smooth pursuit, largely because the exact role of the basal ganglia in their generation has not been defined neurophysiologically. Several diseases other than HD and PD both involve the basal ganglia and have effects on eye movements; such diseases include progressive supranuclear palsy and Wilson's disease. Unfortunately, the pathological processes in these conditions are too widespread to allow comment on how well oculomotor abnormalities fit in with predictions.     

Visual pathway abnormalities Wilson's disease: an electrophysiological study using electroretinography and visual evoked potentials

The pathogenesis of the pattern reversal visual evoked potential (PRVEP) abnormalities in patients with Wilson's disease (WD) has not been investigated earlier. Since electroretinography (ERG) assesses the functional integrity of the retina, it was used along with PRVEP to localize the abnormalities in PRVEP in Wilson's patients. Ten newly diagnosed Wilson's disease patients underwent PRVEP and flash ERG soon after the diagnosis was established. The PRVEP latencies were prolonged in comparison with the controls (P<0.001). Photopic and scotopic A waves and oscillatory potentials were prolonged (P<0. 02) with reduction in amplitudes of photopic A and B waves (P<0.001). Six of these patients were subjected to repeat PRVEP and flash ERG after the clinical improvement with specific therapy. Comparison of the pre and post-treatment visual electrophysiological studies revealed significant reduction in latencies of PRVEP and flash ERG A wave (P<0.05) with increase in amplitudes of P100 of PRVEP (P<0.05), A and B waves of flash ERG (P<0.01). These findings confirm the reported PRVEP changes in WD and in addition demonstrate the reversibility of the retinal dysfunction which partially contributes to the PRVEP abnormalities. To the best of our knowledge this is the first study of ERG in patients with Wilson's disease in the literature. Further, there have been no earlier reports in the literature evaluating the effect of specific treatment on the PRVEP and ERG in Wilson's disease.     

Wilson''s disease: clinical groups in 400 cases

Existence of clinical subgroups among cases of Wilson's disease has long been postulated and various classifications suggested but none statistically tested. This study analyses, by means of pattern recognition techniques, 400 cases from 4 series including our own (n = 195). Factor analysis (to summarise variables) and cluster analysis (to derive groups of patients) were performed. From each series 4 clusters were derived, each containing a "hepatic" and at least one "neurological" cluster, other clusters being "mixed hepatic & neurological" (3 series) and "asymptomatic" (3 series). Two series contained 2 "neurological" clusters; one dividing in terms of age and the other in terms of presence or absence of psychopathology. At least 2 factors, "hepatic" and "neurological", emerged from each series. Reasons for differences are discussed. In conclusion, Wilson's disease is not homogenous: clinical groupings are supported by statistical classification.     

The role of event related potentials in evaluation of subclinical cognitive dysfunction in epileptic patients

BACKGROUND/AIM: Cognitive dysfunction in epileptic patients may develop due to the neurophysiological changes related to seizures or antiepileptic drugs. The aim of this study was to evaluate the cognitive dysfunction in epileptic patients under antiepileptic drug therapy by the aid of event related potentials. METHOD: P300 latencies were obtained from Fz, Cz and Pz electrod positions from both epileptic patients (n=40) and age and sex matched control group (n=40). Epileptic patients were classified either idiopathic primary generalized (IPGE) (n=9) or secondary generalized epilepsy (SGE) (n=31) based on the ILAE classification. The effect of epilepsy type, treatment types (monotherapy/polytherapy), daily dosages and serum levels of antiepileptic drugs, age at onset and EEG abnormalities on P300 latencies were studied. RESULTS: P300 latencies were longer in the epileptics when compared to controls (P < 0.05). Besides, our results pointed out that P300 latencies were longer in IPGE when compared to SGE (P < 0.05). No statistically significant difference was determined between ERP parameters neither in monotherapy nor in polytherapy groups (p > 0.05). Antiepileptic drug subgroups revealed variable effects on ERP latencies. CONCLUSION: We believe P300 latencies may have an important role in the evaluation of subclinical cognitive dysfunction in epileptic patients treated with antiepileptic drugs.     

