Long-Duration Progressive Supranuclear Palsy: Clinical Course and Pathological Underpinnings.

OBJECTIVES: To identify the clinical characteristics of the subgroup of benign progressive supranuclear palsy with particularly long disease duration; to define neuropathological determinants underlying variability in disease duration in progressive supranuclear palsy. METHODS: Clinical and pathological features were compared among 186 autopsy-confirmed cases with progressive supranuclear palsy with ≥10 years and shorter survival times. RESULTS: The 45 cases (24.2%) had a disease duration of ≥10 years. The absence of ocular motor abnormalities within the first 3 years from disease onset was the only significant independent clinical predictor of longer survival. Histopathologically, the neurodegeneration parameters in each survival group were paralleled anatomically by the distribution of neuronal cytoplasmic inclusions, whereas the tufted astrocytes displayed anatomically an opposite severity pattern. Most interestingly, we found significantly less coiled bodies in those who survive longer, in contrast to patients with less favorable course. INTERPRETATION: A considerable proportion of patients had a more "benign" disease course with ≥10 years survival. They had a distinct pattern and evolution of core symptoms compared to patients with short survival. The inverted anatomical patterns of astrocytic tau distribution suggest distinct implications of these cell types in trans-cellular propagation. The tempo of disease progression appeared to be determined mostly by oligodendroglial tau, where the high degree of oligodendroglial tau pathology might affect neuronal integrity and function on top of neuronal tau pathology. The relative contribution of glial tau should be further explored in cellular and animal models. ANN NEUROL 2022;92:637-649.

A Modified Progressive Supranuclear Palsy Rating Scale.

BACKGROUND: The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status. OBJECTIVE: The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones. METHODS: Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy. RESULTS: The modified scale retained 14 items (yielding 0-2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months). CONCLUSIONS: The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society.

The Profile and Evolution of Neuropsychiatric Symptoms in Multiple System Atrophy: Self- and Caregiver Report.

OBJECTIVE: Recent research shows that patients with multiple system atrophy (MSA) have significant cognitive and neuropsychiatric comorbidities that can color the clinical presentation of the disease and affect their quality of life. The aims of this study were to determine the neuropsychiatric profile in a cohort of patients with the parkinsonian type of MSA (MSA-P) and their dynamic changes over a 1-year follow-up period and to compare rates of neuropsychiatric symptoms (NPSs) reported by caregivers and the patients themselves. METHODS: Forty-seven patients were assessed at baseline; of these, 25 were assessed again after 1 year. NPS assessment tools included the Neuropsychiatric Inventory (NPI), the Beck Depression Inventory, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Apathy Evaluation Scale. RESULTS: The prevalence of NPSs in patients with MSA-P was very high, with depression, sleep disturbances, apathy, and anxiety being the most frequently occurring features. The evolution of NPSs was found to be independent of motor, autonomic, and cognitive symptoms. None of the scales measuring NPSs, including the NPI, were capable of detecting changes over the 1-year follow-up period. Although the overall prevalence of depression, apathy, and anxiety obtained from caregivers and the patients themselves was similar, reports from these two sources cannot be considered interchangeable. CONCLUSIONS: The progression of neuropsychiatric symptoms was not a subject of rapid change in MSA-P, in contrast to the observed motor, autonomic, and cognitive deterioration. These findings suggest the need to investigate the utility of available instruments in capturing the evolution of NPSs in MSA over time.

Formulation of topical acidic products and acidification of the skin - Contribution of glycolic acid.

