Neurological Wilson's Disease Patients Research Articles

Clinical Spectrum, Radiological Correlation and Outcome of Movement Disorders in Wilson's Disease.

Movement disorders are the commonest clinical presentation in patients with neurological Wilson's disease (NWD). There are very few studies evaluating the spectrum, severity and their correlation with magnetic resonance imaging (MRI) changes of movement disorders in NWD. To study the spectrum, topographic distribution, radiological correlate, temporal course and outcome in our cohort of NWD patients. Retrospective chart review of the NWD patients having movement disorders was performed and analyzed. Sixty-nine patients (males- 47) with NWD were analysed and the mean age at the onset of neurological symptoms was 13.6 ± 6.6 years (median 13 years; range 7-37 years). The first neurological symptom was movement disorder in 55 (79.7%) patients. Tremor (43.6%) and dystonia (41.8%) was the commonest movement disorder as the first neurological symptom. Dystonia (76.8%) was the most common overall movement disorder followed by parkinsonism (52.1%) and tremors (47.8%). Chorea (10.1%), myoclonus (1.4%) and ataxia (1.4%) were the least common movement disorder. Putamen was the most common affected site (95.6%) followed by caudate nucleus (73.9%), thalamus (60.8%), midbrain (59.4%), internal capsule (49.2%), pons (46.3%). Putamen was the most common area of abnormality in dystonia (98%), tremors (85%). Caudate (75%) and putamen (75%) was the most common areas of abnormality in parkinsonism. Favourable outcome was observed in 42 patients (60.8%) following treatment. Dystonia is the most common movement disorder in NWD in isolation or in combination with parkinsonism and tremors. Putamen is the most common radiological site of lesions and more frequently affected in patients with dystonia and tremors. Favourable outcome does occur with appropriate medical and surgical treatment.

Free water imaging as a novel biomarker in Wilson's disease: A cross-sectional study

BackgroundThe bi-tensor free water imaging may provide more specific information in detecting microstructural brain tissue alterations than conventional single tensor diffusion tensor imaging. The study aimed to investigate microstructural changes in deep gray matter (DGM) nuclei of Wilson's disease (WD) using a bi-tensor free water imaging and whether the findings correlate with the neurological impairment in WD patients. MethodsThe study included 29 WD patients and 25 controls. Free water and free water corrected fractional anisotropy (FAT) in DGM nuclei of WD patients were calculated. The correlations of free water and FAT with the Unified WD Rating Scale (UWDRS) neurological subscale of WD patients were performed. ResultsFree water and FAT values were significantly increased in multiple DGM nuclei of neurological WD patients compared to controls. WD patients with normal appearing on conventional MRI also had significantly higher free water and FAT values in multiple DGM nuclei than controls. Positive correlations were noted between the UWDRS neurological subscores and free water values of the putamen and pontine tegmentum as well as FAT values of the dentate nucleus, red nucleus, and globus pallidus. In addition, the measured free water and FAT values of specific structures also showed a positive correlation with specific clinical symptoms in neurological WD patients, such as dysarthria, parkinsonian signs, tremor, dystonia, and ataxia. ConclusionsFree water imaging detects microstructural changes in both normal and abnormal appearing DGM nuclei of WD patients. Free water imaging indices were correlated with the severity of neurological impairment in WD patients.

Clinical and Genetic Analysis in Neurological Wilson's Disease Patients With Neurological Worsening Following Chelator Therapy.

