Synchronized brain network underlying postural tremor in Wilson's disease.

Common neurological manifestation of Wilson's disease (WD) is a postural tremor of the upper extremities. Recently, the primary sensorimotor cortex (S1/M1) has been shown to be involved in WD postural tremor generation. However, neuropathological changes in WD are mostly observed in subcortical structures. We therefore aimed to investigate whether S1/M1 may be functionally interconnected with other brain areas. In five WD patients, we used magnetoencephalography and surface electromyography (EMG) to record simultaneously cerebral neuronal activity and muscular activity during sustained posture of the right forearm. As demonstrated previously, the strongest coupling to tremor EMG was observed in the contralateral S1/M1. This area was taken as reference in order to identify and localize cerebro-cerebral coherence at tremor frequency and its first harmonic. The analysis revealed significant coherence within an oscillatory network including S1/M1, higher cortical motor areas (premotor cortex, PM; supplementary motor area, SMA), posterior parietal cortex (PPC) and thalamus contralateral as well as the cerebellum ipsilateral to the tremor forearm. Flow of information was mainly of bidirectional nature. Taken together, our results indicate that WD postural tremor is generated within a synchronized cerebello-thalamo-cortical network, comprising S1/M1, higher cortical motor areas (SMA, PM), and PPC.     

Successful treatment of tremor in Wilson's disease by thalamotomy: A case report.

Little information is available on the surgical treatment of movement disorders in Wilson's disease. We report a successful outcome of left-sided stereotactic thalamotomy in a 30-year-old man with Wilson's disease, who had severe postural-kinetic tremor of both hands. The improvement was bilateral. Our case illustrates that stereotactic thalamotomy may be considered as an option in treating severe tremor in selected patients of Wilson's disease and merit further trials.     

Undulating tongue in Wilson's disease

We report an unusual occurrence of involuntary movement involving the tongue in a patient with confirmed Wilson''s disease (WD). She manifested with slow, hypophonic speech and dysphagia of 4 months duration, associated with pseudobulbar affect, apathy, drooling and dystonia of upper extremities of 1 month duration. Our patient had an uncommon tongue movement which was arrhythmic. There was no feature to suggest tremor, chorea or dystonia. It might be described as athetoid as there was a writhing quality, but of lesser amplitude. Thus, the phenomenology was uncommon in clinical practice and the surface of the tongue was seen to “ripple” like a liquid surface agitated by an object or breeze. Isolated lingual dyskinesias are rare in WD. It is important to evaluate them for WD, a potentially treatable disorder.     

Extrapyramidal symptoms in Wilson's disease are associated with olfactory dysfunction.

Wilson's disease is a rare autosomal recessive disorder characterized by the accumulation of copper, mainly in the liver and the brain. As copper accumulation in the brain leads to disturbances in basal ganglia function, neurological-type patients typically present with hypo- and hyperkinetic extrapyramidal symptoms, with Parkinsonism being very common. Although there are numerous reports on olfactory deficits in primary neurodegenerative disorders, olfactory function has not been investigated in metabolic disorders presenting with extrapyramidal features. Twenty-four patients with Wilson's disease participated in the investigation. All patients were treated pharmacologically. They comprised patients with liver disease alone (including mild enzyme elevation in asymptomatic individuals; n = 11) and/or neurological symptoms (n = 13) at the time of testing. Twenty-one patients underwent both [18F]fluoro-2-deoxy-D-glucose positron emission tomography ([18F]FDG-PET) and magnetic resonance imaging (MRI). The severity of extrapyramidal symptoms was judged using a clinical score system ranging from 0 (no symptoms) to 3 (severe symptoms). In all patients, psychophysical testing was performed using the Sniffin' Sticks, which involved tests for odor threshold, discrimination, and identification. Results from the present study revealed that Wilson's disease patients with neurological symptoms show a significant olfactory dysfunction compared to hepatic-type patients. Individuals who are more severely neurologically affected also present with a more pronounced olfactory deficit. Of interest, there was no significant effect of long-term treatment with penicillamine on olfactory function. Olfactory function did not correlate significantly with the presence of MRI visible lesions in the basal ganglia or with any regional glucose metabolism as measured by [18]F-FDG-PET. In conclusion, these findings indicate that the underlying pathological alterations with degeneration in the basal ganglia and neuronal loss in association with a marked increase of the copper content in this brain region play a role in the olfactory deficit.     

