European Academy of Neurology and European Stroke Organization consensus statement and practical guidance for pre­hospital management of stroke

Background and purpose The reduction of delay between onset and hospital arrival and adequate pre­hospital care of persons with acute stroke are important for improving the chances of a favourable outcome. The objective is to recommend evidence­based practices for the management of patients with suspected stroke in the pre­hospital setting. Methods The GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to define the key clinical questions. An expert panel then reviewed the literature, established the quality of the evidence, and made recommendations. Results Despite very low quality of evidence educational campaigns to increase the awareness of immediately calling emergency medical services are strongly recommended. Moderate quality evidence was found to support strong recommendations for the training of emergency medical personnel in recognizing the symptoms of a stroke and in implementation of a pre­hospital 'code stroke' including highest priority dispatch, pre­hospital notification and rapid transfer to the closest 'stroke­ready' centre. Insufficient evidence was found to recommend a pre­hospital stroke scale to predict large vessel occlusion. Despite the very low quality of evidence, restoring normoxia in patients with hypoxia is recommended, and blood pressure lowering drugs and treating hyperglycaemia with insulin should be avoided. There is insufficient evidence to recommend the routine use of mobile stroke units delivering intravenous thrombolysis at the scene. Because only feasibility studies have been reported, no recommendations can be provided for pre­hospital telemedicine during ambulance transport. Conclusions These guidelines inform on the contemporary approach to patients with suspected stroke in the pre­hospital setting. Further studies, preferably randomized controlled trials, are required to examine the impact of particular interventions on quality parameters and outcome.

European Academy of Neurology and European Stroke Organization consensus statement and practical guidance for pre-hospital management of stroke.

BACKGROUND AND PURPOSE: The reduction of delay between onset and hospital arrival and adequate pre-hospital care of persons with acute stroke are important for improving the chances of a favourable outcome. The objective is to recommend evidence-based practices for the management of patients with suspected stroke in the pre-hospital setting. METHODS: The GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to define the key clinical questions. An expert panel then reviewed the literature, established the quality of the evidence, and made recommendations. RESULTS: Despite very low quality of evidence educational campaigns to increase the awareness of immediately calling emergency medical services are strongly recommended. Moderate quality evidence was found to support strong recommendations for the training of emergency medical personnel in recognizing the symptoms of a stroke and in implementation of a pre-hospital 'code stroke' including highest priority dispatch, pre-hospital notification and rapid transfer to the closest 'stroke-ready' centre. Insufficient evidence was found to recommend a pre-hospital stroke scale to predict large vessel occlusion. Despite the very low quality of evidence, restoring normoxia in patients with hypoxia is recommended, and blood pressure lowering drugs and treating hyperglycaemia with insulin should be avoided. There is insufficient evidence to recommend the routine use of mobile stroke units delivering intravenous thrombolysis at the scene. Because only feasibility studies have been reported, no recommendations can be provided for pre-hospital telemedicine during ambulance transport. CONCLUSIONS: These guidelines inform on the contemporary approach to patients with suspected stroke in the pre-hospital setting. Further studies, preferably randomized controlled trials, are required to examine the impact of particular interventions on quality parameters and outcome.

Intravenous thrombolysis for patients with in-hospital stroke onset: propensity-matched analysis from the Safe Implementation of Treatments in Stroke-East registry.

