Anti-copper Treatment Research Articles

Neurological Deterioration in Wilson's Disease-Types, Etiology, Course, and Management.

Wilson's disease (WD) is an inherited disorder of copper metabolism in which pathological copper accumulation, mainly in the liver and the brain, leads to hepatic and/or neuropsychiatric signs and symptoms. Chelators and zinc salts can successfully induce negative copper balance in many patients; however, neurological deterioration may still be observed. This phenomenon can be divided into: (1) early 'paradoxical' neurological deterioration, which usually develops in the first 6 months of anti-copper treatment and may be commonly related to drug type, or (2) late neurological deterioration, which mostly occurs after 6 months of treatment and is often related either to non-compliance with treatment, overtreatment resulting in copper deficiency, or adverse drug reactions. Another explanation, especially for early neurological deterioration, is natural WD progression, which can be difficult to differentiate from drug-related deterioration, but usually leads to a worse outcome. There is still no consensus on how to define neurological deterioration in WD using scales or biomarkers, how to distinguish it from the natural disease progression, its risk factors, and optimal management. This narrative review, based on the current literature, aims to provide definitions, prevalence, pathological mechanisms and factors related to neurological deterioration, and also proposes schemes for diagnosis and treatment.

Impact of treatment on blood-brain barrier impairment in Wilson's disease.

Our study assessed changes in concentrations of serum markers for brain damage and blood-brain barrier (BBB) dysfunction in untreated and treated Wilson's disease (WD) patients, and examined correlations between these changes and neurological impairment. These results hold the potential to determine BBB impairment and neurological advancement in WD to develop the most effective treatment for patients with severe neurological deterioration. The study groups included 171 patients with WD (77 with hepatic and 94 with neurological manifestations), treated either for up to 5 or 15 years, and 88 healthy controls. Serum concentrations of intercellular adhesion molecule 1 (ICAM1), P-selectin, matrix metallopeptidase 9 (MMP9), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein B (S100B) were measured before and during anti-copper treatment. The Unified Wilson's disease Rating Scale (UWDRS) was used to assess neurological advancement. ICAM1 concentrations were elevated before and during anti-copper treatment compared to controls (p < 0.01), but therapy led to substantial decreases both in patients with hepatic (p < 0.01) and in patients with neurological manifestations (p < < 0.05). P-selectin concentrations remained elevated before and during treatment (p < 0.05) regardless of the treatment duration and disease form. MMP9 concentrations before treatment were lower (p < 0.05), but reached control levels during treatment. GFAP concentrations were significantly elevated only in untreated patients with neurological symptoms in the longer-treated group compared to controls (p < 0.05). A significant reduction during treatment was observed only in the shorter-treated neurological group (p < 0.05). No substantial changes were observed in S100B. Only ICAM1 concentrations positively correlated (r = 0.27, p < 0.001) with the UWDRS. Our results provide evidence of endothelial activation in WD. However, inconclusive GFAP results, and no increase in S100B, do not allow us to conclude whether the reactive gliosis is not prominent or alternatively whether the BBB is disrupted. Elevated ICAM1 concentrations and their correlation with neurological advancement indicate BBB impairment. A decrease in ICAM1 during treatment suggests that the inflammatory process is reduced, and the BBB partially repaired. Decreased MMP9 concentrations may be the result of active liver fibrosis and higher copper concentrations. Elevated P-selectin concentrations indicate a systemic inflammatory process.

Copper Deficiency as a Serious Complication of Anti-Copper Treatment in Wilson's Disease.

Copper Deficiency as a Serious Complication of Anti-Copper Treatment in Wilson's Disease.

Changes in Hepatic Function After Splenectomy for Hepatolenticular Degeneration, Cirrhosis, and Hypersplenism.