Brain-stem auditory evoked potentials in different types of hepatic diseases

Brain-stem auditory evoked potentials (BAEPs) were studied in 69 patients with different types of hepatic diseases. BAEPs were normal in viral hepatitis, but the peak V and interpeak I-V latencies were prolonged in liver cirrhosis. Prolongation in peaks III, IV and V and interpeaks I-III, III-V and I-V were observed in both alcoholic liver disease and Wilson's disease with the latter more severely affected. The present data indicate that BAEPs may be used to study the effect of various hepatic diseases on the CNS.     

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.     

Neurogenetics--the challenge for neurology. 1. Neurogenetic diseases]

Progress in molecular genetics has provided insight into a number of neurogenetic disorders. The chromosomal location of the genes for Huntington's disease, Wilson's disease, myotonic dystrophy and Friedreich's ataxia are now known. In families affected by these illnesses, linkage analysis can now be employed for presymptomatic or prenatal diagnosis. The genes for Duchenne and Becker muscular dystrophy and neurofibromatosis I have been cloned and sequenced, allowing the direct analysis of the genetic defect in many cases, and thereby providing further insight into the pathophysiology. In addition, the classification of several neurogenetic diseases, such as the hereditary motor and sensory neuropathies or the spinal muscular atrophies can now be based on the chromosomal location of the affected gene(s).     

Plasma and erythrocyte copper, zinc, manganese and magnesium concentrations in Wilson's disease

Plasma copper was significantly reduced in Wilson's disease with decreased ceruloplasmin levels, while there was no significant difference in erythrocyte copper levels between Wilson's disease and controls. Mean zinc and manganese levels in plasma were increased in Wilson's disease, but these differences were not significant. Mean magnesium level in plasma was normal. The levels of these metals in erythrocytes showed no difference between Wilson's disease and controls. Our results suggest that the abnormal copper level in plasma is not due to the primary metabolic defects, but is probanly due to the level of the binding proteins in plasma to this metal, ceruloplasmin, in Wilson's disease.     

Frequency of His1069Gln and Gly1267Lys mutations in Polish Wilson's Disease population

Wilson's disease is an autosomal recessive disorder. More than 60 mutations of the Wilson's disease gene have been described so far. We have analysed 148 Polish Wilson's disease patients from 95 families for His1069Gln and Gly1267Lys mutations and correlated this finding with age and clinical form of the disease at presentation. To identify these mutations, single strand conformation polymorphism analysis was performed. In our group there were 94 patients with neurological presentation, 28 with hepatic presentation, whilst 26 were in a pre-clinical stage of the disease. His1069Gln mutation was present on 171 (57%) of the 296 studied chromosomes, and Gly1267Lys mutation was present on 27 chromosomes (9.1%). Most of our patients were homozygous or heterozygous for His1069Gln mutation (39.9% and 30.4%, respectively); 4% of the patients were homozygous for Gly1267Lys mutation and 5.4% had both of these described mutations on their chromosomes. His1069Gln and Gly1267Lys mutations occurred often in our Wilson's disease patient population but we did not find any relationship between investigated mutations and the clinical form of Wilson's disease or age of first symptoms.     

Wilson’s病基因连锁分析及早期诊断和杂合子检出

本文利用３个ＤＮＡ标记探针对１５个ＷＤ家系８５名成员进行连锁分析，同时结合其临床铜生化检测结果。在４０名同胞中，检出６名为症状前患者，１５名为杂合子，１０名为正常人，此结果在８０％可信限内。结果表明，应用此三个ＤＮＡ标记对ＷＤ基因进行连锁分析是有效的。     

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. Received: 6 July 2001, Received in revised form: 14 November 2001, Accepted: 3 December 2001     

Wilson's disease associated with olfactory paranoid syndrome and idiopathic thrombocytopenic purpura]