BACKGROUND AND PURPOSE: Recent cross-sectional study data suggest that intravenous thrombolysis (IVT) in patients with in-hospital stroke (IHS) onset is associated with unfavorable functional outcomes at hospital discharge and in-hospital mortality compared to patients with out-of-hospital stroke (OHS) onset treated with IVT. We sought to compare outcomes between IVT-treated patients with IHS and OHS by analysing propensity-score-matched data from the Safe Implementation of Treatments in Stroke-East registry. METHODS: We compared the following outcomes for all propensity-score-matched patients: (i) symptomatic intracranial hemorrhage defined with the safe implementation of thrombolysis in stroke-monitoring study criteria, (ii) favorable functional outcome defined as a modified Rankin Scale (mRS) score of 0-1 at 3 months, (iii) functional independence defined as an mRS score of 0-2 at 3 months and (iv) 3-month mortality. RESULTS: Out of a total of 19 077 IVT-treated patients with acute ischaemic stroke, 196 patients with IHS were matched to 5124 patients with OHS, with no differences in all baseline characteristics (P > 0.1). Patients with IHS had longer door-to-needle [90 (interquartile range, IQR, 60-140) vs. 65 (IQR, 47-95) min, P < 0.001] and door-to-imaging [40 (IQR, 20-90) vs. 24 (IQR, 15-35) min, P < 0.001] times compared with patients with OHS. No differences were detected in the rates of symptomatic intracranial hemorrhage (1.6% vs. 1.9%, P = 0.756), favorable functional outcome (46.4% vs. 42.3%, P = 0.257), functional independence (60.7% vs. 60.0%, P = 0.447) and mortality (14.3% vs. 15.1%, P = 0.764). The distribution of 3-month mRS scores was similar in the two groups (P = 0.273). CONCLUSIONS: Our findings underline the safety and efficacy of IVT for IHS. They also underscore the potential of reducing in-hospital delays for timely tissue plasminogen activator delivery in patients with IHS.

Brain iron accumulation in Wilson disease: a post mortem 7 Tesla MRI - histopathological study.

AIMS: In Wilson disease (WD), T2/T2*-weighted (T2*w) MRI frequently shows hypointensity in the basal ganglia that is suggestive of paramagnetic deposits. It is currently unknown whether this hypointensity is related to copper or iron deposition. We examined the neuropathological correlates of this MRI pattern, particularly in relation to iron and copper concentrations. METHODS: Brain slices from nine WD and six control cases were investigated using a 7T-MRI system. High-resolution T2*w images were acquired and R2* parametric maps were reconstructed using a multigradient recalled echo sequence. R2* was measured in the globus pallidus (GP) and the putamen. Corresponding histopathological sections containing the lentiform nucleus were examined using Turnbull iron staining, and double staining combining Turnbull with immunohistochemistry for macrophages or astrocytes. Quantitative densitometry of the iron staining as well as copper and iron concentrations were measured in the GP and putamen and correlated with R2* values. RESULTS: T2*w hypointensity in the GP and/or putamen was apparent in WD cases and R2* values correlated with quantitative densitometry of iron staining. In WD, iron and copper concentrations were increased in the putamen compared to controls. R2* was correlated with the iron concentration in the GP and putamen, whereas no correlation was observed for the copper concentration. Patients with more pronounced pathological severity in the putamen displayed increased iron concentration, which correlated with an elevated number of iron-containing macrophages. CONCLUSIONS: T2/T2*w hypointensity observed in vivo in the basal ganglia of WD patients is related to iron rather than copper deposits.

Effect of prestroke antiplatelets use on first-ever ischaemic stroke severity and early outcome.

OBJECTIVES: We aimed to investigate whether prior use of antiplatelet agents (AP) may be associated with lower severity and improved short-term outcome of the first-ever acute ischaemic stroke. METHODS: This was a retrospective, case-control study based on a prospective hospital stroke registry covering consecutive acute stroke patients admitted to a single stroke centre in highly urbanised area (Warsaw, Poland) between 1995 and 2013. Patients receiving oral anticoagulants were excluded from the analysis. Statistical analysis included multiple regression and logistic regression adjusted for age, sex, hypertension, atrial fibrillation, congestive heart failure, diabetes, coronary heart disease and history of myocardial infarction. RESULTS: During the study period, there were 3036 eligible patients, of whom 879 (29%) received AP before stroke onset. Patients from the AP group were older and more often burdened with stroke risk factors. There were no differences in baseline stroke severity, hospital mortality and proportion of patients alive and independent at discharge. However, AP turned out to be independently associated with lower NIHSS score on admission (ß = -0.045, p = 0.008) and increased odds for being alive and independent at discharge (odds ratio 1.36, 95% CI: 1.13-1.67) and decreased odds for in-hospital mortality (odds ratio 0.77, 95% CI: 0.59-0.99). CONCLUSIONS: Our findings provide further evidence supporting modest benefit of AP therapy on the course and outcome of first-ever ischaemic stroke. Further large studies are needed to confirm this effect.