Patients with hepatic reticulum degeneration (HLD) may eventually develop complications of cirrhosis with splenomegaly and hypersplenism, requiring splenectomy to alleviate hypersplenism and complete lifelong copper therapy. The purpose of this study is to investigate the effect of splenectomy on liver function in patients with hypersplenism. A retrospective systematic analysis was conducted on the liver function indicators of 220 HLD patients who underwent splenectomy from January 2015 to January 2018 before surgery and on days 1, 3, 5, 7, and 14 after surgery. Among them, 30 patients were followed up for 6 months. The Child score increased on the 1st day after surgery and gradually decreased after the 1st day. The level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) increased 5 days after surgery (P < .01) and decreased on the 14th day after surgery (P < .01); the level of albumin (ALB) decreased on the 1st, 3rd, and 5th day after surgery (P < .01) and increased on the 14th day (P < .01). The follow-up results of the patient for 6 months showed that the levels of ALT and AST decreased, while the levels of ALB increased 6 months after surgery. Splenectomy is proved to be beneficial for the improvement of liver function in HLD patients combined with hypersplenism, which realize a lifelong anti-copper treatment.

Blood Based Biomarkers of Central Nervous System Involvement in Wilson's Disease.

Wilson's disease (WD) is an inherited disorder of copper metabolism with clinical symptoms related to pathological copper accumulation, which are mainly hepatic and/or neuropsychiatric. The disease is potentially treatable with pharmacological agents (chelators or zinc salts). As such, key factors for a favorable treatment outcome are early diagnosis and anti-copper treatment initiation as well as appropriate treatment monitoring for safety and efficacy. Despite the generally favorable outcome in most treated patients, almost 10% of the general population of WD patients and about 25% of patients in the group with initial neurological phenotype of disease experience early neurological deterioration. In almost 50% of patients with neurological symptoms, the symptoms persist. A search for new treatment modalities (e.g., gene therapy, molybdenum salts) aims to prevent early neurological deterioration as well as improve treatment outcomes. In addition to evaluating the clinical signs and symptoms of the disease, serum biomarkers for diagnosis and treatment monitoring are very important for WD management. Sensitive serum biomarkers of copper metabolism and liver injury are well described. However, there is a need to establish blood-based biomarkers of central nervous system (CNS) injury to help identify patients at risk of early neurological deterioration and aid in their monitoring. Based on the available literature and studies of WD patients, the authors reviewed serum biomarkers of CNS involvement in WD, as well as their potential clinical significance.

Analysis of risk factors for neurological symptoms in patients with purely hepatic Wilson’s disease at diagnosis

ObjectiveTo analyze and explore the risk factors for neurological symptoms in patients with purely hepatic Wilson's disease (WD) at diagnosis.MethodsThis retrospective study was conducted at the First Affiliated Hospital of the Guangdong Pharmaceutical University on 68 patients with purely hepatic WD aged 20.6 ± 7.2 years. The physical examinations, laboratory tests, color Doppler ultrasound of the liver and spleen, and magnetic resonance imaging (MRI) of the brain were performed.ResultsThe elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels and 24-h urinary copper level were higher in the purely hepatic WD who developed neurological symptoms (NH-WD) group than those in the purely hepatic WD (H-WD) group. Adherence to low-copper diet, and daily oral doses of penicillamine (PCA) and zinc gluconate (ZG) were lower in the NH-WD group than those in the H-WD group. Logistic regression analysis showed that insufficient doses of PCA and ZG were associated with the development of neurological symptoms in patients with purely hepatic WD at diagnosis.ConclusionThe development of neurological symptoms in patients with purely hepatic WD was closely associated with insufficient doses of PCA and ZG, and the inferior efficacy of copper-chelating agents. During the course of anti-copper treatment, the patient's medical status and the efficacy of copper excretion should be closely monitored.

Pathognomonic neuroradiological signs in Wilson's disease – Truth or myth?

