Adherence to Epilepsy's Medical Recommendations.

The primary problem in the treatment of epilepsy is poor seizure control. Several studies have shown that non-adherence to doctors' recommendations regarding drug dosage, time of drug administration as well as lifestyle modifications are the most frequent causes of the persistence or reoccurrence of seizures, other than cases of misdiagnosis and poor drug selection. The aim of this study was to assess the prevalence of non-compliance with medical recommendations, both in relation to medicine dosage, regularity of administration and lifestyle, and also to determine the factors affecting patients with diagnosed epilepsy. This study was carried out on a total of 169 patients diagnosed with epilepsy who were under the care of an outpatient neurology clinic. The assessment of compliance was performed using the Patient Rating of Compliance Scale (PRCS), Clinician Rating Scale (CRS) and authors' scale. Depending on the scale used, varying degrees of non-compliance were noted. They were as follows-65.3% on the authors' scale, 10% on the PRCS and 9% on the CRS. The following factors influenced compliance with doctors' recommendations: type of epilepsy, consumption of alcoholic beverages, frequency of follow-up visits to the neurology clinic, type of pharmacotherapy and number of medicines taken.

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment.

Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.

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.

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.

Clinical efficacy and safety of anterior thalamic deep brain stimulation for intractable drug resistant epilepsy.

BACKGROUND: Deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) is a neuromodulation therapy for patients with refractory focal seizures evolving into bilateral tonic-clonic seizures when pharmacotherapy as well other neuromodulation techniques including vagus nerve stimulation or responsive neurostimulation have failed. OBJECTIVE: We performed a prospective single-center study investigating the clinical efficacy and exact ANT DBS lead location in patients with DRE. METHODS: The primary outcome measure was the proportion of patients with more than 50 % reduction in diary-recorded seizures when compared to three preoperative months (baseline seizure frequency). The close postoperative follow-up was performed every 3 months. The seizure frequency, stimulation settings and adverse events were closely monitored during follow-up visits. We also analyzed the seizure outcome with location of ANT DBS active contacts. RESULTS: Between May 2020 and October 2022, 10 adult patients with a mean age of 38.5 years (range, 30-48 years) underwent bilateral ANT DBS surgery (mean duration of DRE 28.6 years, range 16-41 years). The median seizure count in three months period preceding surgery (baseline seizure count) was 43.2 (range, 4-150). Nine patients achieved more than 50 % seizure reduction at the last follow-up (mean range 3-33 13.6 months, months). ANT DBS caused seizure reduction 3 months after procedure as well as at last follow-up by 60.4 % and 73.3 %, respectively. Due to relatively small number of studying individuals we cannot precisely locate the area within ANT associated with good clinical outcome. Patients with temporal lobe epilepsy had a remarkable reduction of seizure frequency. No patient suffered transient or permanent neurological deficits. CONCLUSIONS: Clinical efficacy of ANT DBS may support more widespread utilization of this neuromodulation technique especially for seizures originating from temporal lobes.

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.

Cladribine tablets for highly active relapsing-remitting multiple sclerosis in Poland: a real-world, multi-centre, retrospective, cohort study during the COVID-19 pandemic.