OBJECTIVE: The acidic skin pH is one of the regulating factors of skin barrier homeostasis. Topical products as extrinsic factors which influence skin pH could be used for acidification of the skin and consequent beneficial effect. To formulate stabile and safe topical emulsion product with low pH is on-going challenge and areas interesting to explore are related to the effect of acidic products on the skin pH together with development of protocols for these studies. Aim of our work was to investigate formulations of acidic topical products with glycolic acid (GA) stabilized with long chain alkyl polyglucoside emulsifier, in regard to the specific colloidal structure of the vehicle, together with effect of products with different concentration of acidic active on skin pH. METHODS: Investigated formulations were basic vehicle and two creams with glycolic acid (concentration 2 and 10 wt%). Microstructure was investigated by polarization microscopy, Raman spectral imaging, thermal analysis and rheological measurements. Effects on the skin were assessed by measurement of biophysical skin parameters in vivo studies (5-hour, 24-hour and 7-days). In vitro screening of antimicrobial activity was performed against bacteria Staphylococcus epidermidis. RESULTS: Polarization micrographs and Raman images have shown that GA does not disturb the specific colloidal structure. Together with rheological and thermal analysis obtained results have shown that GA in higher concentrations contributes to vehicles' lamellar structure. In 5-hour study the mean values of skin pH ranged from 3.98-4.25 and 3.89-4.10 after application of products with smaller and higher GA concentration. GA samples lowered skin surface pH to 5 and less in 24-hour and 7-day study, with stronger effect of sample with more GA. Sample with 10% of GA had significant inhibitory effect on growth of S. epidermidis in 1:1 concentration. CONCLUSIONS: Investigated APG emulsifier could be used as a stabilizer for acidic topical products with GA which are characterized by satisfactory safety profile. Topical products induce acidification of the skin after short- and long-term application without barrier impairment or sign of irritation. Acidification of the skin depends on presence of ingredients which are proton donors and their concentrations.

OBJECTIF: Le pH acide de la peau est l'un des facteurs de régulation de l'homéostasie de la barrière cutanée. Les produits topiques pourraient être utilisés en tant que facteurs extrinsèques d'influence du pH cutané pour permettre l'acidification de la peau et obtenir l'effet bénéfique qui en résulte. Formuler des émulsions topiques stables et sûres à faible pH représente un défi constant et les domaines d'étude dignes d'intérêt portent sur l'effet des produits acides sur le pH cutané et sur l'élaboration de protocoles pour ces études. L'objectif de notre travail était d'étudier des formulations de produits topiques acides à base d'acide glycolique (AG) stabilisé à l'aide d'un émulsionnant à base d'alkylpolyglucoside (APG) à longue chaîne, par rapport à la structure colloïdale spécifique de l'excipient, ainsi que l'effet des produits à différentes concentrations d'acide actif sur le pH cutané. MÉTHODES: Les formulations étudiées étaient un excipient de base et deux crèmes à base d'acide glycolique (concentration égale à 2 % et 10 % de la fraction massique). La microstructure a été étudiée par microscopie à polarisation, par spectroscopie Raman, par analyse thermique et par mesures rhéologiques. Les effets cutanés ont été évalués par la mesure des paramètres cutanés biophysiques dans des études in vivo (5 heures, 24 heures et 7 jours). Un dépistage in vitro de l'activité antimicrobienne a été effectué sur la bactérie Staphylococcus epidermidis. RÉSULTATS: Les micrographies après polarisation et les images obtenues par spectroscopie Raman ont montré que l'AG ne perturbe pas la structure colloïdale spécifique. Avec les analyses rhéologique et thermique, les résultats obtenus ont montré que l'AG à des concentrations plus élevées joue un rôle dans la structure lamellaire des excipients. Dans l'étude de 5 heures, les valeurs moyennes du pH cutané allaient de 3,98 à 4,25 et de 3,89 à 4,10 après l'application des produits présentant une concentration d'AG plus faible et plus élevée. Grâce aux échantillons d'AG, le pH de la surface cutanée a diminué, passant ainsi à une valeur de 5 et à des valeurs inférieures dans les études de 24 heures et de 7 jours, et l'échantillon contenant davantage d'AG a eu un effet plus important. L'échantillon contenant 10 % d'AG a eu un effet inhibiteur significatif sur la croissance de la bactérie S. epidermidis à une concentration de 1:1. CONCLUSION: L'émulsionnant à base d'APG étudié pourrait être utilisé comme stabilisateur pour les produits topiques acides à base d'AG caractérisés par un profil d'innocuité satisfaisant. Les produits topiques induisent une acidification de la peau après une application à court et à long terme sans altération de la barrière cutanée ou signe d'irritation. L'acidification de la peau dépend de la présence de donneurs de proton parmi les composants et de leurs concentrations.