IntroductionWilson's disease (WD) is a treatable genetic disorder caused by impaired copper metabolism. Early diagnosis and correct anti-copper treatment are crucial for therapeutic success. Brain magnetic resonance imaging (MRI) is used both for diagnosis and treatment monitoring. Several neuroradiological signs have been proposed to be pathognomonic for WD; however, their frequency and significance are not established. The frequency and significance of these brain MRI signs were analyzed in a large cohort of WD patients. MethodsWe retrospectively analyzed 100 newly diagnosed, treatment-naive WD patients. Brain MRI was performed and the frequency of typical MRI changes was analyzed with demographic, clinical and laboratory characteristics of WD. ResultsPotentially pathognomonic brain MRI signs for WD occurred in 24% patients and in 43% (24/55) patients with neurological WD. Signs detected included the “face of the giant panda” in 15% of all patients (27.3% of neurological cases), “miniature panda” in 12% (21.8% of neurological cases), “split thalamus” in 7% (12.7% of neurological cases), and “bright claustrum” and “whorl” signs in 1 patients each. Signs were observed only in patients with neurological symptoms and were significantly associated with early age of onset/diagnosis, more severe neurological presentation and lower ceruloplasmin level (all p < 0.05). ConclusionsPotentially brain MRI pathognomonic signs occurred relatively rarely across all patients, most often in patients with early onset and severe neurological symptoms, and this knowledge may improve WD diagnosis. However, as these signs are also found in brain MRI in other disorders, they may not be truly pathognomonic of WD.

The Maternal and Fetal Outcomes of Pregnancy in Wilson's Disease: A Systematic Literature Review and Meta-Analysis.

Wilson’s disease (WD) is a rare, treatable genetic disorder with multi-organ symptoms related mainly to copper accumulation. Most patients become aware of the disease as young adults, thus knowledge on fertility, pregnancy course and outcome is very important both for patients and physicians. The aim of this study was to perform a systematic review and meta-analysis of pregnancy outcomes in women with WD. This systematic literature review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were identified by searching the PubMed database (up to 12 January 2022) and by screening reference lists. We found 49 publications, including 13 retrospective studies and 36 series and case reports on pregnancy outcomes in WD patients. In total, descriptions of 449 pregnant women with 822 pregnancies were retrieved. Successful deliveries were achieved in 78.3% (644/822) of all pregnancies. Spontaneous abortions were observed in 21.7% (178/822) of pregnancies, more frequently in patients who were untreated 68.6% (96/140). Analyzing maternal outcome, 2.2% (18/822) of pregnancies were associated with the aggravation of neurological symptoms. Symptoms of hepatic deterioration were observed in 4.6% (38/822) of cases. These were usually transient and recovered after pregnancy; however, death due to liver failure was observed in 0.2% (2/822) of cases. Birth defects occurred in 4.7% (39/822) of pregnancies. The available meta-analysis showed statistically significant positive associations between anti-copper treatment and pregnancy outcome. Our results document the significance of anti-copper treatment as the main factor leading to successful pregnancy, as well as positive outcomes for women with WD.

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.

Impact of COVID-19 pandemic on the neuropsychiatric status of Wilson's disease.

We have read with interest the Letter to the Editor by Drs. Zhuang and Zhong, who presented the clinical data of 68 patients with Wilson’s disease (WD) who were admitted to the hospital before and during the coronavirus disease 2019 (COVID-19) pandemic, and appreciated their findings on hepatic and some extrahepatic manifestations. Nevertheless, given the strong impact of the pandemic on patients with neurological and psychiatric disorders, we would have expected a worsening of the psychiatric and/or neurological impairments in these patients. In contrast, according to the authors, these manifestations remained, somewhat unexpectedly, unchanged. This finding is in contrast with most of the current literature that highlights not only an increased incidence of mental health disorders in the general population but also an exacerbation of neurological and psychiatric symptoms in patients with chronic diseases, especially in those with pre-existing neuropsychiatric disorders, such as WD. Although the study was mainly focused on the hepatic features of WD patients taking anti-copper treatment, a generic and cumulative definition of neurological and psychiatric manifestations, as in this study, does not allow for further considerations. Future studies during and after the pandemic are necessary to clarify the real impact, either direct or indirect, of the COVID-19 pandemic on the neurological and psychiatric symptoms of WD patients.

Motor Evoked Potentials in Newly Diagnosed and Treated Patients With Wilson Disease.