Neurological manifestations in Wilson's disease: Report of 119 cases.

We describe the neurological manifestations of 119 patients with WD (93 index cases and 26 affected family members) seen between 1963 and 2004. The mean age at symptoms onset was 19.6 years (range, 7-37 years). Medical records were reviewed for the patient's first neurological examination. The most frequent neurological manifestations observed were dysarthria (91%), gait disturbance (75%), risus sardonicus (72%), dystonia (69%), rigidity (66%), tremor (60%), and dysphagia (50%). Less frequent manifestations were chorea (16%) and athetosis (14%). Rare neurological presentations were seizures (4.2%), and pyramidal signs (3%).     

Quality of life in Wilson's disease

Background:

Assessment of Quality of life (QoL) is fast assuming significance as the measure of health in many disorders.

Aim:

To correlate clinical severity and QoL in patients with Wilson''s disease (WD).

Materials and Methods:

We evaluated patients of WD on regular follow up for at least two years and aged over 18 years using Neurological Symptom Score (NSS) for clinical severity and WHO-BREF for QoL at a university teaching hospital. Patients with inability to respond to the questionnaire due to behavioral problems, low IQ or other disease related factors were excluded. These 30 patients (M:F:: 23:7) had a mean age of 27.97 ± 11.16 years at evaluation and the mean duration of treatment of 9.2 ± 6.4 years.

Results:

All four domains of WHO-QoL-BREF viz., Physical, Psychological, Social and Environmental correlated well with each other (p < 0.01). The NSS correlated inversely with the physical domain (p < 0.02), while the duration of treatment had a positive correlation with the physical domain (p < 0.01). None of the other features of QoL showed any significant correlation with age, NSS or duration of treatment.

Conclusion:

QoL is complementary to formal neurological assessment and should be routinely incorporated in the evaluation of outcome of patients with WD and other chronic neurological disorders.     

Symptomatic copper deficiency in three Wilson's disease patients treated with zinc sulphate

Wilson's disease (WD) is caused by excess of copper that leads to accumulation of copper mainly in the liver, brain and needs life-long decoppering therapy. However, overtreatment with anti-copper agents may lead to copper deficiency which may cause neurological and hematological symptoms. Copper is an important cofactor for many enzymes. This report describes three WD patients with diagnosed copper deficiency during zinc sulphate (ZS) treatment. After 5–16 years of therapy all patients developed leucopenia. Spinal cord injury was manifested in two of the patients. One of them also presented myopathy. In conclusion, copper deficiency may occur in different time after treatment onset, therefore regular copper metabolism and hematological monitoring is necessary.     

Wilson's disease presenting with an unusual cough.

A 26-year-old man developed an unusual repetitive, nonproductive cough. Extensive pulmonary and otolaryngology investigations failed to disclose a cause. It was only after he developed additional neurological manifestations ultimately leading to the diagnosis of Wilson's disease (WD) that a neurological basis for the cough was suspected. Features of the cough suggest it was a form of respiratory dyskinesia, a previously unreported presentation of WD.     

