Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case-control study.

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50). Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case­control study

BACKGROUND Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. METHODS The INTERSTROKE study is a case­control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). FINDINGS Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46­1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61­2.11) than ICH (OR 1.19 95% CI 1.00­1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24­4.10) and PAR (18.6%, 15.1­22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63­2.87) and undetermined cause (OR 1.97, 95% CI 1.55­2.50). Both filtered (OR 1.73, 95% CI 1.50­1.99) and non-filtered (OR 2.59, 95% CI 1.79­3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69­2.27), ischemic stroke (OR 1.89, 95% CI 1.59­2.24) and ICH (OR 2.00, 95% CI 1.60­2.50). INTERPRETATION There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. FUNDING The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Variations in the prevalence of atrial fibrillation, and in the strength of its association with ischemic stroke, in countries with different income levels: INTERSTROKE case-control study

BACKGROUND: The contribution of atrial fibrillation (AF) to the etiology and burden of stroke may vary by country income level. AIMS: We examined differences in the prevalence of AF and described variations in the magnitude of the association between AF and ischemic stroke by country income level. METHODS: In the INTERSTROKE case­control study, participants with acute first ischemic stroke were recruited across 32 countries. We included 10,363 ischemic stroke cases and 10,333 community or hospital controls who were matched for age, sex, and center. Participants were grouped into high-income (HIC), upper-middle-income (subdivided into two groups­UMIC-1 and UMIC-2), and lower-middle-income (LMIC) countries, based on gross national income. We evaluated the risk factors for AF overall and by country income level, and evaluated the association of AF with ischemic stroke. RESULTS: AF was documented in 11.9% (n = 1235) of cases and 3.2% (n = 328) of controls. Compared to HIC, the prevalence of AF was significantly lower in UMIC-2 (aOR 0.35, 95% CI 0.29­0.41) and LMIC (aOR 0.50, 95% CI 0.41­0.60) on multivariable analysis. Hypertension, female sex, valvular heart disease, and alcohol intake were stronger risk factors for AF in lower-income countries, and obesity a stronger risk factor in higher-income countries. The magnitude of association between AF and ischemic stroke was significantly higher in lower-income countries compared to higher-income countries. The population attributable fraction for AF and stroke varied by region and was 15.7% (95% CI 13.7­17.8) in HIC, 14.6% (95% CI 12.3­17.1) in UMIC-1, 5.7% (95% CI 4.9­6.7) in UMIC-2, and 6.3% (95% CI 5.3­7.3) in LMIC. CONCLUSION: Risk factors for AF vary by country income level. AF contributes to stroke burden to a greater extent in higher-income countries than in lower-income countries, due to a higher prevalence and despite a lower magnitude of odds ratio.

Variations in the prevalence of atrial fibrillation, and in the strength of its association with ischemic stroke, in countries with different income levels: INTERSTROKE case-control study.

BACKGROUND: The contribution of atrial fibrillation (AF) to the etiology and burden of stroke may vary by country income level. AIMS: We examined differences in the prevalence of AF and described variations in the magnitude of the association between AF and ischemic stroke by country income level. METHODS: In the INTERSTROKE case-control study, participants with acute first ischemic stroke were recruited across 32 countries. We included 10,363 ischemic stroke cases and 10,333 community or hospital controls who were matched for age, sex, and center. Participants were grouped into high-income (HIC), upper-middle-income (subdivided into two groups-UMIC-1 and UMIC-2), and lower-middle-income (LMIC) countries, based on gross national income. We evaluated the risk factors for AF overall and by country income level, and evaluated the association of AF with ischemic stroke. RESULTS: AF was documented in 11.9% (n = 1235) of cases and 3.2% (n = 328) of controls. Compared to HIC, the prevalence of AF was significantly lower in UMIC-2 (aOR 0.35, 95% CI 0.29-0.41) and LMIC (aOR 0.50, 95% CI 0.41-0.60) on multivariable analysis. Hypertension, female sex, valvular heart disease, and alcohol intake were stronger risk factors for AF in lower-income countries, and obesity a stronger risk factor in higher-income countries. The magnitude of association between AF and ischemic stroke was significantly higher in lower-income countries compared to higher-income countries. The population attributable fraction for AF and stroke varied by region and was 15.7% (95% CI 13.7-17.8) in HIC, 14.6% (95% CI 12.3-17.1) in UMIC-1, 5.7% (95% CI 4.9-6.7) in UMIC-2, and 6.3% (95% CI 5.3-7.3) in LMIC. CONCLUSION: Risk factors for AF vary by country income level. AF contributes to stroke burden to a greater extent in higher-income countries than in lower-income countries, due to a higher prevalence and despite a lower magnitude of odds ratio.