To investigate whether patients with Wilson disease have abnormal motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation. In a prospective, observational, single-center study, transcranial magnetic stimulation was used to examine MEPs recorded from the abductor digiti minimi in 24 newly diagnosed treatment-naive patients and 21 treated patients with Wilson disease. Motor evoked potentials were recorded in 22 (91.7%) newly diagnosed treatment-naive patients and in 20 (95.2%) treated patients. Abnormal MEP parameters were found in a similar proportion of newly diagnosed and treated patients: MEP latency (38% vs. 29%), MEP amplitude (21% vs. 24%), central motor conduction time (29% vs. 29%), and resting motor threshold (68% vs. 52%). Abnormal MEP amplitude (P = 0.044) and resting motor threshold (P = 0.011) were more frequent in treated patients with brain MRI abnormalities but not in newly diagnosed patients. We did not observe significant improvement in MEPs parameters after 1 year of treatment introduction in eight examined patients. However, in one patient where MEPs were initially nondetectable, they were present 1 year after treatment introduction with zinc sulfate, although MEPs were not in the normal range. Motor evoked potential parameters did not differ between newly diagnosed and treated patients. There was no significant improvement in MEP parameters one year after treatment introduction. Further studies conducted on large cohorts are necessary to determine the usefulness of MEPs in detecting pyramidal tract damage and improvement after anticopper treatment introduction in Wilson disease.

Associations of Brain Atrophy and Cerebral Iron Accumulation at MRI with Clinical Severity in Wilson Disease.

Background Abnormal findings at brain MRI in patients with neurologic Wilson disease (WD) are characterized by signal intensity changes and cerebral atrophy. T2 signal hypointensities and atrophy are largely irreversible with treatment; their relationship with permanent disability has not been systematically investigated. Purpose To investigate associations of regional brain atrophy and iron accumulation at MRI with clinical severity in participants with neurologic WD who are undergoing long-term anti-copper treatment. Materials and Methods Participants with WD and controls were compared in a prospective study performed from 2015 to 2019. MRI at 3.0 T included three-dimensional T1-weighted and six-echo multigradient-echo pulse sequences for morphometry and quantitative susceptibility mapping, respectively. Neurologic severity was assessed with the Unified WD Rating Scale (UWDRS). Automated multi-atlas segmentation pipeline with dual contrast (susceptibility and T1) was used for the calculation of volumes and mean susceptibilities in deep gray matter nuclei. Additionally, whole-brain analysis using deformation and surface-based morphometry was performed. Least absolute shrinkage and selection operator regression was used to assess the association of regional volumes and susceptibilities with the UWDRS score. Results Twenty-nine participants with WD (mean age, 47 years ± 9 [standard deviation]; 15 women) and 26 controls (mean age, 45 years ± 12; 14 women) were evaluated. Whole-brain analysis demonstrated atrophy of the deep gray matter nuclei, brainstem, internal capsule, motor cortex and corticospinal pathway, and visual cortex and optic radiation in participants with WD (P < .05 at voxel level, corrected for family-wise error). The UWDRS score was negatively correlated with volumes of putamen (r = -0.63, P < .001), red nucleus (r = -0.58, P = .001), globus pallidus (r = -0.53, P = .003), and substantia nigra (r = -0.50, P = .006) but not with susceptibilities. Only the putaminal volume was identified as a stable factor associated with the UWDRS score (R2 = 0.38, P < .001) using least absolute shrinkage and selection operator regression. Conclusion Individuals with Wilson disease (WD) had widespread brain atrophy most pronounced in the central structures. The putaminal volume was associated with the Unified WD Rating Scale score and can be used as a surrogate imaging marker of clinical severity. © RSNA, 2021 Supplemental material is available for this article. See also the editorial by Du and Bydder in this issue.