The prestroke use of vitamin K antagonists for atrial fibrillation - trends over 15 years.

BACKGROUND: Effective anticoagulation with vitamin K antagonists (VKAs) is the standard of stroke prevention in patients with non-valvular atrial fibrillation (AF). Although, everyday practice is becoming increasingly guideline-driven, proper anticoagulation is still problematic. We aimed to investigate changes in the use of VKAs for stroke prevention in patients with AF admitted because of acute stroke over a period of 15 years. METHODS: We analysed consecutive acute stroke patients admitted to our centre between June 1995 and December 2010. Data were prospectively collected in a detailed stroke registry. We distinguished between three periods: 1995-2000 (used as reference for comparisons), 2001-2005 and 2006-2010. RESULTS: The AF rate prior to stroke was similar in ischaemic stroke patients (1995-2000: 25%, 2001-2005: 24%, 2006-2010: 24%) but increased in patients with intracerebral haemorrhage (ICH) (6%, 11%, 19%, p = 0.003 since 2006). The proportion of patients with AF using VKAs before stroke has became higher in ischaemic stroke (10%, 16%, 28%, p < 0.001 since 2006) with non-significant trend in ICH (0%, 33%, 45%). The proportion of ischaemic strokes occurring in patients with AF using VKAs with INR < 2 tended to increase over time (58%, 83%, 80.3%). There was also tendency towards increasing proportion of ICHs occurring in patients with AF over treated with VKAs (INR > 3). CONCLUSIONS: The prescription rate of VKA for stroke prevention appears to be improving. However, because of a high proportion of patients on non-therapeutic INR, the proportion of cardioembolic ischaemic strokes remains stable. It may suggest that everyday use of VKAs is still far from optimal.

Routine serum C-reactive protein and stroke outcome after intravenous thrombolysis.

OBJECTIVES: The clinical usefulness of blood biomarkers in acute stroke is not yet fully established, especially after thrombolytic therapy. Our aim was to investigate the association between routine serum C-reactive protein (CRP) measured within 24 h after admission and outcome in ischaemic stroke patients treated with intravenous thrombolysis, adjusting for a history of recent infection. METHODS: We analysed the data of consecutive stroke patients who received intravenous alteplase in our centre between October 2003 and December 2011, collected in a detailed prospective registry. Routine serum CRP was measured within 24 h from admission; concentration >5 ng/ml was considered elevated. RESULTS: Serum CRP was measured in 341 of 406 stroke patients treated with alteplase. Patients with elevated CRP (135/341, 42.5%) compared to those with normal CRP values, were significantly older, more frequently presented with a preexisting disability, comorbidities and suffered more severe strokes. They had a higher proportion of symptomatic intracranial haemorrhage according to ECASS II definition (7.2% vs 1.6%, P = 0.010), higher 3-month mortality (25.6% vs 11.3%, P = 0.001), and were less frequently alive and independent after 3 months (45.9% vs 63.7%, P = 0.002). However, those associations were not confirmed after adjustment for age, stroke severity, diabetes, congestive heart failure, lack of prestroke disability and signs of recent infection. CONCLUSIONS: According to our findings, elevated routine serum CRP measured within 24 h after admission does not seem to independently affect the outcome in patients receiving intravenous thrombolysis for stroke. However, further studies of blood samples taken directly before the treatment are needed.

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

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Benefit of thrombolysis for stroke is maintained around the clock: results from the SITS-EAST Registry.