Distribution patterns of tau pathology in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

Copathology in Progressive Supranuclear Palsy: Does It Matter?

BACKGROUND: The influence of concomitant brain pathologies on the progression rate in PSP is unclear. OBJECTIVES: To analyze the frequency and severity of copathologies and their impact on the progression in PSP. METHODS: We analyzed clinic-pathological features of 101 PSP patients. Diagnoses and stages of copathologies were established according to standardized criteria, including Alzheimer's disease-related pathology, argyrophilic grains, Lewy-related pathology, transactive response DNA-binding protein 43 pathology, fused in sarcoma pathology, cerebral amyloid angiopathy, and small vessel disease. Demographic data and major clinical milestones (frequency and latency to onset) were extracted from patients' files. RESULTS: Only 8% of 101 patients presented with pure PSP pathology without any copathology. Alzheimer's disease-related pathology was the most frequent (84%), followed by argyrophilic grains (58%), both occurring as single copathology or in combination with other proteinopathies or cerebrovascular disease. Lewy-related and transactive response DNA-binding protein 43 copathology occurred rarely (8% and 6%, respectively). Fused in sarcoma-positive cases were not found. While being common, copathology was mostly mild in severity, with the exception of frequently widespread argyrophilic grains. Small vessel disease was also frequent (65%). Cerebral amyloid angiopathy occurred only in the presence of Alzheimer's disease-related changes (25%). The copathologies did not have major impact on prevalence and time frame of major disease milestones. CONCLUSIONS: In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

A comparison of Myribase and Doublebase gel: Does qualitative similarity of emollient products imply their direct interchangeability in everyday practice?

Emollients are acknowledged as a part of standard care in therapeutic and prevention protocols as well as a part of everyday skin care routine. When it comes to making a final decision between two emollient products, the ingredient list, that is, the formulation composition could be the determining factor. In such cases the consumer, and some healthcare providers, believe that products with the same qualitative composition (ingredient list) must have the same efficacy. In this study, we have investigated the skin hydration performance of two emollient preparations (DBG and MBG), which appear to contain the same ingredients, and hence, could be considered interchangeable in everyday practice. Our studies showed that the effects of DBG were overall superior to the ones attributed to MBG at each investigated time point (1, 2, 4, and 24 h post application) when tested on normal and dry skin. Consequently, it is shown that two apparently qualitatively identical products do not necessarily provide matching efficacy.

Tracking brain damage in progressive supranuclear palsy: a longitudinal MRI study.

OBJECTIVES: In this prospective, longitudinal, multiparametric MRI study, we investigated clinical as well as brain grey matter and white matter (WM) regional changes in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). METHODS: Twenty-one patients with PSP-RS were evaluated at baseline relative to 36 healthy controls and after a mean follow-up of 1.4 years with clinical rating scales, neuropsychological tests and MRI scans. RESULTS: Relative to controls, patients with PSP-RS showed at baseline a typical pattern of brain damage, including midbrain atrophy, frontal cortical thinning and widespread WM involvement of the main infratentorial and supratentorial tracts that exceeded cortical damage. Longitudinal study showed that PSP-RS exhibited no further changes in cortical thinning, which remained relatively focal, while midbrain atrophy and WM damage significantly progressed. Corpus callosum and frontal WM tract changes correlated with the progression of both disease severity and behavioural dysfunction. CONCLUSIONS: This study demonstrated the feasibility of carrying out longitudinal diffusion tensor MRI in patients with PSP-RS and its sensitivity to identifying the progression of pathology. Longitudinal midbrain volume loss and WM changes are associated with PSP disease course.

Use of the Neuropsychiatric Inventory to Characterize the Course of Neuropsychiatric Symptoms in Progressive Supranuclear Palsy.