Objectives: None of the previous studies have focused on the genetic effect on neurological worsening in neurological Wilson’s disease (WD) patients following chelator therapy. We aimed to evaluate the clinical and genetic role in the occurrence of neurological worsening. Methods: We retrospectively reviewed the medical records of neurological WD patients who received initial chelator therapy and genetic test. Clinical, laboratory, and genetic data were collected. The genotype was classified into two types: 1) severe mutation genotype: patients who carried at least one of the following three types of mutations: frameshift mutation, splicing mutation, or nonsense mutation; 2) non-severe mutation genotype: patients who only carried missense mutations. Then, the clinical features and genotype of the patients with and without neurological worsening were investigated. Results: Forty-seven neurological WD patients were identified with a median age at onset of 16.17 years (range 7.75–47 years) and 35 (74.5%) males. The mean interval from onset to diagnosis was 0.6 years (range: 0.5 months-6.25 years). Neurological deterioration was observed in 29 patients (61.7%) and the other 18 patients (38.3%) were stable or improved during anti-copper treatment. The neurological worsening was completely irreversible in 6 cases (20.7%) and partially irreversible in 16 cases (55.2%). The common deteriorated symptoms were as follows: rigidity in 20 cases (69%), speech difficulties in 20 cases (69%)), walking difficulties in 13 cases (44.8%), dysphagia in 9 cases (31%), and salivation in 9 cases (31%). The patients with neurological worsening had significantly younger age (p = 0.028), shorter delayed diagnosis time (p = 0.011), higher rate of dystonia (p = 0.003), and severe mutation genotype (p = 0.036), compared to those without neurological worsening. Conclusion: We found that younger age of onset, the presence of dystonia, and genotype with severe mutations may be predictive of neurological worsening in the neurological WD patients that received chelator therapy. For those patients, chelator therapy should be given with caution and needs closer observation during follow-up.

Paramagnetic Metal Accumulation in the Deep Gray Matter Nuclei Is Associated With Neurodegeneration in Wilson's Disease.

BackgroundNeuropathological studies have revealed copper and iron accumulation in the deep gray matter (DGM) nuclei of patients with Wilson’s disease (WD). However, the association between metal accumulation and neurodegeneration in WD has not been well studied in vivo. The study was aimed to investigate whether metal accumulation in the DGM was associated with the structural and functional changes of DGM in neurological WD patients.MethodsSeventeen neurological WD patients and 20 healthy controls were recruited for the study. Mean bulk susceptibility values and volumes of DGM were obtained from quantitative susceptibility mapping (QSM). Regions of interest including the head of the caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, red nucleus, and dentate nucleus were manually segmented. The susceptibility values and volumes of DGM in different groups were compared using a linear regression model. Correlations between susceptibility values and volumes of DGM and Unified Wilson’s Disease Rating Scale (UWDRS) neurological subscores were investigated.ResultsThe susceptibility values of all examined DGM in WD patients were higher than those in healthy controls (P < 0.05). Volume reductions were observed in the head of the caudate nucleus, globus pallidus, putamen, thalamus, and substantia nigra of WD patients (P < 0.001). Susceptibility values were negatively correlated with the volumes of the head of the caudate nucleus (rp = −0.657, P = 0.037), putamen (rp = −0.667, P = 0.037), and thalamus (rp = −0.613, P = 0.046) in WD patients. UWDRS neurological subscores were positively correlated with the susceptibility values of all examined DGM. The susceptibility values of putamen, head of the caudate nucleus, and dentate nucleus could well predict UWDRS neurological subscores.ConclusionOur study provided in vivo evidence that paramagnetic metal accumulation in the DGM was associated with DGM atrophy and neurological impairment. The susceptibility of DGM could be used as a biomarker to assess the severity of neurodegeneration in WD.

Predictors of caregiver burden in patients with neurologic Wilson disease.