INTRODUCTION: Treatment with cladribine tablets is indicated in highly active relapsing-remitting multiple sclerosis (RRMS). Cladribine tablets proved safe and effective in the pivotal CLARITY trial, but that trial included primarily treatment-naïve patients. In clinical practice however, cladribine tablets are often given to patients who have failed other treatments. Therefore, this study investigated the real-world safety and efficacy of cladribine tablets. MATERIAL AND METHODS: We gathered data from nine MS clinical centres across Poland for patients with RRMS who started treatment with cladribine tablets from December 2019 to June 2022. RESULTS: We enrolled 140 patients, with follow-up data available for 136 in year 1 and for 66 in year 2. At baseline, the mean age was 35.6 years, mean disease duration was 7.3 years, median EDSS score was 2.5, and 94% of patients were treatment- -experienced. Thirty-nine patients (27.9%) had undergone COVID-19, and 94 (67.1%) were vaccinated against COVID-19. The annualised relapse rate (ARR) decreased from 1.49 at baseline to 0.33 in year 1 (p < 0.001) and to 0.25 in year 2 (p < 0.001). The percentage of relapse-free patients increased from 11.5% at baseline to 70.2% in year 1 and 82.1% in year 2. The percentage of patients with active lesions decreased from 91.4% at baseline to 36.2% in year 1 and 18.2% in year 2. EDSS score remained stable or improved in 83.7% of patients in year 1 and 89.6% in year 2. No evidence of disease activity (NEDA-3) was achieved in 42.7% of patients in year 1 and 66.7% in year 2. Only one patient (0.72%) had grade 4 lymphopenia and 21 (15.1%) had grade 3 lymphopenia. Varicella zoster virus infections occurred in three patients. Eight patients discontinued treatment with cladribine: five due to inefficacy, one due to lymphopenia, and two due to a personal decision. CONCLUSIONS: Cladribine tablets proved safe and effective in a real-world cohort of treatment-experienced patients. However, the efficacy measures improved to a lesser extent in our cohort than in the pivotal clinical trial, which is probably due to a higher proportion of treatment-experienced patients in our cohort.

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.

Attitudes towards the switching of anti-epileptic medications in pharmacies: the patients' perspective.

Purpose: A survey of epilepsy patients' experiences of and attitudes towards the pharmacy switching of anti-epileptic medications. Methods: A structured questionnaire was administered to a group of epilepsy patients treated at the Institute of Psychiatry and Neurology and the Medical University of Silesia, Poland. Two hundred and eleven patients (mean [± SD] age: 41.0 ± 15.6 years) were recruited; 60.6% were women. 68.2% had been treated for over 10 years. Results: Most individuals (63%) claimed that they had never bought a generic substitute medication. Among the patients who declared that a switch had been proposed to them at a pharmacy (~40%), only 68.7% received any explanation at all from a pharmacist. Some reported positive emotions mostly related to a lower price of the new drug but also to the explanations received. Most respondents who accepted the pharmacy switch (67.4%) did not notice any significant changes in the efficacy or tolerability of treatment, while the remaining subjects reported an increase in seizure frequency (23.2%) and deterioration in treatment tolerance (9%). Conclusions: Around 40% of Polish epilepsy patients have been confronted with a proposal to switch their anti-epileptic medications at a pharmacy. More of them report negative attitudes towards the pharmacist's proposal than do not. It is possible that one of the major reasons for this is the insufficient information provided by pharmacists. It remains to be established whether the reported decrease in seizure control could be accounted for by a low concentration of the anti-epileptic drug in the blood after the switch.

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.

Reliability of the modified Rankin Scale in clinical practice of stroke units and rehabilitation wards.

Introduction: The Modified Rankin Scale (mRS) is the most common tool to quantify post-stroke disability in everyday practice and by certified raters in clinical trials. However, interobserver variability may affect reliability of retrospective observational studies, including clinical registries. Our aim was to assess real-life consistency between neurologists and physical and rehabilitation medicine physicians using mRS to rate post-stroke disability of patients transferred directly from stroke unit (SU) to rehabilitation ward (RW). Methods: This is a retrospective analysis of 132 consecutive acute stroke patients transferred from single tertiary SU to RW located in the same hospital in Poland. Patients were assessed by one rater from each department at the day of transfer. We distinguished between physicians previously certified in using mRS for clinical trials and not-certified physicians using mRS in everyday practice. Results: mRS at discharge from SU and on admission to RW was recorded for 105 of 132 patients. The overall agreement was 70.5% (kappa 0.55). Similar agreement was observed in the subset of 30 patients rated by certified physicians in both departments (70.0%, kappa 0.57) and in the subset of 61 patients rated by a pair of certified neurologist and not-certified rehabilitation physician (73.8%, kappa 0.58). Conclusions: Everyday consistency between raters from SU and RW in using mRS is modest as in previous validation studies. However, it may be considered sufficient for the purpose of observational studies or stroke registries. It emphasizes the need for easily accessible training in conventional mRS or implementation of specialized tools with predefined questions.