Evaluation of the Unified Wilson's Disease Rating Scale (UWDRS) in German patients with treated Wilson's disease

Wilson's disease (WD) is an inherited autosomal‐recessive disorder of copper metabolism characterized by a wide variety of neurological, hepatic, and psychiatric symptoms. The aim of the present study was the development and evaluation of a clinical rating scale, termed Unified Wilson's Disease Rating Scale (UWDRS), to assess the whole spectrum of clinical symptoms in WD. Altogether 107 patients (mean age 37.6 ± 11.9 years; 46 male, 61 female) with treated WD participated in the study. Cronbach's alpha as a measure of the internal consistency for the entire scale was 0.92, whereas the intraclass correlation coefficient (ICC) was 0.98 (confidence interval (CI_95%) 0.97–0.99), indicating an excellent interrater reliability as determined in 32 patients. Besides the total score was significantly correlated with the earning capacity of the patients as indicated by an estimated Spearman's ρ ≈ 0.54 (CI_95% 0.40–0.69, P < 0.001). In summary, the UWDRS appears to be a promising tool to assess the disease severity in WD. Its usefulness in clinical research and drug trials should be further addressed. © 2007 Movement Disorder Society     

Fine motor skills disorders in the course of Wilson's disease

Objectives

Fine motor skills disorders belong to the neurological manifestation of Wilson''s disease. The aim of this study is to investigate if fine motor performance changes during the course of the disease and with therapy.

Methods:

In 15 neurological patients with Wilson''s disease, severity of neurological symptoms was assessed with a neurology score. A test battery consisting of the hand writing of a test sentence, lines of “double-I” and retracing a circle was carried out for analysis. By means of a computer-aided analysis of the patient''s handwriting, 10 kinematic parameters of the writing trace were calculated. These parameters were determined once at the very beginning of the study and then again after 7 years.

Results:

Improvement of clinical symptoms was observed after onset of therapy only within the first 2 years. In contrast to the standard population, a reduced degree of automation could be detected both at the beginning and at the end of the 7-year interval. There was no significant change in 8 out of the 10 kinematic parameters during the observation period, 2 deteriorated.

Discussion:

The absence of a significant increase in fine motor disturbances proves, on the one hand, the efficacy of the therapy regime applied. On the other hand, the end point of a possible reversibility had been reached. A computer-aided analysis of the patient''s handwriting allows for a sensitive detection of the “functional scar” in the extrapyramidal control and can subsequently prompt a timely correction of therapy in case of progression.     

Neuropsychological findings in treated Wilson's disease

Seventeen patients, treated for Wilson's disease (WD), underwent a set of neuropsychological tests and were compared with a closely matched control group. There were clear differences between the groups (chi 2-test, p less than 0.0001). Wilson patients with only hepatic involvement, however, did not at all differ from their controls. Wilson patients with neuropsychiatric signs differed from controls on a reasoning test (p = 0.0016), and the entire WD group differed on a perceptual speed task (p = 0.0025). Compared to normal test values, however, the patients' group means were all within plus or minus one standard deviation from the normal mean. Special testing procedures and construction of the test battery excluded a factor of motor deficits as a major cause for the differences. The neuropsychological findings are viewed in relation to other findings in patients with motor disorders and predominantly subcortical lesion sites. Wilson's disease may be a dementing condition, but not when treated adequately.     

Neurological presentation of Wilson's disease in a patient after liver transplantation

We report of a 32‐year‐old man who showed dystonic symptoms within few days after liver transplantation (LT). The clinical, biochemical, and, finally, genetic evaluation confirmed Wilson's disease diagnosis in this patient. We suspect that extrapyramidal signs in this case could be a result of acute brain injury because of the massive copper release from liver to the circulation just before and during LT. © 2008 Movement Disorder Society     

Metabolic changes in 37 newly diagnosed Wilson's disease patients assessed by magnetic resonance spectroscopy