BACKGROUND AND PURPOSE: The outcome of thrombolysis for early morning and sleep time strokes may be worse because of uncertainty of stroke onset time or differences in logistics. The aim of the study was to analyze if stroke outcome after intravenous thrombolysis differs depending on time of day when the stroke occurs. METHODS: The data collected in the Safe Implementation of Treatments in Stroke - Eastern Europe (SITS-EAST) Registry between September 2000 and December 2011 were used. Strokes were categorized as night-time 00:00-07:59, day-time 08:00-15:59 and evening-time 16:00-23:59 and were compared in terms of several outcome measures. All results were adjusted for baseline differences. RESULTS: A total of 8878 patients were enrolled: 18% had night-time, 54% day-time and 28% evening-time strokes. Onset-to-treatment time in patients with night-time strokes was 10 min longer than in day-time and evening-time strokes (P < 0.001). Symptomatic intracerebral hemorrhage by ECASS II definition occurred in 5.6%, 5.6% and 5.3% (adjusted P = 0.41) of the night-time, day-time and evening-time stroke patients, respectively; by SITS definition it occurred in 2.5%, 1.9% and 1.3% (adjusted P = 0.013) and by NINDS definition in 7.8%, 7.6% and 7.5% (adjusted P = 0.74). Patients with night-time, day-time and evening-time strokes achieved modified Rankin Scale score 0-1 in 33%, 31%, 31% (adjusted P = 0.34) and 0-2 in 52%, 51%, 50% (adjusted P = 0.23), and 13%, 15%, 16% respectively of patients died (adjusted P = 0.17) by 3 months. CONCLUSIONS: The time when stroke occurs (day versus evening versus night) does not affect the outcome after thrombolysis despite the fact that patients with night-time strokes have worse time management.

Compliant treatment with anti-copper agents prevents clinically overt Wilson's disease in pre-symptomatic patients.

BACKGROUND AND PURPOSE: Wilson's disease (WD) is an inherited copper metabolism disorder that leads to dysfunction of affected tissues, mostly in the liver and brain. Anti-copper treatment should prevent clinically overt WD in pre-symptomatic patients but this has not been supported by strong evidence. Our aim was to evaluate the long-term effectiveness of treatment in clinically pre-symptomatic patients, with particular emphasis on patient compliance with treatment. METHODS: Data were analyzed for 87 consecutive patients with no clinical symptoms of WD who were identified between 1957 and 2009 by family screening. All of them since diagnosis were treated with either zinc sulphate (Zn) (66.7%) or D-penicillamine (DPA) (33.3%). RESULTS: During a median follow-up of 12 years (range 3-52), 55 (63%) patients remained without clinical symptoms, 13 (15%) developed neuropsychiatric symptoms and 21 (24%) developed hepatic dysfunction, including five deaths from hepatic failure. Non-compliance for at least three consecutive months was observed in 39 patients, and in 29 cases this extended for more than 12 months. Multivariate analysis showed that the odds of developing symptomatic WD were independently increased by non-compliance (odds ratio 24.0, 95% confidence interval 6.0-99.0). According to Kaplan-Meier analysis patients who were compliant to treatment had a significantly higher likelihood of remaining symptom-free, and their overall survival was similar to the survival rate observed in the general population. CONCLUSION: The use of anti-copper agents in clinically pre-symptomatic patients diagnosed with WD allows clinically overt disease to be effectively prevented. However, compliance with therapy is extremely important.

No effects of anodal transcranial direct stimulation on language abilities in early rehabilitation of post-stroke aphasic patients.

BACKGROUND AND PURPOSE: Recent research suggests that an increased level of stroke-affected left hemisphere cortical (especially frontal) excitability is associated with better language improvement in aphasic patients. Anodal transcranial direct current stimulation (A-tDCS), increasing cortical activity, may facilitate perilesional left hemisphere recruitment to subserve language processing and enhance effects of behavioural therapy. The aim of the study (randomized, double-blind, sham-controlled) was to evaluate the effectiveness of repeated A-tDCS over Broca area as a strategy to enhance aphasia recovery during early post-stroke rehabilitation. MATERIAL AND METHODS: Thirty-seven participants with moderate or severe aphasia were randomized to receive 15 consecutive daily sessions of A-tDCS (1 mA, 10 min; experimental group, n = 18) or sham stimulation (1 mA, 25 s; control group, n = 19) followed by language therapy. Effects of tDCS were assessed using the Boston Diagnostic Aphasia Examination, performed before and after the rehabilitation, and three months later. RESULTS: The results did not confirm a positive impact of repeated A-tDCS, preceding language therapy, on language abilities in our patients. Although both groups improved after the therapy, there were no statistically significant differences between groups in either short-term or long-term tDCS effects. Effect sizes for the experimental group, at post-treatment and the 3-month follow-up, were slightly higher than in controls but insufficient to infer any beneficial influence of the applied intervention. CONCLUSIONS: The findings do not support A-tDCS functional benefits during early rehabilitation of post-stroke aphasia. Further research is needed to explore the effectiveness of this kind of neuromodulation.