Iron metabolism is disturbed and anti-copper treatment improves but does not normalize iron metabolism in Wilson\u2019s disease

Wilson’s disease (WD) is a rare hereditary disorder of copper metabolism. Some data suggest that iron metabolism is disturbed in WD and this may affect the course of the disease. The current study aimed to determine whether anti-copper treatment could affect iron metabolism in WD. One hundred thirty-eight WD patients and 102 controls were examined. Serum ceruloplasmin and copper were measured by colorimetric enzyme assay or atomic adsorption spectroscopy, respectively. Routine and non-routine parameters of iron metabolism were measured by standard laboratory methods or enzyme immunoassay, respectively. WD patients, both newly diagnosed and treated, had less serum copper and ceruloplasmin than controls (90.0, 63.0, 22.0 mg/dL, respectively, p < 0.001); in the treated patients blood copper and ceruloplasmin were lower than in untreated patients (p < 0.001). Untreated patients (n = 39) had a higher median blood iron (126.0 vs 103.5 ug/dL, p < 0.05), ferritin (158.9 vs 47.5 ng/mL, p < 0.001), hepcidin (32, 6 vs 12.1 ng/mL, p < 0.001) and sTfR (0.8 vs. 0.7 ug/mL, p < 0.001) and lower blood transferrin (2.4 vs. 2.7 g/L, p < 0.001), TIBC (303.0 vs 338.0 ug/dL, p < 0.001), hemoglobin (13.1 vs 13.9 g/dL, p < 0.01) and RBC (4.3 vs. 4.6, p < 0.002) than controls. Treated patients (n = 99) had a significantly lower median iron (88.0 vs. 126.0 ug/dL, p < 0.001), ferritin (77.0 vs. 158.9 ng/mL, p < 0.005) and hepcidin (16.7 vs. 32.6 ng/mL, p < 001) and higher transferrin (2.8 vs. 2.4 g/L, p < 0.005), TIBC (336.0 vs 303.0 ug/dL, p < 0.001), RBC (4.8 vs. 4.3 M/L, p < 0.001) and hemoglobin (14.4 vs. 13.1 g/dL, p < 0.001) than untreated; the median iron (p < 0.005) was lower, and ferritin (p < 0.005), RBC (p < 0.005) and hepcidin (p < 0.002) were higher in them than in the control group. Changes in copper metabolism are accompanied by changes in iron metabolism in WD. Anti-copper treatment improves but does not normalize iron metabolism.

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.

Eye movement abnormalities are associated with brainstem atrophy in Wilson disease

This study aims to characterize eye movement abnormalities in Wilson disease and examine their association with the degree of brainstem atrophy. Twenty patients (10 males, mean age 46.8, SD 8.9years) with genetically confirmed neurological WD on stable anti-copper treatment and 20 age- and sex-matched healthy subjects were examined. Eye movements, including prosaccade and antisaccade tasks, were evaluated using infrared videooculography. MRI was performed using 1.5T system, and T2-weighted images were used for the measurement of midbrain and pontine area on mid-sagittal slices. Clinical severity was assessed using the Unified Wilson's Disease Rating Scale (UWDRS). Compared to healthy controls, WD patients showed prolonged latencies of horizontal prosaccades and hypometry of both horizontal (p = 0.04) and vertical (p = 0.0046) prosaccades. In the antisaccade task, WD patients showed prolonged latency of both horizontal (p = 0.04) and vertical antisaccades (p = 0.047) and increased error rate of vertical antisaccades (p = 0.04). There is a significant association between midbrain area and horizontal latencies (r = -0.53; p = 0.02) and vertical maximum speed in prosaccades (r = 0.47; p = 0.04). The pons area inversely correlated with horizontal prosaccade and antisaccade latencies (p = 0.007). We showed impairments of ocular saccades such as prolonged latencies, hypometry, and increased error rate in antisaccades. The strong association between prolonged latencies of prosaccades and the brainstem atrophy suggests that VOG might serve as a sensitive electrophysiological marker of brainstem dysfunction in WD.