In this study we report an individual of Wilson's disease associated with olfactory paranoid syndrome and idiopathic thrombocytopenic purpura. The initial symptom of this female patient was olfactory paranoia at age 17. Although that psychiatric symptom was well controlled under pharmacological treatment for two years, she developed olfactory paranoia as well as sialorrhea, dysarthria and finger tremor at age 20. A year later rigidity was also present in the extremities. At age 23, idiopathic thrombocytopenic purpura was found based on hematological examinations. Because her extrapyramidal symptoms were progressive, she was referred to our department to evaluate her neurologic condition. She was diagnosed as having Wilson's disease based on (1) the presence of Kayser-Fleischer rings, (2) extrapyramidal signs, and (3) a decreased level of serum copper and ceruloplasmin. T2 and FLAIR images of brain MRI showed hyperintense lesions in the putamen, thalamus and pontine tegmentum. Diffusion-weighted images also showed hyperintense lesions in the thalamus and pontine tegmentum. The biopsy specimen of the liver revealed chronic hepatitis with copper accumulation. Since D-penicillamine treatment was initiated, she has shown no olfactory paranoia and exacerbation of ITP. Her gait disturbance has also improved. Olfactory paranoia and ITP are rare clinical complications of Wilson's disease. Further analysis may warrant consideration of the pathophysiological mechanism of the psychiatric, hematological and neuroradiological condition seen in Wilson's disease.     

退行性膝骨关节病中医辨证分型的聚类分析

背景：目前各医家对膝关节退行性骨关节病的理解与认识还不完善,对于病机、治法及证型等仍然存在一定的分歧,使得治疗时存在较大的差异,究其原因是对于中医证型分类及诊断的客观研究较少。因而运用聚类分析的数理统计方法深入研究证型分类,对于指导中医和中西医结合临床的治疗工作意义颇大。 目的：系统聚类分析了解膝关节退行性骨关节病中医证型分布的情况。 方法：根据膝关节退行性骨关节病患者的临床表现设计调查表,收集70例患者的中医症状、体征、舌象、脉象等四诊信息,运用系统聚类分析统计方法,结合临床专业知识,探索总结本病的中医证型特征。 结果与结论：膝关节退行性骨关节病病位在膝,与肝肾两脏关系密切,病机以肝肾亏虚、风寒湿痹为主,系统聚类分析结果显示本病可大致分为3类证型:第1类以肝肾亏虚表现为主;第2类以风寒湿痹表现为主;第3类以气滞血瘀表现为主。结果表明肝肾亏虚为主兼以风寒湿痹是膝关节退行性骨关节病的基本证型,聚类分析可用于疾病的证候分类。     

Neurophysiological classification of ulnar entrapment across the elbow

Ulnar nerve entrapment across the elbow (UAE), a common entrapment, requires neurophysiological evaluation for a diagnosis, but a standardized neurophysiological classification is not available. The aim of our study was to evaluate the validity of a neurophysiological classification of UAE, developed by us. To this end, we examined whether sensorimotor deficits, as observed by the physician and as referred by the patients, increased with the neurophysiological severity according to the classification. We performed a multiperspective assessment of 63 consecutive arms from 52 patients with a clinical diagnosis of UAE. Neurophysiological, clinical and patient-oriented validated measurements were used. The neurophysiological classification is based on the presence or absence of evoked responses and on the normality or abnormality of conduction findings. A strict relationship was observed between the degree of neurophysiological severity and the clinical findings (sensorimotor deficits). Moreover, a significant positive correlation between hand functional deficit and neurophysiological classification was observed. Conversely, a clear correlation between neurophysiological pattern and symptoms was not found. The neurophysiological classification is easy to use and reliable, but further multicentric studies should be performed. Received: 9 February 2001 / Accepted in revised form: 18 April 2001     

Mania as the first manifestation of Wilson's disease

Background:  Although mental changes are frequent in Wilson's disease, severe psychiatric disorders occur uncommonly and usually accompany the neurological picture. There are few reports in the literature of Wilson's disease patients with typical bipolar affective disorder (BPAD).
Case report:  The authors report the case of a patient with Wilson's disease whose initial manifestation was a manic episode followed by depression. Tremor in the upper limbs appeared one year after the onset of symptoms. The diagnosis of Wilson's disease was established three years after the first symptoms appeared, based on the neuropsychiatric picture, the detection of Kayser–Fleischer rings and the results of diagnostic tests indicating chronic liver disease and copper excess. ATP7B genotyping and magnetic resonance imaging of the brain with proton spectroscopy study were also performed. The patient became asymptomatic two years after starting treatment with penicillamine and remained non-symptomatic controlled during the eight-year follow-up period, without any specific treatment for the BPAD.
Conclusions:  To our knowledge, this is a singular report of a case of Wilson's disease in which a manic episode preceded the onset of neurological symptoms. The association between Wilson's disease and bipolar disorder is discussed.     