External quality monitoring facilitates improvement in already well-performing stroke units: insights from RES-Q Poland.

INTRODUCTION: The Registry of Stroke Care Quality (RES-Q) is used in Poland for quality monitoring by numerous hospitals participating in the Angels Initiative. Our aim was to assess the degree of improvement in highly stroke-oriented centres that report cases to the RES-Q each year. MATERIAL AND METHODS: This retrospective analysis included Polish stroke units that from January 2017 to December 2020 contributed to the RES-Q at least 25 patients annually. RESULTS: Seventeen out of 180 Polish stroke units reported patients each year (2017, n = 1,691; 2018, n = 2,986; 2019, n = 3,750; 2020, n = 3,975). The percentage of ischaemic stroke patients treated with alteplase remained stable (26%, 29%, 30% and 28%, respectively). The door-to-needle time progressively decreased, from a median 49 minutes to 32 minutes. The percentage of patients treated ≤ 60 minutes and ≤ 45 minutes significantly increased (from 68% to 86% and from 43% to 70%, respectively), with no change observed between 2019 and 2020. Despite a general improvement in dysphagia screening (81%, 91%, 98% and 99%), screening performed within the first 24h from admission became less frequent (78%, 76%, 69% and 65%). In-hospital mortality significantly increased (11%, 11%, 13% and 15%), while the proportion of patients discharged home remained stable. CONCLUSIONS: Quality-oriented projects facilitate the improvement of stroke care, even in centres demonstrating good baseline performance. Polish stroke units that consistently reported cases to the RES-Q demonstrated improvement in terms of door-to- -needle time and dysphagia screening. However, there is still a need to shorten the time to dysphagia screening, and carefully monitor stroke unit mortality following the COVID-19 pandemic.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Protein Carbonylation Contributes to Prothrombotic Fibrin Clot Phenotype in Acute Ischemic Stroke: Clinical Associations.

BACKGROUND: Acute ischemic stroke (AIS) is associated with enhanced oxidative stress and unfavorably altered fibrin clot properties. We investigated determinants of plasma protein carbonylation (PC) in AIS, its impact on the prothrombotic state, and prognostic value during follow-up. METHODS: We included 98 consecutive AIS patients aged 74±12 years (male:female ratio, 50:48 [51%:49%]) at the Neurology Center in Warsaw, Poland, between January and December 2014. As many as 74 (75.5%) patients underwent thrombolysis, and 24 were unsuitable for thrombolysis. We determined plasma PC, along with thrombin generation, fibrin clot permeability, and clot lysis time on admission, at 24 hours, and 3 months. Stroke severity was assessed using the National Institutes of Health Stroke Scale and stroke outcome with the modified Rankin Scale. Hemorrhagic transformation was assessed on the computed tomography scan within 48 hours from the symptom onset, while stroke-related mortality was evaluated at 3 months. RESULTS: On admission, PC levels (median, 4.61 [3.81-5.70] nM/mg protein) were associated with the time since symptom onset (r=0.41; P<0.0001) and with the National Institutes of Health Stroke Scale score (P=0.36; P=0.0003). Higher PC levels on admission correlated with denser fibrin clot formation and prolonged clot lysis time but not with thrombin generation. In thrombolysed patients, lower PC levels were observed after 24 hours (-34%) and at 3 months (-23%; both P<0.001). PC levels at baseline and after 24 hours predicted the modified Rankin Scale score >2 at 3 months (OR, 1.90 [95% CI, 1.21-3.00]; OR, 2.19 [95% CI, 1.39-3.44], respectively). Higher PC at baseline predicted hemorrhagic transformation of stroke (OR, 1.95 [95% CI, 1.02-3.74]) and stroke-related mortality (OR, 2.02 [95% CI, 1.08-3.79]), while higher PC at 24 hours predicted solely stroke-related mortality (OR, 2.11 [95% CI, 1.28-3.46]). CONCLUSIONS: Elevated plasma PC levels in patients with AIS, related to prothrombotic fibrin clot properties, are associated with stroke severity. Thrombolysis reduces the extent of PC. The current study suggests a prognostic value of PC in AIS.