ObjectivesCaregiver burden in neurologic Wilson disease (NWD) has received little attention. We investigated predictors of caregiver burden in Chinese NWD patients.MethodsParticipants in this retrospective study were NWD patients admitted to The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from 1 August to 31 December 2019. Sociodemographic information was recorded for caregivers and NWD patients. Caregiver burden was evaluated using the Caregiver Burden Inventory (CBI). Cognitive impairment, functional problems, depression and anxiety were evaluated by professional interviewers. Path analysis was used to evaluate predictors of CBI scores.ResultsSixty NWD patients were enrolled (mean age: 21.35 ± 4.89 years; mean NWD duration: 7.85 ± 3.11 years). The mean CBI score was 52.00 ± 17.16. Care duration had a significant direct effect on CBI score after controlling for confounders (r = 0.493). Cognitive impairment (r = −0.426), functional problems (r = 0.581), depression (r = 0.349) and anxiety (r = 0.317) had significant indirect effects on CBI score.ConclusionCaregivers of NWD patients may experience a medium level of caregiver burden. NWD duration, cognitive impairment, functional problems, depression and anxiety in NWD patients may be useful predictors of caregiver burden.

Semiquantitative Scale for Assessing Brain MRI Abnormalities in Wilson Disease: A Validation Study.

MRI is a sensitive method for the assessment of brain abnormalities in Wilson disease, that is, T2 hyperintensities, T2 hypointensities, and atrophy, but a validated scoring system for the classification of radiological severity is lacking. The objective of this study was to develop and validate a brain MRI visual rating scale for Wilson disease. The proposed Wilson disease brain MRI severity scale consists of acute toxicity and chronic damage subscores from predefined structures. The former, calculated by summing scores of T2 hyperintensities (excluding cavitation), is likely to be partially reversible with treatment. The latter, representing the sum of scores of T2 hypointensities and brain atrophy, reflects pathology that is not readily reversible. Validation was performed on MRI scans acquired using 1.5T system from 39 Wilson disease patients examined at baseline and after 24 months on anticopper treatment. Intraclass correlation coefficients of 5 ratings from 3 raters were calculated. Temporal evolution of the MRI severity score and its association with clinical severity, assessed using the Unified Wilson Disease Rating Scale part III, was calculated. Intrarater and interrater agreement were good (r > 0.93; P < 0.001; and r > 0.74; P < 0.001, respectively). In neurologic Wilson disease patients, the total MRI severity score improved over 2 years (P = 0.032), mainly because of reduced acute toxicity (P = 0.0015), whereas the chronic damage score deteriorated (P = 0.035). Unified Wilson Disease Rating Scale part III score was positively associated with chronic damage and total score at baseline (P = 0.005 and P = 0.003, respectively) and in month 24 (P < 0.001 and P = 0.001, respectively). The Wilson disease brain MRI severity scale is a simple, reliable, and valid instrument that allows semiquantitative assessment of radiological Wilson disease severity. © 2020 International Parkinson and Movement Disorder Society.

Liver Transplantation and Auxiliary Partial Orthotopic Transplantation Outcomes in Wilson’s Disease

Introduction Liver transplantation (LT) is an effective option for Wilson's disease (WD) patients with neurologic symptoms, acute liver failure and with advance decompansated liver disease. In this retrospective study we aimed to review our LT results for WD patients. Materials and Methods Between December 1988 and October 2017 we performed 580 LT procedures at our center (age range, 6 months-64 years). We performed 53 LT in WD (45 living donor LT, 8 deceased donor LT) and after discharge we followed them for 12-350 months. We evaluated the regression of neurologic symptoms and reported survival, graft function of WD patients after LT. Results We performed LT for acute liver failure in 7 WD patients and for end stage liver failure in 41 WD patients. Five patients had LT for neurological WD. One of these neurological WD patients had auxiliary partial orthotopic LT (APOLT) due to neurological WD without hepatic failure (child A). After APOLT he is doing well with normal liver functions and ceruloplasmin levels. All neurologic symptoms were regressed in all of these 5 neurological WD patients. Four of these 53 WD patients had retransplantation (due to 1 primary non-function and 3 chronic rejections) and 3 retransplant patients are doing well with normal liver functions. Thirteen of 53 WD patients died; 6 patients died in early postoperative period, 7 patients died during their follow up due to complications unconnected to WD. The remaining 40 patients have normal liver functions in their follow up (range 12-350 months). Our long term survival is 85%. Conclusion Liver transplantation for WD with end stage liver failure and neurological WD has good outcomes. We may also consider auxiliary partial orthotopic LT for progressive neurological WD patients with no hepatic insufficiency.

