Patient and caregiver experiences with pantothenate kinase-associated neurodegeneration (PKAN): results from a patient community survey.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive genetic disorder of PANK2, which enables mitochondrial synthesis of coenzyme A. Its loss causes neurodegeneration with iron accumulation primarily in motor-related brain areas. Symptoms include dystonia, parkinsonism, and other disabilities. PKAN has been categorized as classic PKAN, with an age of onset ≤ 10 years, rapid progression, and early disability or death; and atypical PKAN, with later onset, slower progression, generally milder, and more diverse symptom manifestations. Available treatments are mostly palliative. Information on the lived experience of patients with PKAN and their caregivers or on community-level disease burden is limited. It is necessary to engage patients as partners to expand our understanding and improve clinical outcomes. This patient-oriented research study used multiple-choice and free-form question surveys distributed by patient organizations to collect information on the manifestations and disease burden of PKAN. It also assessed respondents' experiences and preferences with clinical research to inform future clinical trials. RESULTS: The analysis included 166 surveys. Most respondents (87%) were parents of a patient with PKAN and 7% were patients, with 80% from Europe and North America. The study cohort included 85 patients with classic PKAN (mean ± SD age of onset 4.4 ± 2.79 years), 65 with atypical PKAN (13.8 ± 4.79 years), and 16 identified as "not sure". Respondents reported gait disturbances and dystonia most often in both groups, with 44% unable to walk. The classic PKAN group reported more speech, swallowing, and visual difficulties and more severe motor problems than the atypical PKAN group. Dystonia and speech/swallowing difficulties were reported as the most challenging symptoms. Most respondents reported using multiple medications, primarily anticonvulsants and antiparkinsonian drugs, and about half had participated in a clinical research study. Study participants reported the most difficulties with the physical exertion associated with imaging assessments and travel to assessment sites. CONCLUSIONS: The survey results support the dichotomy between classic and atypical PKAN that extends beyond the age of onset. Inclusion of patients as clinical research partners shows promise as a pathway to improving clinical trials and providing more efficacious PKAN therapies.

Copper Deficiency as Wilson's Disease Overtreatment: A Systematic Review.

BACKGROUND: Treatment of Wilson's disease (WD), an inherited disease characterized by copper overload, is lifelong and there is the possibility that copper deficiency (CD) may occur. We systematically reviewed the literature to describe treatment patterns, symptoms and outcomes associated with CD. METHODS: Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, the PubMed database was searched up to 6 April 2023. RESULTS: Across 17 articles, 20 cases of CD were described, most commonly (15 cases) in WD patients treated with zinc salts (ZS), less often on combined chelator and ZS therapy (3 cases), molybdate salts plus ZS (1), or molybdate alone (1). CD symptoms occurred insidiously, including sideroblastic anemia, neutropenia, axonal sensory neuropathy, posterior cord myelopathy and increased ratio of epileptic seizures (or epilepsy). CD diagnosis was based on symptoms and severely reduced urinary copper excretion (<20 µg/24 h [<0.3 µmol/24 h] on ZS, or <100 µg/24 h [<1.6 µmol/24 h] on chelators) with low total serum copper and ceruloplasmin. CONCLUSIONS: Awareness of CD and regular monitoring of copper metabolism is needed during WD treatment. Temporary cessation of anti-copper treatment usually reverses serum copper reductions as well as pancytopenia; however, some symptoms, especially neuropathy and myelopathy, may persist.

Early neurological deterioration in Wilson's disease: a systematic literature review and meta-analysis.