Tackling the neurological manifestations in Wilson's disease - currently available treatment options.

INTRODUCTION: Wilson's disease (WD) is a potentially treatable, inherited disorder resulting from impaired copper metabolism. Pathological copper accumulation causes a range of symptoms, most commonly hepatic and a wide spectrum of neurological symptoms including tremor, dystonia, chorea, parkinsonism, dysphagia, dysarthria, gait and posture disturbances. To reduce copper overload, anti-copper drugs are used that improve liver function and neurological symptoms in up to 85% of patients. However, in some WD patients, treatment introduction leads to neurological deterioration, and in others, neurological symptoms persist with no improvement or improvement only after several years of treatment, severely affecting the patient's quality of life. AREAS COVERED: This review appraises the evidence on various pharmacological and non-pharmacological therapies, neurosurgical procedures and liver transplantation for the management of neurological WD symptoms. The authors also discuss the neurological symptoms of WD, causes of deterioration and present symptomatic treatment options. EXPERT OPINION: Based on case and series reports, current recommendations and expert opinion, WD treatment is focused mainly on drugs leading to negative copper body metabolism (chelators or zinc salts) and copper-restricted diet. Treatment of WD neurological symptoms should follow general recommendations of symptomatic treatment. Patients should be always considered individually, especially in the case of severe, disabling neurological symptoms.

High neutrophil-to-lymphocyte ratio (NLR) predicts poor response to intravenous thrombolysis in white Caucasian stroke patients.

OBJECTIVES: Our aim was to investigate usefulness of the neutrophil-to-lymphocyte ratio (NLR) for predicting poor response to intravenous rtPA in white Caucasian ischemic stroke patients treated within 4.5 hours from the onset. MATERIALS AND METHODS: This retrospective analysis included all consecutive acute ischemic stroke patients (N = 344) treated with rtPA in a tertiary stroke center from 2011 to 2017. NLR was calculated from complete blood counts obtained on admission. The patients were classified into NLR terciles (T1 <1.75, T2<2.97, T3≥2.97). Significant neurological improvement was defined as an 8-point reduction in the NIHSS score or reaching the score of 0 to 1. RESULTS: Compared to NLR T1, patients from NLR T3 were significantly older, more often disabled before stroke, and had longer onset-to-needle time. They less often achieved neurological improvement at day 7 (38% vs 59% p=0.002) and had higher 90-day mortality (27% vs 13%, p=0.020), with no differences in neurological improvement at 24 hours, occurrence of sICH and 7-day mortality. Each additional 4 units of NLR decreased unadjusted and adjusted odds for achieving favorable outcome at day 7 (OR 0.65, 95% CI: 0.46-0.92; aOR 0.62, 95% CI: 0.39-1.00), and increased the odds for death at 3 months (OR 1.60, 95% CI: 1.15-2.24; aOR 1.82, 95% CI:1.14-2.92) CONCLUSIONS: High NLR can predict poor response to intravenous rtPA in Caucasian patients with acute ischemic stroke, especially in terms of not achieving significant neurological improvement at day 7 and death at day 90. It encourages attempts to incorporate NLR in already validated scores.