Wilson's Disease (WD) is a rare autosomal recessive disorder. The literature about proton MR spectroscopy (MRS) in WD is based mostly on data derived from patients undergoing treatment. The aim of this study was to identify brain metabolic changes in newly diagnosed WD patients using MRS to elucidate the pathomechanism of the cerebral pathology of WD. The globus pallidus and thalamus of 37 patients with WD were examined bilaterally with MRS. The calculations were performed for: myoinositol (mI), choline (Cho), creatine (Cr), N-acetyl-aspartate (NAA), lipid (Lip), glutamine, and glutamate (Glx). In all WD patients a significantly decreased mI/Cr and NAA/Cr ratio levels and an increased Lip/Cr ratio in the pallidum were observed. Analysis revealed a significantly increased Glx/Cr and Lip/Cr ratio in the thalamus. In the pallidum of neurologically impaired patients, Cho/Cr, Glx/Cr and Lip/Cr ratios were higher than in control subjects, and the NAA/Cr was significantly lower. In hepatic patients, the mI/Cr, Cho/Cr and NAA/Cr ratio levels were lower than in controls. The Cho/Cr and Lip/Cr ratios were higher in the thalami of neurologically impaired patients, and Lip/Cr ratios were higher than controls' in hepatic patients. Both findings were statistically significant. Compared to the thalamus, the basal ganglia are more sensitive to ongoing degenerative changes and portal-systemic encephalopathy in WD. The NAA/Cr reduction in hepatic and neurologically impaired patients could indicate that neurodegeneration is associated with all presentations of WD. In hepatic patients a mI and Cho decrease and in neurological Glx increase can be caused by porto-systemic shunting.     

Thalamic neurometabolic alterations in tremulous Parkinson's disease: A preliminary proton MR spectroscopy study

IntroductionThe objective of this study was to investigate the thalamic biochemical changes in tremor-dominant Parkinson's disease (tPD) patients in comparison with essential tremor with resting tremor (rET) patients, by using proton MR spectroscopy (¹H-MRS).MethodsFourteen tPD patients, 12 rET patients and 10 controls participated in this study. All patients underwent dopamine transporter single-photon emission computed tomography (DAT-SPECT) with ¹²³I-ioflupane, and a short-echo single-voxel ¹H-MRS on a 3T scanner. A voxel of 10 × 15 × 10 mm involving the Vim nucleus was acquired in both thalami of all subjects. Peak areas of N-acetyl-aspartate (NAA), creatine (Cr), glycerophosphocholine (Cho), and glutamate (Glu) were measured for each voxel using LCModel. The NAA/Cr, Cho/Cr, and Glu/Cr ratios were then calculated.ResultsDAT-SPECT was abnormal in tPD patients, whereas it was normal in rET patients. Patients with tPD showed a significant reduction of NAA/Cr and Cho/Cr in the thalami compared to rET and healthy controls; whereas there were no significant differences between rET patients and controls. The combination of thalamic NAA/Cr and Cho/Cr ratios showed a 100% accuracy in distinguishing tPD patients from rET patients and controls.ConclusionsThis study provides preliminary evidence that thalamic neurometabolic abnormalities occur in tremor-dominant phenotype of PD, and suggests that ¹H-MRS can help differentiate patients with tPD from those with rET.     

Abnormal antisaccades and smooth pursuit eye movements in patients with Wilson's disease

Neurological symptoms in Wilson's disease (WD) may include oculomotor abnormalities. However, to date, eye movements in WD patients were rarely investigated and the data concerning this issue are sparse. The purpose of this study was to evaluate reflexive and voluntary eye movements in WD patients. We examined horizontal saccadic and smooth pursuit eye movements using infra‐red oculography in 50 WD patients, including 29 neurologically symptomatic (WDn) and 21 asymptomatic ones (WDa), and in 29 healthy controls. We found statistically significant increase in mean antisaccadic latency (378 ms) and in mean antisaccadic error rate (22.5) in the WDn group, when compared with WDa group (317 ms and 9.1, respectively) and controls (318 ms and 9.7, respectively). In contrast, there were no statistically significant differences in mean latency of prosaccades and in size of the gap effect. Patients with neurological manifestations had also abnormal smooth pursuit—increased number of saccadic intrusions (mean: 8.6) and decreased gain (mean: 0.69) comparing with WDa patients (4.1 and 0.83, respectively) and controls (2.2 and 0.91, respectively). The data suggest that WD is associated both with impairment of voluntary control of saccades and with disturbed smooth pursuit eye movements while reflexive saccades seem to be preserved. © 2008 Movement Disorder Society