INTRODUCTION: Neurological deterioration, soon after anti-copper treatment initiation, is problematic in the management of Wilson's disease (WD) and yet reports in the literature are limited. The aim of our study was to systematically assess the data according to early neurological deteriorations in WD, its outcome and risk factors. METHODS: Using PRISMA guidelines, a systematic review of available data on early neurological deteriorations was performed by searching the PubMed database and reference lists. Random effects meta-analytic models summarized cases of neurological deterioration by disease phenotype. RESULTS: Across the 32 included articles, 217 cases of early neurological deterioration occurred in 1512 WD patients (frequency 14.3%), most commonly in patients with neurological WD (21.8%; 167/763), rarely in hepatic disease (1.3%; 5/377), and with no cases among asymptomatic individuals. Most neurological deterioration occurred in patients treated with d-penicillamine (70.5%; 153/217), trientine (14.2%; 31/217) or zinc salts (6.9%; 15/217); the data did not allow to determine if that reflects how often treatments were chosen as first line therapy or if the risk of deterioration differed with therapy. Symptoms completely resolved in 24.2% of patients (31/128), resolved partially in 27.3% (35/128), did not improve in 39.8% (51/128), with 11 patients lost to follow-up. CONCLUSIONS: Given its occurrence in up to 21.8% of patients with neurological WD in this meta-analysis of small studies, there is a need for further investigations to distinguish the natural time course of WD from treatment-related early deterioration and to develop a standard definition for treatment-induced effects.

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.

Heart Rate Variability Impairment Is Associated with Right Ventricular Overload and Early Mortality Risk in Patients with Acute Pulmonary Embolism.

The association between heart rate variability (HRV) and mortality risk of acute pulmonary embolism (APE), as well as its association with right ventricular (RV) overload is not well established. We performed an observational study on consecutive patients with confirmed APE. In the first 48 h after admission, 24 h Holter monitoring with assessment of time-domain HRV, echocardiography and NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurement were performed in all participants. We pre-examined 166 patients: 32 (20%) with low risk of early mortality, 65 (40%) with intermediate-low, 65 (40%) with intermediate-high, and 4 (0.02%) in the high risk category. The last group was excluded from further analysis due to sample size, and finally, 162 patients aged 56.3 ± 18.5 years were examined. We observed significant correlations between HRV parameters and echocardiographic signs of RV overload. SDNN (standard deviation of intervals of all normal beats) correlated with echocardiography-derived RVSP (right ventricular systolic pressure; r = -0.31, p = 0.001), TAPSE (tricuspid annulus plane systolic excursion; r = 0.21, p = 0.033), IVC (inferior vena cava diameter; r = -0.27, p = 0.002) and also with NT-proBNP concentration (r = -0.30, p = 0.004). HRV indices were also associated with APE risk stratification, especially in the low-risk category (r = 0.30, p = 0.004 for SDNN). Univariate and multivariate analyses confirmed that SDNN values were associated with signs of RV overload. In conclusion, we observed a significant association between time-domain HRV parameters and echocardiographic and biochemical signs of RV overload. Impaired HRV parameters were also associated with worse a clinical risk status of APE.

Plasma Troponins Identify Patients with Very Low-Risk Acute Pulmonary Embolism.

INTRODUCTION: Although in the non-vitamin K oral anticoagulants (NOAC) era majority of low-risk acute pulmonary embolism (APE) patients can be treated at home, identifying those at very low risk of clinical deterioration may be challenging. We aimed to propose the risk stratification algorithm in sPESI 0 point APE patients, allowing them to select candidates for safe outpatient treatment. MATERIALS AND METHODS: Post hoc analysis of a prospective study of 1151 normotensive patients with at least segmental APE. In the final analysis, we included 409 sPESI 0 point patients. Cardiac troponin assessment and echocardiographic examination were performed immediately after admission. Right ventricular dysfunction was defined as the right ventricle/left ventricle ratio (RV/LV) > 1.0. The clinical endpoint (CE) included APE-related mortality and/or rescue thrombolysis and/or immediate surgical embolectomy in patients with clinical deterioration. RESULTS: CE occurred in four patients who had higher serum troponin levels than subjects with a favorable clinical course (troponin/ULN: 7.8 (6.4-9.4) vs. 0.2 (0-1.36) p = 0.000). Receiver operating characteristic (ROC) analysis showed that the area under the curve for troponin in the prediction of CE was 0.908 (95% CI 0.831-0.984; p < 0.001). We defined the cut-off value of troponin at >1.7 ULN with 100% PPV for CE. In univariate and multivariate analysis, elevated serum troponin level was associated with an increased risk of CE, whereas RV/LV > 1.0 was not. CONCLUSIONS: Solely clinical risk assessment in APE is insufficient, and patients with sPESI 0 points require further assessment based on myocardial damage biomarkers. Patients with troponin levels not exceeding 1.7 ULN constitute the group of "very low risk" with a good prognosis.