D-Penicillamine-Induced Myasthenia Gravis-A Probable Complication of Wilson's Disease Treatment-A Case Report and Systematic Review of the Literature.

Wilson's disease (WD) is a genetic disorder with copper accumulation in various tissues leading to related clinical symptoms (mainly hepatic and neuropsychiatric) which can be in 85% of patients successfully treated with anti-copper agents. However, during WD treatment neurological deterioration may occur in several patients. D-penicillamine (DPA) is one of the most frequently used drugs in WD treatment. Despite its efficacy, DPA can produce many adverse drug reactions, which should be recognized early. We present the case of a 51-year-old man diagnosed with the hepatic form of WD and initially treated with DPA in whom after 15 months of treatment, diplopia and evening ptosis occurred. WD treatment non-compliance as well as overtreatment were excluded. Supported by neurological symptoms, a positive edrophonium test, and high serum levels of antibodies against acetylcholine receptors (AChR-Abs), as well as low concentrations of antibodies against muscle-specific kinase (MuSK-Abs), the diagnosis of myasthenia gravis (MG), induced by DPA, was established. DPA was stopped; zinc sulfate for WD and pyridostigmine for MG symptoms were introduced. Diplopia and ptosis subsided after a few days, which supported our diagnosis. During a follow-up visit after 6 months, the patient did not present any MG symptoms. AChR-Abs level gradually decreased and MuSK-Abs were no longer detected. Pyridostigmine was stopped, and within 9 months of follow-up, the neurological symptoms of MG did not reoccur. The authors discussed the patient's neurological deterioration, performed a systematic review of DPA-induced MG in WD and concluded that MG is a rare and usually reversible complication of DPA treatment. DPA-induced MG generally occurs 2-12 months after treatment initiation and ocular symptoms predominate. Response to pyridostigmine treatment is good and MG symptoms usually reverse within one year after DPA treatment cessation. However, symptoms may persist in some cases where DPA treatment is only a trigger factor for MG occurrence.

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

INTRODUCTION: 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. OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 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.

Risk Factors for Stroke in the Young (18-45 Years): A Case-Control Analysis of INTERSTROKE Data from 32 Countries.

BACKGROUND: It is not clear whether conventional vascular risk factors are responsible for most strokes in patients younger than 45 years of age. Our objective was to evaluate the association of common risk factors with stroke in individuals under 45 years. METHODS: INTERSTROKE was a case-control study carried out in 32 countries between 2007 and 2015. Patients presenting within 5 days of symptom onset of a first stroke were enrolled as cases. Controls were age and sex matched to cases and had no history of stroke. Cases and controls underwent similar evaluations. Odds ratios (ORs) and population attributable risks (PARs) were calculated to determine the association of various risk factors with all stroke, ischemic stroke, and intracranial hemorrhage, for patients 45 years of age or younger. FINDINGS: 1,582 case-control pairs were included in this analysis. The mean age of this cohort was 38.5 years (SD 6.32). Overall, 71% strokes were ischemic. Cardiac causes {OR: 8.42 (95% confidence interval [CI]: 3.01-23.5)}; binge drinking of alcohol (OR: 5.44 [95% CI: 1.81-16.4]); hypertension (OR: 5.41 [95% CI: 3.40-8.58]); ApoB/ApoA1 ratio (OR: 2.74 [95% CI: 1.69-4.46]); psychosocial stress (OR: 2.33 [95% CI: 1.01-5.41]); smoking (OR: 1.85 [95% CI: 1.17-2.94]); and increased waist-to-hip ratio (OR: 1.69 [95% CI: 1.04-2.75]) were the most important risk factors for ischemic stroke in these young cases. For intracerebral hemorrhage, only hypertension (OR: 9.08 [95% CI: 5.46-15.1]) and binge drinking (OR: 4.06 [95% CI: 1.27-13.0]) were significant risk factors. The strength of association and population attributable risk (PAR) for hypertension increased with age (PAR 23.3% in those <35 years of age, 50.7% in 35-45 years of age). INTERPRETATION: Conventional risk factors such as hypertension, smoking, binge drinking of alcohol, central obesity, cardiac causes, dyslipidemia, and psychosocial stress are important risk factors for stroke in those younger than 45 years of age. Hypertension is the most significant risk factor in all age groups and across all regions and both stroke subtypes. These risk factors should be identified and modified in early adulthood to prevent strokes in young individuals.