The aim of this study was to determine the neuropsychiatric profile in a cohort of progressive supranucelar palsy (PSP) patients and their dynamic changes over a follow-up period of 1 year. A total of 59 patients were assessed at baseline, while 25 of them were accessible after 1 year of the follow-up. The most common symptoms were apathy and depression, which were also found to be, among other variables, the independent determinants of increased Neuropsychiatric Inventory (NPI) total score. Moreover, apathy deteriorated most profoundly over the follow-up period. The NPI seemed to be a sensitive measure of behavioral changes in PSP.

Psychiatric Symptoms in the Initial Motor Stage of Parkinson's Disease.

Neuropsychiatric symptoms (NPS) are common in Parkinson's disease (PD). The aim of this study was to estimate the correlates of NPS in patients with PD in the initial motor stage of the disease (hemiparkinsonism). A total of 111 patients with PD and 105 healthy control participants were assessed. Patients with PD experienced apathy, depression, and anxiety more frequently compared with healthy controls. Sleep disturbances occurred commonly in early PD patients. Patients with PD and mild cognitive impairment (MCI) had depression and anxiety more frequently, but not apathy, compared with patients with PD without MCI. The results of this study confirm a high burden of NPS even in the earliest motor stage of PD.

Mild Cognitive Impairment in Early Parkinson's Disease Using the Movement Disorder Society Task Force Criteria: Cross-Sectional Study in Hoehn and Yahr Stage 1.

BACKGROUND: Mild cognitive impairment (MCI) in Parkinson's disease (PD) is common and confers a higher risk for developing dementia. METHODS: In this cross-sectional study of MCI in PD conducted at a university hospital, a comprehensive neuropsychological battery covering five domains (attention/working memory, executive, verbal, and visual memory, language, and visuospatial) was administered to 111 nondemented PD patients in Hoehn and Yahr stage 1 and to 105 healthy matched control subjects (HC). MCI was diagnosed according to level 2 of the Movement Disorder Society Task Force criteria. RESULTS: Criteria for MCI associated with PD (PD-MCI) were fulfilled by 24% of PD patients in the initial stage of the disease at the z cutoff scores of -1.5 SD in contrast to 7% of HC fulfilling criteria for MCI. Memory and visuospatial domains were the most commonly affected at -1.5 SD. PD-MCI patients mostly had a multiple-domain MCI subtype (78%). They presented a more severe bradykinesia and higher mood and apathy scores in comparison with cognitively normal PD patients. Basic motor scores predicted performance on some cognitive tests and specific cognitive-motor relationships emerged. CONCLUSIONS: MCI, predominantly of a multiple-domain subtype, was quite prevalent even in the initial stage of PD.

De novo mutation in the GNAL gene causing seemingly sporadic dystonia in a Serbian patient.

BACKGROUND: Mutations in GNAL (DYT25) have recently been established as the first confirmed cause of focal or segmental adult-onset dystonia. Mutation carriers show craniocervical involvement; however, the GNAL mutational and phenotypic spectrum remain to be further characterized, and guidelines for diagnostic testing need to be established. METHODS: The authors used Sanger sequencing to test for changes in the GNAL coding or splice-site regions in 236 Serbian patients suffering from isolated dystonia with craniocervical involvement. RESULTS: One novel likely pathogenic substitution (c.1061T>C; p.Val354Ala) in GNAL was detected in a sporadic cervical dystonia patient (mutation frequency: 0.4%). This mutation was not present in the DNA of either parent, despite confirmed parentage. CONCLUSIONS: This is the first report of a de novo GNAL mutation causing genetically proven, seemingly sporadic DYT25 dystonia. Our finding highlights the importance of genetic testing for GNAL mutations in establishing the molecular diagnosis even for patients with a negative family history.

Attentional set-shifting in Parkinson's disease patients with freezing of gait-acquisition and discrimination set learning deficits at the background?