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

INTRODUCTION: Wilson'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. METHODS: We 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. RESULTS: Potentially 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). CONCLUSIONS: Potentially 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.

Serum neurofilament light chain and initial severity of neurological disease predict the early neurological deterioration in Wilson's disease.

BACKGROUND: In Wilson's disease (WD), early neurological deterioration after treatment initiation is associated with poor outcomes; however, data on this phenomenon are limited. Our study analysed the frequency and risk factors of early neurological deterioration in WD. METHODS: Early neurological deterioration, within 6 months from diagnosis, was defined based on the Unified Wilson's Disease Rating Scale (UWDRS): any increase in part II or an increase of ≥ 4 in part III. In total, 61 newly diagnosed WD patients were included. UWDRS scores, brain magnetic resonance imaging (MRI) scores, copper metabolism parameters, treatment type and serum neuro-filament light chain (sNfL) concentrations at diagnosis were analysed as potential risk factors of early deterioration. RESULTS: Early neurological deterioration was observed in 16.3% of all WD patients; all cases of worsening occurred in the neurological phenotype (27.7%). Higher scores were seen in those who deteriorated compared with those who did not for UWDRS part II (4.3 ± 5.0 vs 2.0 ± 5.9; p < 0.05), UWDRS part III (21.5 ± 14.1 vs 9.3 ± 16.4; p < 0.01) and MRI-assessed chronic damage (3.2 ± 1.6 vs 1.4 ± 2.2; p = 0.006); all these variables indicated the initial severity of neurological disease. Pre-treatment sNfL concentrations were significantly higher in patients who deteriorated compared with those who did not (33.2 ± 23.5 vs 27.6 ± 62.7 pg/mL; p < 0.01). In univariate logistic regression amongst all patients, chronic damage MRI scores, UWDRS part III scores and sNfL concentrations predicated early deterioration. In the neurological WD, only sNFL were a significant predictor. In bivariate logistic regression amongst all patients, sNfL remained the only significant predictor of deterioration when corrected for MRI scores. CONCLUSION: sNfL concentrations are a promising biomarker of the risk of early neurological deterioration in WD.

Decreased Haemoglobin Level Measured at Admission Predicts Long Term Mortality after the First Episode of Acute Pulmonary Embolism.

Background: Decreased hemoglobin concentration was reported to predict long term prognosis in patients various cardiovascular diseases including congestive heart failure and coronary artery disease. We hypothesized that hemoglobin levels may be useful for post discharge prognostication after the first episode of acute pulmonary embolism. Therefore, the aim of the current study was to evaluate a potential prognostic value of a decreased hemoglobin levels measured at admission due to the first episode of acute PE for post discharge all cause mortality during at least 2 years follow up. Methods: This was a prospective, single-center, follow-up, observational, cohort study of consecutive survivors of the first PE episode. Patients were managed according to ESC current guidelines. After the discharge, all PE survivors were followed for at least 24 months in our outpatient clinic. Results: During 2 years follow-up from the group of 402 consecutive PE survivors 29 (7.2%) patients died. Non-survivors were older than survivors 81 years (40−93) vs. 63 years (18−97) p < 0.001 presented higher sPESI 2 (0−4) vs. 1 (0−5), p < 0.001 driven by a higher frequency of neoplasms (37.9% vs. 16.6%, p < 0.001); and had lower hemoglobin (Hb) level at admission 11.7 g/dL (6−14.8) vs. 13.1 g/dL (3.1−19.3), p < 0.001. Multivariable analysis showed that only Hb and age significantly predicted all cause post-discharge mortality. ROC analysis for all cause mortality showed AUC for hemoglobin 0.688 (95% CI 0.782−0.594), p < 0.001; and for age 0.735 (95% CI 0.651−0.819) p < 0.001. A group of 59 subjects with hemoglobin < 10.5 g/dL showed mortality rate of 16.9% (OR for mortality 4.19 (95% CI 1.82−9.65), p-value < 0.00, while among 79 patients with Hb > 14.3 g/dL only one death was detected. Interestingly, patients in age > 64 years hemoglobin levels < 13.2 g/dL compared to patients in the same age but with >13.2 g/dL showed OR 3.6 with 95% CI 1.3−10.1 p = 0.012 for death after the discharge. Conclusions: Lower haemoglobin measured in the acute phase especially in patients in age above 64 years showed significant impact on the prognosis and clinical outcomes in PE survivors.