Depressive symptoms and risk of acute stroke: INTERSTROKE case-control study

METHODS: The INTERSTROKE is an international case-control study of risk factors of first acute stroke, conducted in 32 countries. Cases were patients with CT- or MRI-confirmed incident acute hospitalized stroke, and controls were matched for age, sex, and within sites. Standardized questions asked about self-reported depressive symptoms during the previous 12 months and the use of prescribed antidepressant medications were recorded. Multivariable conditional logistic regression was used to determine the association of prestroke depressive symptoms with acute stroke risk. Adjusted ordinal logistic regression was used to explore the association of prestroke depressive symptoms with poststroke functional outcome, measured with the modified Rankin scale at 1 month after stroke. RESULTS: Of 26,877 participants, 40.4% were women, and the mean age was 61.7 ± 13.4 years. The prevalence of depressive symptoms within the last 12 months was higher in cases compared with that in controls (18.3% vs 14.1%, p < 0.001) and differed by region (p interaction <0.001), with lowest prevalence in China (6.9% in controls) and highest in South America (32.2% of controls). In multivariable analyses, prestroke depressive symptoms were associated with greater odds of acute stroke (odds ratio [OR] 1.46, 95% CI 1.34-1.58), which was significant for both intracerebral hemorrhage (OR 1.56, 95% CI 1.28-1.91) and ischemic stroke (OR 1.44, 95% CI 1.31-1.58). A larger magnitude of association with stroke was seen in patients with a greater burden of depressive symptoms. While preadmission depressive symptoms were not associated with a greater odds of worse baseline stroke severity (OR 1.02, 95% CI 0.94-1.10), they were associated with a greater odds of poor functional outcome at 1 month after acute stroke (OR 1.09, 95% CI 1.01-1.19). DISCUSSION: In this global study, we recorded that depressive symptoms are an important risk factor of acute stroke, including both ischemic and hemorrhagic stroke. Preadmission depressive symptoms were associated with poorer functional outcome, but not baseline stroke severity, suggesting an adverse role of depressive symptoms in poststroke recovery.

Olfactory dysfunction in patients with Wilson's Disease.

INTRODUCTION: Many neurodegenerative disorders are associated with olfactory dysfunction (OD), but little is known about OD in Wilson's Disease (WD). We evaluated olfactory function in patients with WD. MATERIAL AND METHODS: OD was examined in 68 patients with WD and 70 sex- and age-matched healthy controls using subjective testing with 'Sniffin Sticks'. Threshold discrimination identification (TDI) score and its three components (odour detection threshold, discrimination, and identification) were assessed. RESULTS: Compared to controls, patients with WD had a significantly weaker sense of smell in terms of TDI (p < 0.01), odour discrimination (p < 0.01), and identification (p < 0.01), but not in terms of odour detection threshold (p = 0.27). Patients with predominantly neurological symptoms were characterised by greater OD by TDI (p < 0.01), odour detection threshold (p = 0.01), and discrimination (p = 0.03). The presence of pathological lesions (p = 0.04) in brain magnetic resonance imaging and generalised brain atrophy (p = 0.02) predisposed to worse TDI. In the WD group, weak inverse correlations between age and TDI score (r = -0.27), odour detection threshold (r = -0.3), and discrimination (r = -0.3) were found. Male gender was a risk factor for abnormal TDI in both WD and controls (both p = 0.02). CONCLUSIONS: Patients with WD, particularly older individuals, more frequently had OD than healthy volunteers. Predominantly neurological symptoms, and the presence of typical brain MRI changes, predisposed patients with WD to smell disorders.