Cognitive loading aggravates the freezing of gait (FoG), which is observed in approximately 50% of patients with Parkinson's disease (PD) in the advanced stages. To investigate whether a specific pattern of executive deficits, that is, attentional set-shifting and/or inhibitory control, are associated with FoG in PD, 30 PD patients with FoG (PD-FoG+) and 36 PD patients without FoG (PD-FoG-) and 22 control healthy subjects were examined with a comprehensive neuropsychological battery. Intra-Extra Dimensional Set shifting Test (IED) and Stop Signal Task (SST), selected from the Cambridge Automated Neuropsychological Battery (CANTAB battery), were administered to analyze set-shifting and motor inhibition, respectively. The IED task was significantly sensitive for differentiating between PD-FoG+ and PD-FoG- groups (p<.01), as well Adenbrook's clock drawing task (p=.033). By contrast, no differences emerged on any aspect of the SST task and other cognitive tasks. The attrition rate during the IED task showed that the problem in the PD-FoG+ group appeared at the pre-ID level, on the discrimination-learning set; the 32% PD-FoG+ subjects did not achieve the ID level of the task in comparison to negligible 4% of the PD-FoG- patients (p=.011). The logistic regression analysis, indicated the higher the IED stage successfully completed, the less likely presence of FoG in PD subjects. These results demonstrate that the complex cognitive-motor interplay might be responsible for FoG in PD and have had real life implication for the patients.

Development of a prospective isopropyl alcohol-loaded pharmaceutical base using simultaneous in vitro/in vivo characterization methods of skin performance.

CONTEXT: Approaching of pharmaceutical and cosmetic industries in some aspects inevitably influence formulation of topical pharmaceuticals, urging researchers to introduce novel excipients with proven benefits over traditional ones. In that context, alkyl polyglucosides (APG) emerge as prominent natural-origin emulsifiers with numerous favorable features (biodegradability, dermatological acceptability, desirable sensory properties). OBJECTIVE: To evaluate APG-stabilized bases (alone and upon addition of isopropyl alcohol) and their impact on skin performance. A simultaneous in vitro/in vivo skin absorption study was conducted to evaluate whether the tape stripping technique could be recommended as an in vivo tool for skin penetration assessment during formulation optimization process. MATERIALS AND METHODS: After a comprehensive physicochemical characterization, biopharmaceutical properties of APG-bases versus reference ones were assessed through a combined in vitro (release/permeation) and in vivo approach. RESULTS AND DISCUSSION: Physicochemical characterization revealed substantial difference in structural ordering due to the formation of various mesomorphic phases. The enhancer-loaded APG base resulted in significantly higher drug levels at all depths into the stratum corneum, indicating that the selected enhancer along with specific colloidal structure has increased the extent of drug delivery. CONCLUSION: Results recommend the investigated emulsifier for stabilization of topical drug delivery systems, not only for their ability to sustain the addition of isopropyl alcohol which proved to be a valuable enhancer, but also satisfactory skin absorption and tolerability when compared to samples stabilized by conventional emulsifier. Tape stripping proved to be a useful and yet inexpensive tool for in vivo trials, able to discriminate subtle differences in dermal availability.

Effect of small changes in natural origin-based emulsion systems on hydrocortisone skin absorption and performance: a comparison of two in vivo methods.

CONTEXT: Alkyl polyglucoside surfactants (APG) remain prominent natural origin stabilizers offering a prospect of combining satisfactory stability with mild dermatological properties and complete biodegradability. OBJECTIVE: With the purpose of adjusting the dose to a patient's needs, dilution of commercial corticosteroid formulations is a practice which may modify efficacy uncontrolledly. The rational of the study was to investigate whether a simple change in ready-to-use bases (co-solvent addition) could address these needs in a more predictive manner. METHODS: Hydrocortisone (HC) delivery from such emulsion systems was comparatively assessed employing two in vivo methods: the established human skin blanching assay versus skin stripping technique. RESULTS: HC permeation data obtained after three dose durations showed better overall performance of the APG-stabilized bases relative to reference ones. Although the solubility study showed that all the assessed active samples retained equal thermodynamic activity, diverse HC permeation/penetration implies the importance of the applied base's colloidal structure and/or changes endured. Isopropyl alcohol (IPA) addition offered faster drug penetration enhancement, while glycerol as a moisturizing agent influenced HC penetration through the increase in skin hydration. CONCLUSION: Although the performed in vivo methods cannot be considered alternative, skin stripping technique proved to be a cost-efficient mode of percutaneous penetration assessment, providing additional information on vehicle-skin interactions.