Seven decades of clinical experience with Wilson's disease: Report from the national reference centre in Poland.

BACKGROUND AND PURPOSE: Wilson's disease (WD) is a rare autosomal recessive disorder causing excessive copper deposition and a spectrum of manifestations, particularly neurological and hepatic symptoms. We analysed the clinical characteristics of patients with WD admitted to the country's only reference centre, which provided long-term care to most adult patients in Poland over seven decades (pre-1959 to 2019). METHODS: Electronic prospective data collection began in the 2000s and, for prior years, medical records were analysed retrospectively. Demographic and clinical characteristics, treatment and outcomes were analysed by decade of diagnosis. Life-years lost were estimated in patients with WD compared with the general population. Kaplan-Meier curves were used for a time-to-death analysis using 2000-2009 as a reference. RESULTS: In total, 929 patients were analysed. The number of patients increased from 21 before 1959 to 315 for 2000 to 2009 period. Mostly males were diagnosed before the 1990s, but the numbers of female patients diagnosed increased thereafter. Initially, most patients presented with neurological manifestations; however, the incidence of hepatic manifestations and asymptomatic presentations increased over time as patients were diagnosed early and consequently were more independent at diagnosis. Fewer Kayser-Fleischer rings were detected recently. Prior to 1970, patients were treated with D-penicillamine (DP); however, since the introduction of zinc, both therapies have been used as often. Since the 1990s, switches between DP and zinc were recorded in 6%-7% of patients. Consistent improvement in survival has been observed over the years. CONCLUSIONS: This is the largest cohort of patients with WD reported in Poland, with the longest follow-up. Earlier diagnosis and prognosis have improved over seven decades.

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.

Brain Atrophy Is Substantially Accelerated in Neurological Wilson's Disease: A Longitudinal Study.

BACKGROUND: Although brain atrophy is common in neurological Wilson's disease, longitudinal studies are lacking. OBJECTIVE: The objective of this study was to measure longitudinal brain atrophy rate and to relate it to the change in neurological impairment in Wilson's disease. METHODS: We included patients with brain imaging done at diagnosis and at least 12 months later. The atrophy rate was measured as percentage change in ventricular volume, whereas the change in neurological impairment was scored on the Unified Wilson's Disease Rating Scale. RESULTS: Of 57 patients, 36 had neurological presentation, 17 had hepatic presentation, and 4 were presymptomatic. The annualized atrophy rate was significantly greater in patients with the neurological presentation than in other patients (P = 0.001). In the neurological presentation, the atrophy rate correlated with the change in impairment (rho = 0.39, P = 0.018) and was significantly greater in those with worsening after diagnosis than in those without worsening (P < 0.001). CONCLUSIONS: Brain atrophy rate appears as a promising marker of neurodegeneration in Wilson's disease. © 2022 International Parkinson and Movement Disorder Society.

Age-Adjusted D-Dimer Levels May Improve Diagnostic Assessment for Pulmonary Embolism in COVID-19 Patients.