The interaction of motor, memory, and emotional dysfunction in Wilson's disease.

Measures of the degree of motor, psychiatric, and declarative memory disability were made in neurologically impaired and neurologically asymptomatic patients with Wilson's disease. All three types of disability were significantly greater in the neurologically impaired than in the asymptomatic patients. There was no significant interaction between these disabilities in the impaired patients suggesting that motor, psychiatric, and memory symptoms are three relatively independent sequelae of the copper-induced central nervous system (CNS) damage that underlies Wilson's disease.     

Somatosensory evoked potentials: monitoring cerebral functions following liver transplantation

Serial somatosensory evoked potentials (SEPs) were obtained from a patient with Wilson's disease who had had liver transplantation. Correlating with recovery of hepatic encephalopathy and liver functions following the surgery, SEPs showed progressive normalization of peak latencies and waveforms. The data indicate that SEP may be a useful objective method in assessing recovery of cerebral functions following liver transplantation.     

Circling seizures in a case with Wilson's disease.

We report a case of Wilson's disease with circling seizures. Because of the existence of other types of frontal automatism and the EEG focus on the frontal regions, circling seizures of the patient were thought to originate from the frontal lobe. Magnetic resonance imaging demonstrated large cavitary lesions on bilateral frontal lobes. The mechanisms of circling behavior are discussed in association with Wilson's disease.     

Abnormal conduction in corticospinal pathways in Wilson's disease: investigation of nine cases with magnetic brain stimulation.

Electromyographic (EMG) responses evoked by transcranial magnetic brain stimulation were studied in nine patients with Wilson's disease (WD). Six of the nine patients had prolonged central motor latencies (CMLs), reduced amplitude, or absent responses in at least one of the examined muscles. In one patient, abnormal EMG responses normalized following treatment with penicillamine. Pathophysiologically abnormal EMG responses might result from a potentially reversible impairment of corticomotoneuronal pathways and/or a reduced excitability of motoneurons due to basal ganglia dysfunction. The possible pathophysiological mechanisms are discussed.     

Genetic disorders of copper transport--diagnosis and new treatment for the patients of Wilson's disease

Wilson's disease and Menkes disease are inherited genetic disorders of copper metabolism. Each disease results from the absence or dysfunction of homologous copper-transporting ATPases present in the trans-Golgi network of cells. The Wilson ATPase transports copper into the hepatocyte secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, patients with Wilson's disease of the autosomal recessive trait present with signs and symptoms arising from impaired biliary copper excretion. The Menkes ATPase transports copper across the placenta, gastrointestinal tract, and blood-brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same fashion within the cell. The different clinical features of each disease are the results of the tissue specific expression of these ATPases. In Wilson's disease, impaired biliary copper excretion leads to accumulation of this metal in the liver. When the capacity for hepatic storage is exceeded, cell death ensues, with copper release into the plasma resulting in hemolysis and deposition of copper in extrahepatic tissues. Affected patients usually present in the first or second decade of life with chronic hepatitis and cirrhosis or acute liver failure. Copper accumulation in the cornea results in Kayser-Fleischer rings. Neuropsychiatric symptoms are more common in adults and include dystonia, tremor, personality changes, and cognitive impairment as a results of copper accumulation in the basal ganglia and other brain regions. The diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper, and elevated hepatic copper concentration. A large number of different mutations occur in the genes of patients with Wilson disease. Copper chelation drugs and zinc are effective in most cases. New treatment guidelines now advise physicians to start patients on zinc.