Frequencies of initial gait disturbances and falls in 100 Wilson's disease patients

Wilson's disease (WD) is an inherited copper metabolism disorder. Gait disturbances may present with both extrapyramidal and cerebellar patterns. The frequencies of particular types of gait abnormalities have not been established; thus, the aim of the present study was to determine the occurrence of initial gait disturbances among our neurological WD patients. We analyzed 103 WD patients with neurological features at the time of diagnosis, between 2005 and 2014. The neurological and gait assessments were based on the Unified Wilson's Disease Score Scale (UWDRS), from which, we distinguished three main patterns of gait: dystonic, ataxic, or Parkinsonian. All types of gait impairment were assessed using four stages of severity (0=normal, 4=severe). We also obtained each patient's history of falls. Three patients had severe dystonia of limbs and were unable to stand or walk. Gait abnormalities were noted in 59% (59/100) of the remaining group of patients. The most common observed pattern was ataxic gait (45%; 27/59), which presented as impaired tandem in most cases. A mixed gait impairment was observed in 25% (15/59) of patients (ataxic, dystonic, and Parkinsonian, n=8; ataxic and Parkinsonian, n=7), a Parkinsonian gait in 18% (11/59), and a dystonic gait in 10% (6/59) of patients. Falls were noted in 35% of patients, but were occasionally observed in most cases. Gait disturbances are frequent in WD, and reflect the involvement of many brain structures.

Diverse attention deficits in patients with neurologically symptomatic and asymptomatic Wilson's disease.

Cognitive deficits in patients with Wilson's disease (WD) have been reported in several studies, but there was no detailed analysis of the various components of attention, one of the most significant factors of the executive system. Our study determined the pattern of deficits in attention subsystems in WD patients, including selective attention, divided attention, attention switching, and sustained attention. We examined 67 WD patients using the Test of Everyday Attention (TEA)-33 participants with neurological symptoms and 34 who were neurologically asymptomatic, but most with mild hepatic dysfunctions. The results were compared with 43 matched healthy controls. The group of WD patients with neurological symptoms performed significantly worse (p < .05) in all components of attention: sustained attention, selective attention, divided attention, and attentional switching. WD patients without neurological symptoms exhibited significantly lower results in one component-sustained attention (p < .05). None of the TEA subtests scores were associated significantly with Unified Wilson's Disease Rating Scale scores, which may reflect that the cognitive and neurological consequences of WD are relatively independent. We found a deficiency in all components of attention in neurological WD patients. The most frequently disturbed function was attention switching. Relatively milder deficits concerned divided, selective, and sustained attention. These are all abilities creating the core of the executive system and are regulated by subcortical prefrontal circuits, which are usually dysfunctional in WD patients. In neurologically asymptomatic patients, an isolated deficit of sustained attention occurs; this may be a sign of mild hepatic encephalopathy.