Acute focal dystonia induced by a tricyclic antidepressant in a patient with Wilson disease: a case report.

The authors present the case of a 19-year-old patient with Wilson disease (WD) who developed symptoms of acute focal dystonia of the left hand (a 'starfish' hand presentation) shortly after treatment with the tricyclic antidepressant clomipramine. The diagnosis of WD was made 8 months earlier based on abnormal copper metabolism parameters and was confirmed by genetic testing. Initially, the patient presented with akathisia, sialorrhea, oromandibular dystonia (occasionally grimacing) and slight dysarthria. The patient's symptoms diminished after treatment with d-penicillamine was initiated. No further deterioration was observed after copper-chelating therapy was started. The authors diagnosed acute focal dystonia induced by clomipramine. Botulinum toxin and intensive rehabilitation was initiated; complete regression of hand dystonia was observed. Based on the case, the authors suggest that care should be exercised with regard to starting medications that could potentially impact the extrapyramidal system in WD patients.

[Management of acute stroke - guidelines from the Expert Group of the Section of Cerebrovascular Diseases of the Polish Neurological Society. Update 2013: thrombolysis]. / Postepowanie w udarze mózgu - wytyczne Grupy Ekspertów Sekcji Chorób Naczyniowych Polskiego Towarzystwa Neurologicznego. Aktualizacja 2013: leczenie trombolityczne.

Thrombolysis is the most effective therapy for ischaemic stroke. The current guidelines and approvals have limited its use to patients available for treatment within 4.5 hours of onset and those aged 80 or less. There are also a number of other limitations derived from clinical trial protocols, i.e. minor and major strokes. The available evidence has indicated its possible efficacy in patients treated within 6 hours of onset and not fulfilling other limitations. Last year, the results of the IST-3 (Third International Stroke Trial: Thrombolysis) and a meta-analysis of all available trials including IST-3 were published. They point out the possible benefit of thrombolysis in patients not meeting the current criteria, which has been acknowledged in the Polish guidelines for management of stroke.

Effect of liver transplantation on brain magnetic resonance imaging pathology in Wilson disease: a case report.

The authors present a case report of a 28-year-old patient with hepatic, but no neurological, signs of Wilson disease, with pathological changes in both the globi pallidi and caudate found with routine brain magnetic resonance imaging (MRI). The patient was recommended for liver transplantation by hepatologists, and during the two years of observation after liver transplantation, MRI brain abnormalities due to Wilson disease completely regressed. On the basis of this case, the authors present an argument for the prognostic significance of brain MRI in Wilson disease as well as current recommendations concerning liver transplantation in Wilson disease.

Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one--time administration of encephalitogenic T cells.