The study of Wilson disease in pregnancy management

IntroductionPregnancy management in women with Wilson disease (WD) remains an important clinical problem. This research was conducted to investigate how to avoid worsening of WD symptoms during pregnancy and increase pregnancy success in women with WD by identifying the best pregnancy management approaches in these patients.Patients and methodsThe clinical data of 117 pregnancies among 75 women with WD were retrospectively analyzed. Related information of the fetus was also recorded and analyzed. At the same time, regression analysis was performed for data of 22 pregnant women without WD, as normal controls.ResultsOf a total of 117 pregnancies among the 75 women with WD and 31 pregnancies among the 22 control womenincluded in this study, there were 108 successful pregnancies and 9 spontaneous abortions. Among the 108 successful pregnancies, 97 women a history of copper chelation therapy before pregnancy; all 97 women stopped anti-copper therapy during pregnancy. The nine women with spontaneous abortion had no pre-pregnancy history of copper displacement therapy. The incidence of lower limb edema was higher in the WD group than in normal controls (P = 0.036). Compared with the control group, there was a higher proportion in the WD group of male infants (P = 0.022) and lower average infant birth weight (t = 3.514, P = 0.001).ConclusionIt is relatively safe for women with WD patients to become pregnant. The best management method for pregnancy in women with WD may be intensive pre-pregnancy copper chelation therapy and no anti-copper treatment during pregnancy.

Persistence with treatment for Wilson disease: a retrospective study

BackgroundWilson disease (WD) is genetically induced failure of copper metabolism which can be successfully treated with pharmacological agents. The prognosis for survival in most WD patients is favorable if diagnosis and anti-copper treatment are provided early. Many observations imply that persistence with drug treatment is generally low in patients with chronic diseases, which impact the treatment effectiveness, but such results are very limited in WD. The aim of our study was to assess persistence with treatment among WD patients, to analyze its effect on patient outcome and to identify factors that might be related to persistence.Methods170 newly diagnosed, symptomatic patients with WD who started treatment between 1995 and 2005 were analyzed retrospectively to assess treatment non-persistence, which was defined as at least one reported break of more than 3 months or minimum two breaks lasting longer than 2 months. Results were further analyzed according to selected clinical variables.ResultsOnly 74.1% of patients were persistent with treatment during the mean 11.7 years of follow up. Treatment persistence closely impacted positive clinical outcomes. In patients classified as persistent, improvement and lack of WD progression were observed more often compared to those classified as non-persistent (29.4 and 68.3% vs. 2.3 and 45.5%; p < 0.001, respectively). In contrast, non-persistent patients presented more often with worsening WD than persistent patients (52.3% vs. 2.4%). Type of WD treatment, gender, phenotypic presentation, adverse events and duration of treatment were not related to treatment persistence. Higher or upper/post-secondary education and a supportive family attitude towards treatment were the most important factors related to persistence.ConclusionsOne quarter of WD patients were not taking anti-copper treatment regularly and this had an important negative effect on clinical outcome. Family support played an important role in treatment persistence.

Multiparametric Quantitative Brain MRI in Neurological and Hepatic Forms of Wilson's Disease.

In Wilson's disease (WD), demyelination, rarefaction, gliosis, and iron accumulation in the deep gray matter cause opposing effects on T2 -weighted MR signal. However, the degree and interplay of these changes in chronically treated WD patients has not been quantitatively studied. To compare differences in brain multiparametric mapping between controls and chronically treated WD patients with neurological (neuro-WD) and hepatic (hep-WD) forms to infer the nature of residual WD neuropathology. Cross-sectional. Thirty-eight WD patients (28 neuro-WD, 10 hep-WD); 26 healthy controls. 3.0T: susceptibility, T2 *, T2 , T1 relaxometry; 1.5T: T2 , T1 relaxometry. The following 3D regions of interest (ROIs) were manually segmented: globus pallidus, putamen, caudate nucleus, and thalamus. Mean bulk magnetic susceptibility, T2 *, T2 , and T1 relaxation times were calculated for each ROI. The effect of group (neuro-WD, hep-WD, controls) and age was assessed using a generalized least squares model with different variance for each ROI and quantitative parameter. A general linear hypothesis test with Tukey adjustment was used for post-hoc between-group analysis; P < 0.05 was considered significant. Susceptibility values were higher in all ROIs in neuro-WD compared to controls and hep-WD (P < 0.001). In basal ganglia, lower T2 and T2 * were found in neuro-WD compared to controls (P < 0.01) and hep-WD (P < 0.05) at 3.0T. Much smaller intergroup differences for T2 in basal ganglia were observed at 1.5T compared to 3.0T. In the thalamus, increased susceptibility in neuro-WD was accompanied by increased T1 at both field strengths (P < 0.001 to both groups), and an increased T2 at 1.5T only (P < 0.001 to both groups). We observed significant residual brain MRI abnormalities in neuro-WD but not in hep-WD patients on chronic anticopper treatment. Patterns of changes were suggestive of iron accumulation in the basal ganglia and demyelination in the thalamus; 3.0T was more sensitive for detection of the former and 1.5T of the latter abnormality. 2 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1829-1835.