INTRODUCTION: SARS-CoV-2 infection leads to a hypercoagulable state. The prevalence of pulmonary embolism (PE) seems to be higher in this subgroup of patients. PATIENTS AND METHODS: We combined data from two tertiary referral centers specialized in the management of PE. The aims of this study were as follows: (1) to evaluate the prevalence of PE among a large population of consecutive patients admitted for COVID-19 pneumonia in two centers, (2) to identify a plasma D-dimer threshold that may be useful in PE diagnostic assessment, (3) to characterize the abnormalities associated with PE and mortality in COVID-19 patients. RESULTS: The incidence of symptomatic acute PE was 19.3%. For diagnosing PE in COVID-19 patients, based on ROC curve analysis, we identified a D-dimer concentration/patient's age ratio of 70, which improved D-dimer diagnostic capacity for PE and led to a reclassification improvement of 14% (NRI 0.14, p = 0.03) when compared to a cut-off level of 1000 ng/mL. Especially in severe COVID-19 lung involvement, D-dimer/age ratio cut-off equal to 70 was characterized by high diagnostic feasibility (sensitivity, specificity, negative predictive value, positive predictive value of 83%, 94%, 96%, and 73%, respectively). Apart from PE status, lung involvement and troponin T concentration were also independent predictors of in-hospital mortality. In the subgroup of PE patients, mortality was comparable with non-PE patients (19/88 (21.5%) vs. 101/368 (27.4%) for non-PE, p = 0.26) and was associated with older age, higher Bova scores, and higher troponin T concentrations. Age was the sole independent predictor for mortality in this subgroup. CONCLUSIONS: PE in COVID-19 patients is common, but it may not influence mortality when managed at a specialized center. In suspected PE, age-adjusted D-dimer levels (upper limit of normal obtained from the formula patient's age × 70) may still be a useful tool to start the diagnostic workup. In COVID-19 patients without PE, older age, more extensive parenchymal involvement, or higher D-dimer levels are factors predicting mortality.

Brain magnetic resonance imaging and severity of neurological disease in Wilson's disease - the neuroradiological correlations.

INTRODUCTION: Wilson's disease (WD) is a genetic disorder with pathological copper accumulation and associated clinical symptoms in various organs, particularly the liver and brain. Neurological disease is assessed with the clinical Unified Wilson's Disease Rating Scale (UWDRS). There is a lack of quantitative objective markers evaluating brain involvement. Recently, a semiquantitative brain magnetic resonance imaging (MRI) scale has been proposed, which combines acute toxicity and chronic damage measures into a total score. The relationship between MRI brain pathology and the MRI scale with disease form and neurological severity was studied in a large cohort. METHODS: We retrospectively assessed 100 newly diagnosed treatment-naïve patients with WD with respect to brain MRI pathology and MRI scores (acute toxicity, chronic damage, and total) and analyzed the relationship with disease form and UWDRS part II (functional impairment) and part III (neurological deficits) scores. RESULTS: Most patients had the neurological form of WD (55%) followed by hepatic (31%) and presymptomatic (14%). MRI examination revealed WD-typical abnormalities in 56% of patients, with higher pathology rates in neurological cases (83%) than in hepatic (29%) and presymptomatic (7%) cases. UWDRS part II and III scores correlated with the MRI acute toxicity score (r = 0.55 and 0.55, respectively), chronic damage score (r = 0.39 and 0.45), and total score (0.45 and 0.52) (all P < 0.01). CONCLUSIONS: Brain MRI changes may be present even in patients without neurological symptoms, although not frequently. The semiquantitative MRI scale correlated with the UWDRS and appears to be a complementary tool for severity of brain injury assessment in WD patients.

Serum Neurofilament Light Chain as a Biomarker of Brain Injury in Wilson's Disease: Clinical and Neuroradiological Correlations.

BACKGROUND: Clinical scales and neuroimaging are used to monitor nervous system injury in Wilson's disease, while data on serum markers are scarce. OBJECTIVE: To investigate whether serum concentrations of neurofilament light chain (sNfL) correlate with brain injury in Wilson's disease patients. METHODS: In 61 treatment-naïve patients, the Unified Wilson's Disease Rating Scale and a validated semiquantitative brain magnetic resonance imaging scale were compared with concentrations of sNfL. RESULTS: Concentrations of sNfL were significantly higher in patients with neurological disease compared with patients presenting with other forms (39.7 ± 73.4 pg/mL vs. 13.3 ± 9.2 pg/mL; P < 0.01). Moreover, the sNfL concentration positively correlated with neurological severity scores and with acute and chronic brain damage based on the neuroimaging scale. CONCLUSIONS: Neurofilament light chain concentrations may be used as a marker of brain injury in Wilson's disease, in addition to the clinical and neuroimaging disease severity scales. © 2022 International Parkinson and Movement Disorder Society.