Cognitive dysfunction is relatively frequent in multiple sclerosis (MS) and it happens from the early stages of the disease. There is increasing evidence that the grey matter may be involved in autoimmune inflammation during relapses of MS. The purpose of this study was to evaluate if a single transfer of encephalitogenic T cells, mimicking a relapse of MS, may cause hippocampal damage and memory disturbances in rats. Lewis rats were injected with anti-MBP CD4+ T cells, that induced one-phase autoimmune encephalomyelitis (EAE) with full recovery from motor impairments at 10-15 days. The spatial learning and memory were tested by the Morris water maze test in control and EAE animals, 30 and 90 days post-induction (dpi). The neural injury and inflammation was investigated in the hippocampus by immunohistochemistry and quantitative analyses. There was a marked decrease in the number of CA1 and CA4 pyramidal neurons 5 dpi. The loss of neurons then aggravated till the 90 dpi. An increase in microglial and astroglial activation and in pro-inflammatory cytokines mRNA expression in the hippocampus, were present 30 and 90 dpi. Nerve growth factor and brain-derived neurotrophic factor mRNA levels were also significantly elevated. The water maze test, however, did not reveal memory deficits. The present data indicate that a single transfer of autoimmune T cells results in preserved inflammation and probable on-going neuronal injury in the hippocampus, long after recovery from motor disturbances. These findings suggest that any relapse of the MS may start the neurodegenerative process in the hippocampus, which is not necessarily connected with memory deficits.

Brain metal accumulation in Wilson's disease.

INTRODUCTION: Brain metal accumulation is suggested in the pathogenesis of numerous neurodegenerative disorders. In Wilson's disease (WD), only copper has been examined. The aim of the present study was to evaluate the copper, iron, manganese, and zinc concentrations in autopsy tissue samples from the brains of WD patients. METHODS: The study material consisted of 17 brains (12 WD patients, 5 controls) obtained at autopsy. Samples were taken from four different regions of each brain: frontal cortex, putamen, pons, and nucleus dentatus. The copper, manganese, and zinc content were determined using inductively coupled plasma mass spectrometry, and iron was assessed using flame atomic absorption spectroscopy. The results were analyzed according to select clinical variables. RESULTS: Copper content was increased homogenously in all investigated structures of the WD brains compared to controls (41.0 ± 18.6 µg/g vs.5.4 ± 1.8 µg/g; P<0.01). The mean concentrations of iron, manganese, and zinc were similar in WD and controls, but the iron level in the nucleus dentatus was higher in WD compared to controls (56.8 ± 14.1 µg/g vs. 32.6 ± 6.0 µg/g; P<0.05). Gender, age, and type and duration of WD treatment did not impact brain metals storage, but some correlations between the duration of the disease and copper and iron accumulation were observed. CONCLUSIONS: During the course of WD, copper accumulates equally in different parts of the brain. Zinc and manganese do not seem to be involved in WD pathology, but increased levels of iron were found in the nucleus dentatus. Thus, additional studies of brain iron accumulation in WD are needed.

Association of dopamine receptor gene polymorphisms with the clinical course of Wilson disease.

BACKGROUND: Dopamine receptor D2 (DRD2) polymorphisms are proposed to be important factors in the presentation of neuropsychiatric symptoms in many disorders, including decreased striatum levels of dopamine D2 receptors in Wilson disease. The present study investigated the association between DRD2 gene polymorphisms and clinical manifestation of Wilson disease. METHODS: Analyzing data from 97 symptomatic Wilson disease patients, we investigated the DRD2 gene polymorphisms rs1800497, rs1799732, and rs12364283. We assessed the polymorphisms impact on the phenotypic presentation of the disease. RESULTS: Generally, the DRD2 gene polymorphisms had no impact on the hepatic or neuropsychiatric clinical presentation of Wilson disease. However, rs1799732 deletion allele carriers with neuropsychiatric symptoms had earlier onset of WD symptoms by almost 6 years compared with individuals without this allele (22.5 vs. 28.3 years; P < 0.05). This unfavorable effect of the rs1799732 polymorphism was even more pronounced among adenosine triphosphatase 7B gene (ATP7B) p.H1069Q homozygous patients, in whom carriership of the deletion allele was related to earlier initial neuropsychiatric manifestation by 14 years (18.4 vs. 32.2 years; P < 0.01). CONCLUSIONS: Genetic variation of DRD2, specifically the rs1799732 polymorphism, may produce an earlier clinical presentation of Wilson disease neuropsychiatric symptoms and signs that occur in the course of dopaminergic system impairment due to copper accumulation in the brain. We speculate that this effect may be due to the impact of DRD2 polymorphism on dopamine D2 receptor density, but further studies are needed to understand the mechanisms of such phenotypic effects.