Blood-Brain Barrier-Associated Proteins Are Elevated in Serum of Epilepsy Patients.

Blood-brain barrier (BBB) dysfunction emerges as one of the mechanisms underlying the induction of seizures and epileptogenesis. There is growing evidence that seizures also affect BBB, yet only scarce data is available regarding serum levels of BBB-associated proteins in chronic epilepsy. In this study, we aimed to assess serum levels of molecules associated with BBB in patients with epilepsy in the interictal period. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2, S100B, CCL-2, ICAM-1, P-selectin, and TSP-2 were examined in a group of 100 patients who were seizure-free for a minimum of seven days and analyzed by ELISA. The results were compared with an age- and sex-matched control group. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2 and S100B were higher in patients with epilepsy in comparison to control group (p < 0.0001; <0.0001; 0.001; <0.0001; <0.0001, respectively). Levels of CCL-2, ICAM-1, P-selectin and TSP-2 did not differ between the two groups. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2 and S100B are elevated in patients with epilepsy in the interictal period, which suggests chronic processes of BBB disruption and restoration. The pathological process initiating epilepsy, in addition to seizures, is probably the factor contributing to the elevation of serum levels of the examined molecules.

Changes in serum blood-brain barrier markers after bilateral tonic-clonic seizures.

OBJECTIVE: Seizures have been shown to increase blood-brain barrier (BBB) permeability, yet the role of this phenomenon is not fully understood. Additionally, dysfunction of the BBB leads to initiation and propagation of seizures in animal models. To demonstrate the increased permeability of the BBB in time, we investigated changes of the serum levels of BBB markers in patients with epilepsy after bilateral tonic-clonic seizures. We chose markers that might reflect endothelial activation (ICAM-1, selectins), BBB leakage (MMP-9, S100B) and mechanisms of BBB restoration (TIMP-1, thrombomodulin -TM). METHODS: We enrolled 50 consecutive patients hospitalised after bilateral tonic-clonic seizures who agreed to take part in the study and 50 participants with no history of epilepsy. Serum levels of selected markers were measured by ELISA at 1-3, 24, and 72 hours after seizures and one time in the control group. RESULTS: We found increased levels of S100B, ICAM-1, MMP-9 and P-selectin at 1-3 and 24 hours after seizures and TIMP-1 and TM at 24 and 72 hours after seizures as compared to the control group. The level of E-selectin was decreased at 72 hours after seizures. CONCLUSIONS: Our findings suggest early activation of endothelium and increased BBB permeability after seizures. While we are aware of the limitations due to the non-specificity of the tested proteins, our results might indicate the presence of prolonged BBB impairment due to seizure activity.

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.

Serum Proteins Associated with Blood-Brain Barrier as Potential Biomarkers for Seizure Prediction.

As 30% of epileptic patients remain drug-resistant, seizure prediction is vital. Induction of epileptic seizure is a complex process that can depend on factors such as intrinsic neuronal excitability, changes in extracellular ion concentration, glial cell activity, presence of inflammation and activation of the blood−brain barrier (BBB). In this study, we aimed to assess if levels of serum proteins associated with BBB can predict seizures. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2, S100B, CCL-2, ICAM-1, P-selectin, and TSP-2 were examined in a group of 49 patients with epilepsy who were seizure-free for a minimum of seven days and measured by ELISA. The examination was repeated after 12 months. An extensive medical history was taken, and patients were subjected to a follow-up, including a detailed history of seizures. Serum levels of MMP-2, MMP-9, TIMP-1, CCL-2, and P-selectin differed between the two time points (p < 0.0001, p < 0.0001, p < 0.0001, p < 0.0001, p = 0.0035, respectively). General linear model analyses determined the predictors of seizures. Levels of MMP-2, MMP-9, and CCL-2 were found to influence seizure count in 1, 3, 6, and 12 months of observation. Serum levels of MMP-2, MMP-9, and CCL-2 may be considered potential biomarkers for seizure prediction and may indicate BBB activation.

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.