Liver transplantation as a treatment for Wilson's disease with neurological presentation: a systematic literature review.

INTRODUCTION: Wilson's disease (WD) is a potentially treatable, genetic disorder of copper metabolism, with survival similar to healthy populations if controlled. However, in almost 50% of WD patients, neurological symptoms persist despite treatment, and in up to 10% of patients, neurological deterioration is irreversible. International guidelines on WD treatment do not recommend liver transplantation (LT) as a treatment for neurological symptoms in WD. However, such treatment has been assessed in retrospective analyses, case and series reports. We aimed to systematically assess all available evidence on the effectiveness and safety of LT in WD patients with neurological presentation. METHODS: 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 6 April 2021) and by screening reference lists. RESULTS: Based on the systematic literature review, 48 articles were identified, showing outcomes of LT in 302 WD patients with neurological symptoms. Of these patients, major improvement was found in 215 cases (71.2%), with no difference in neurological status before and after LT in 21 cases (6.9%). There were 29 deaths (9.6%), neurological worsening in 24 cases (7.9%), and 13 cases (4.3%) were lost to follow-up. CONCLUSIONS: The results suggest that LT is a promising method of WD management in patients with severe, neurological symptoms, particularly if the patient has not responded to pharmacological de-coppering treatment. Further studies of LT in these patients are warranted.

Assessment of pulmonary embolism severity and the risk of early death.

Currently, venous thromboembolism, including deep vein thrombosis and acute pulmonary embolism (PE), is globally the third most frequent acute cardiovascular syndrome with rising incidence rates. The clinical presentation of PE is heterogenous: from incidental findings on imaging studies to sudden cardiac death. Hemodynamic instability identifies patients at high risk of early mortality. In hemodynamically stable patients, further stratification into intermediate- and low-risk categories is advised, preferably using a combined risk assessment strategy based on clinical parameters, laboratory findings, and imaging markers. Treatment should be tailored to the risk of early death, with more aggressive treatments reserved for patients at higher risk of complications. This review offers an update on the current strategies for assessing PE severity and the risk of early death and discusses developments in predicting mortality risk in patients with PE.

Autonomic nervous system dysfunction in Wilson's disease - A systematic literature review.

INTRODUCTION: In Wilson's disease (WD), copper accumulation can result in neurological manifestations, particularly extrapyramidal symptoms. There are some data that the autonomic nervous system (ANS) may also be affected, and we aimed to systematically review available studies evaluating ANS dysfunction in WD. MATERIAL AND METHODS: We conducted a systematic review of the literature using the PubMed database (up to 31st August 2020), with search terms including "autonomic" and "function" and "Wilson's disease". RESULTS: Fourteen studies, including 297 patients with neurological, hepatic or psychiatric forms of WD were retrieved. The most frequent methods used for ANS evaluation were orthostatic tests, which were performed in seven studies, with a number of other tests less frequently used. The incidence of ANS abnormalities ranged from ~8% to 79.2%, depending on the evaluation method. ANS abnormalities in patients with WD were often clinically asymptomatic. The features of dysautonomia were more common among patients with neurological symptoms and ANS abnormalities were more common in patients with severe brain injury. Studies confirmed both sympathetic and parasympathetic ANS impairment. The pathophysiology of ANS damage was not clear but may result from central, peripheral nervous system and direct cardiac involvement. Clear improvements were observed in four studies after anti-copper therapy initiation. CONCLUSION: Both sympathetic and parasympathetic divisions of the ANS may be affected in WD. The observed ambiguities regarding ANS abnormalities in WD patients may arise from small study groups, differences in methodology, and a lack of comprehensive ANS evaluation; however, the results indicate that further studies are warranted.