D‐penicillamine versus zinc sulfate as first‐line therapy for Wilson's disease

To compare the course of treatment in patients with symptomatic Wilson's disease (WD) receiving either D-penicillamine (DPA) or zinc sulfate (ZS) as first-line therapy. In all, 143 consecutive patients diagnosed with symptomatic WD from January 2005 to December 2009, followed until December 2010, were included. The decision about first-line therapy was made individually after discussion with the patient. Physicians had no clear preference of one drug over the other. Data were analyzed in subgroups with predominantly neurological (DPA, 35; ZS, 21) and hepatic (DPA, 36; ZS, 51) presentation of WD. According to Kaplan-Meier analysis, neurological WD patients scheduled for DPA had a similar probability of not remaining on first-line therapy as patients receiving ZS (20% vs. 24% at the end of follow-up), with adjusted odds ratio (OR) of 0.9 (95% CI 0.2-3.5). In patients with hepatic WD, this probability was significantly higher for DPA (31% vs. 12%; adjusted OR 3.0, 95% CI 0.9-9.9), especially in the first 6 months. Early worsening occurred only in neurological WD patients, with no differences between both treatment groups (35% vs. 19%; OR 2.8, 95% CI 0.7-10.8). Neurological improvement and decrease of liver enzymes were achieved with similar frequency. Compliance with DPA was better in hepatic (97% vs. 80%) but not in neurological patients (91% vs. 81%). Drug adverse effects were more common on DPA (15% vs. 3%). DPA and ZS are effective in the majority of WD patients. Neither therapy appears to be clearly superior. Therefore ZS may be considered a reasonable alternative to DPA as a first-line therapy.

Clinical features, MRI brain, and MRS abnormalities of drug-naïve neurologic Wilson's disease.

Magnetic resonance imaging (MRI) helps in the diagnosis of neurologic Wilson's disease (WD). The literature regarding MR spectroscopy (MRS) and diffusion-weighted imaging (DWI) in WD is limited. To evaluate the clinical features and neuroimaging findings in drug-naïve neurologic WD and to find correlation between clinical stage and disease duration with different imaging findings. The study subjects included consecutive and follow-up neurologic WD patients attending movement disorder clinic. The initial clinical and MRI features before commencement of chelation therapy were noted. Of 78 patients, 34 underwent DWI study and MRS was done in 38 patients and in 32 control subjects. Dystonia, dysarthria, tremor, and behavioral abnormality were common presenting features. All patients had MRI abnormality with major affection of basal ganglia. The clinical severity and anatomical extent of MRI abnormalities were positively correlated (P < 0.001; r s = 0.709). Presence of diffusion restriction was inversely related to duration of disease (P < 0.001; r s = 0.760). WD patients had reduced N-acetylaspartate/creatine (Cr) and choline (Cho)/Cr ratio (P < 0.001) as compared with control subjects in MRS study. Dystonia, dysarthria and tremor are common neurological features of WD. In this study, MRI abnormalities were positively correlated with disease severity; diffusion restriction was inversely correlated with the duration of the disease process. MRS was also a sensitive tool for diagnosing patient of neurologic WD.

Characteristics of neurological Wilson's disease without Kayser–Fleischer ring

BackgroundAlthough Kayser–Fleischer ring has been regarded as a key diagnostic feature of neurologic Wilson's disease, there have been previous reports of neurologic Wilson's disease patients without Kayser–Fleischer ring. We assessed the characteristics of neurologic Wilson's disease patients without Kayser–Fleischer ring. MethodsWe enrolled neurologic Wilson's disease patients from 4 university hospitals by review of medical records in this study. Patients with neurologic Wilson's disease were diagnosed based on the neurologic symptoms and international scoring system for the diagnosis of Wilson's disease. All subjects were divided into two groups according to the presence of a Kayser–Fleischer ring. We compared demographic data, laboratory findings and imaging findings of the liver and brain between the two groups. ResultsThere were 12 (26.7%) patients without Kayser–Fleischer ring out of a total of 45 neurologic Wilson's disease patients. The Wilson's disease patients without Kayser–Fleischer ring demonstrated a higher ceruloplasmin concentration and serum copper level than those with Kayser–Fleischer ring. In addition, liver cirrhosis and typical signal changes in brain magnetic resonance imaging were less common in neurologic Wilson's disease patients without Kayser–Fleischer ring. ConclusionBased on our results, the absence of Kayser–Fleischer ring can be regarded as a form of neurologic Wilson's disease with less copper involvement. In addition, it is important to understand these features and to perform further investigations if patients without Kayser–Fleischer ring are suspected of having neurologic Wilson's disease.