Early Screening for the Parkinson Variant of Multiple System Atrophy: A 6-Item Score.

BACKGROUND: A 4-item score based on ≥2 features out of orthostatic hypotension, overactive bladder, urinary retention and postural instability was previously shown to early distinguish the Parkinson-variant of multiple system atrophy (MSA-P) from Parkinson's disease (PD) with 78% sensitivity and 86% specificity. OBJECTIVES: To replicate and improve the 4-item MSA-P score. METHODS: We retrospectively studied 161 patients with early parkinsonism [ie, ≤2 years disease duration or no postural instability, aged 64 (57; 68) years, 44% females] and a diagnosis of clinically established MSA-P (n = 38) or PD (n = 123) after ≥24 months follow-up. RESULTS: The 4-item MSA-P score had a 92% sensitivity and 78% specificity for a final MSA-P diagnosis. By including dopaminergic responsiveness and postural deformities into a 6-item score (range: 0-6), reaching ≥3 points at early disease identified MSA-P patients with 89% sensitivity and 98% specificity. CONCLUSIONS: The 6-item MSA-P score is a cost-effective tool to pinpoint individuals with early-stage MSA-P.

Long-term outcome of patients with neurological form of Wilson's disease compliant to the de-coppering treatment.

BACKGROUND: A substantial proportion of Wilson's disease (WD) patients exhibit residual neurological symptoms. Data on the prognostic value of initial clinical features and treatment choices in WD patients compliant to the therapy is relatively sparse. AIM: The aim of the present study was to identify predictors of the long-term outcome of patients with WD with good treatment adherence. METHODS: Forty patients with neurological form of WD were evaluated before the de-coppering treatment initiation (based on the medical records) and after mean 15.25 ± 11.24 years of the stable treatment. Severity of neurological symptoms were assessed with a tier two of Global Assessment Scale (GAS) for Wilson's Disease. RESULTS: The most frequent symptoms prior to treatment initiation were dysarthria (90%), tremor (90%), clumsiness (67.5%), depression (67.5%), and gait disturbance (62.5%). Significant decrease in the frequency of dysarthria, clumsiness, tremor, gait disturbance, postural instability and an improvement in school/work performance were observed after the long-term treatment, while frequency of dysphagia, drooling, bradykinesia and rigidity, dystonic and choreatic features did not change. Overall symptom severity decreased over time. Presence of dystonia before treatment initiation was the only identified predictor of worse residual GAS score. Greater severity of residual dystonia was associated with female gender and longer disease duration. CONCLUSION: Although patients with neurological form of WD compliant to de-coppering treatment had favorable disease outcome, a significant burden of residual neurological symptoms was observed after the long-term follow-up. Dystonia at disease onset was the only identified predictor of the worse long-term outcome.

Severe COVID-19 Infection Management in a Patient with Mild Haemophilia-A Case Report.

Patients with haemophilia present a significant challenge when admitted into the intensive care unit. To prevent haemorrhagic complications related to the infection or due to invasive procedures factor (F) VIII/IX must be substituted. As thromboembolic complications are frequent among critically ill COVID-19 patients, thromboprophylaxis is also applied to patients with haemophilia. This requires careful monitoring of FVIII/IX activity as well as other haemostatic parameters, such as D-dimer and antiXa. We describe a 44-year old patient with mild haemophilia A (FVIII activity of 6%), who required a prolonged intensive care unit stay due to a severe SARS-CoV-2 infection. FVIII was substituted via boluses, and dalteparin was given according to recommendations. The patient successfully recovered from the disease.