Acute onset neurological symptoms in Wilson disease after traumatic, surgical or emotional events: A cross-sectional study.

Acute onset neurological symptoms evoked by traumatic, surgical, or emotional events in Wilson disease (WD) have never been reported and its clinical characteristics are unclear.We aimed to summarize the clinical characteristics of a special WD whose neurological symptoms acutely developed after traumatic, surgical, or emotional events.Retrospective pilot study.Thirty-one patients who had acute onset neurological symptom as an initial presentation of WD or a new presentation of hepatic WD after mild trauma, surgery, or emotional events were retrospectively studied. All patients were followed for half to 1 year after regular anti-copper treatment.The averaged latency for neurological symptom presentation was 2.79 ± 1.21 hours. The most frequent neurological symptoms were tremor (74%) and basal ganglia (BG) lesions were detected on magnetic resonance imaging in all patients. Lesions in other regions were much less frequently detected. Neurological symptom score and its recovery after treatment were correlated with lesion location: BG area and BG plus other brain areas. Neurological symptoms improved in 21 patients who received timely anti-copper treatment but continued to deteriorate in 6 patients who did not accept regular anti-copper treatment for delayed diagnosis.A diagnosis of WD should be considered when adolescents or adults experience acute presentation of extrapyramidal systems after traumatic, surgical, or emotional stimulation. Timely anti-copper therapy usually gives rise to an excellent prognosis.

Neurologic impairment in Wilson disease.

Neurologic symptoms in Wilson disease (WD) appear at an older age compared to hepatic symptoms and manifest in patients with misdiagnosed liver disease, in patients when the hepatic stage is clinically silent, in the case of non-compliance with anti-copper treatment, or with treatment failure. Neurologic symptoms in WD are caused by nervous tissue damage that is primarily a consequence of extrahepatic copper toxicity. Copper levels in brain tissues as well as cerebrospinal fluid (CSF) are diffusely increased by a factor of 10 and its toxicity involves various mechanisms such as mitochondrial toxicity, oxidative stress, cell membrane damage, crosslinking of DNA, and inhibition of enzymes. Excess copper is initially taken-up and buffered by astrocytes and oligodendrocytes but ultimately causes dysfunction of blood-brain-barrier and demyelination. Most severe neuropathologic abnormalities, including tissue rarefaction, reactive astrogliosis, myelin palor, and presence of iron-laden macrophages, are typically present in the putamen while other basal ganglia, thalami, and brainstem are usually less affected. The most common neurologic symptoms of WD are movement disorders including tremor, dystonia, parkinsonism, ataxia and chorea which are associated with dysphagia, dysarthria and drooling. Patients usually manifest with various combinations of these symptoms while purely monosymptomatic presentation is rare. Neurologic symptoms are largely reversible with anti-copper treatment, but a significant number of patients are left with residual impairment. The approach for symptomatic treatment in WD is based on guidelines for management of common movement disorders. The vast majority of WD patients with neurologic symptoms have abnormalities on brain magnetic resonance imaging (MRI). Pathologic MRI changes include T2 hyperintensities in the basal ganglia, thalami and white matter, T2 hypointensities in the basal ganglia, and atrophy. Most importantly, brain damage and neurologic symptoms can be prevented with an early initiation of anti-copper treatment. Introducing population WD screening, e.g., by exome sequencing genetic methods, would allow early treatment and decrease the neurologic burden of WD.