European Academy of Neurology/Movement Disorder Society-European Section Guideline on the Treatment of Parkinson's Disease: I. Invasive Therapies.

BACKGROUND AND PURPOSE: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist should know the therapies and their place in the treatment pathway. METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered. RESULTS: Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended. CONCLUSIONS: Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

European Academy of Neurology/Movement Disorder Society - European Section guideline on the treatment of Parkinson's disease: I. Invasive therapies.

BACKGROUND AND PURPOSE: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway. METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered. RESULTS: Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended. CONCLUSIONS: Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups.

Pneumocephalus as a rare complication: a systematic review plus clinical vignette.

INTRODUCTION: Pneumocephalus is a clinical entity characterised by the presence of gas in the intracranial space. It can result from many different causes. The most common cause is head or facial trauma. Other causes include neoplasms, infections, and surgical or diagnostic procedures. Spontaneous non-traumatic pneumocephalus is a rare condition caused by bone defects, malformations, infections, tumours, intravenous air injection, and other causes. This review, supplemented with a case presentation, aims to summarise the current state of knowledge regarding non-traumatic pneumocephalus. METHODOLOGY: This review involved an electronic search (PubMed, Scopus, Embase, and Web of Science) to identify studies regarding non-traumatic pneumocephalus. In addition, reference lists of identified articles were screened for other potentially relevant papers. RESULTS: In total, 1,107 articles were retrieved by searching databases with the selected query. Based on the selection process, 134 articles were included. These articles were then classified into 'otogenic', 'bone defect', 'malformations', 'infectious', 'tumours', 'associated with intravenous air injection', and other categories. CONCLUSION: Spontaneous non-traumatic pneumocephalus is a rare condition. Symptoms, clinical courses, and prognoses vary depending on the underlying cause of the disease. To the best of our knowledge, this review's example is the first case report of spontaneous pneumocephalus due to air embolism secondary to lung cancer.

Neuroimaging in Parkinson's Disease: necessity or exaggeration?

INTRODUCTION: Neuroimaging plays an increasingly important role in the diagnosis of parkinsonian syndromes. AIM OF THE STUDY: In this paper, the authors elaborate on the necessity of using magnetic resonance imaging (MRI) in Parkinson's Disease (PD) and its potential role in differential diagnosis versus other neurodegenerative parkinsonian syndromes such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal syndrome. STATE OF THE ART: The currently known characteristic abnormalities are listed and tabulated, current recommendations are summarised and sample images are provided. As routine MRI scanning in PD remains controversial, the authors' aim is to show the pros and cons in clinical practice. Additionally, the rationale for functional imaging examination, including [123I]-FP-CIT SPECT (DaTSCAN) and [99mTc]- HMPAO-SPECT, [18F]-FDG-PET, [123I]-mIBG-SPECT is discussed. CLINICAL VIGNETTE: This paper is accompanied by two illustrative clinical cases in which neuroimaging studies played a key role in diagnosis and further management. CONCLUSIONS: Neuroimaging can be helpful in differentiating PD from both atypical and symptomatic parkinsonism. Nevertheless, extensive neurological assessment in a majority of PD cases is sufficient to make a diagnosis. A network of specialists in movement disorders should be established in order to enable better, faster and more precise diagnosis of parkinsonism.

Double vision in Parkinson's Disease: a systematic review.

INTRODUCTION: The prevalence of diplopia in Parkinson's disease (PD) ranges from 10% to 30%. Diplopia is usually limited to specific situations such as reading and looking around, however, it can also be constant. The aim of this review, supplemented by two case studies, was to summarise current knowledge on the frequency, possible causes, differential diagnosis, pathophysiology and treatment approaches to double vision in PD patients. METHODOLOGY: An electronic search (PubMed, Scopus, Embase and Web of Science) to identify studies regarding diplopia in PD patients was performed in May 2020. The following search terms were used: Parkinson's Disease and diplopia. RESULTS: Five articles are included in this literature review. In the literature, the number of included patients with PD who presented with symptoms of diplopia varied from a single case report to 88 patients. Diplopia was usually intermittent and binocular. The most commonly reported type of diplopia was single object diplopia, and the second most common was complete diplopia. Risk factors contributing to developing diplopia were: older age, disease duration, disease severity, cognitive decline, presence of visual hallucinations, and higher levodopa equivalent dose. Results also showed that diplopia had a significant impact on quality of life. Possible comorbidities of diplopia include myasthenia gravis and vascular disease. CONCLUSION: Diplopia is relatively common in PD, but still understudied. The research shows that it has a clear impact on health-related quality of life and patient safety. The acute onset of diplopia should always result in tests to exclude other diseases. Tailored interventions should be developed, leading to improved patient safety, quality of life, and quality of care.

How to Use the New European Academy of Neurology/Movement Disorder Society European Section Guideline for Invasive Therapies in Parkinson's Disease.

BACKGROUND: The decision to choose invasive treatments for Parkinson's disease (PD) is complex and needs careful consideration. OBJECTIVES: Although the recommendations of the European Academy of Neurology/Movement Disorder Society European Section guideline for invasive therapies of PD are useful, the different clinical profiles of people with PD who seek advice for possible invasive therapy need further attention. METHODS AND RESULTS: Here we describe 8 clinical standard situations of people with PD unsatisfied with their current oral treatment where invasive therapies may be considered. These are PD patients presenting with the following symptoms: (1) severe motor fluctuations, (2) beginning of levodopa-responsive fluctuations, severe tremor at (3) young or (4) advanced age, (5) impulse control disorders and related behavioral disorders, (6) hallucinations and psychosis, (7) minimal cognitive impairment or mild dementia, and (8) patients in need of palliative care. For some of these conditions, evidence at lower level or simple clinical considerations exist. CONCLUSIONS: There are no one-fits-all answers, but physician and patient should discuss each option carefully considering symptom profile, psychosocial context, availability of therapy alternatives, and many other factors. The current paper outlines our proposed approach to these circumstances.

The Prevalence of Parkinson's Disease in Poland: Regional and Sex-Related Differences.

Background: Given the growing evidence for an environmental contribution to the etiology of Parkinson's disease (PD), searching for local and regional differences in PD prevalence in multiple areas across the world may further clarify the role of environmental toxins. Objective: To provide local and regional prevalence estimates of PD in Poland. Methods: We analyzed the prevalence of PD and its trend over the last decade (2010 to 2019) based on data from the National Health Fund in Poland. We specifically examined sex differences in PD prevalence, as well as differences across Polish regions. Results: During the above period, the prevalence of PD in Poland increased from 226 per 100,000 to 269 per 100,000 inhabitants. Unexpectedly, we found that PD was 1.2-times more common in women than men. The increase in prevalence over the past decade was different between both sexes: an increase from 250 to 283 per 100,000 for women (13.3% increase), and from 200 to 254 per 100,000 for men (27.1% increase). In addition, we observed differences in prevalence across different Polish regions, with some regions having up to 51% lower prevalence rates than others. Conclusions: The prevalence of PD in Poland is in line with previously reported prevalence rates across Europe. However, unlike the situation in most of the world, PD was more prevalent in women than men. We discuss several possible explanations as well as potential measures that might help to reduce the growth of PD.

Current opinions and practices in post-stroke movement disorders: Survey of movement disorders society members.

BACKGROUND: Post-stroke movement disorders (PSMD) encompass a wide array of presentations, which vary in mode of onset, phenomenology, response to treatment, and natural history. There are no evidence-based guidelines on the diagnosis and treatment of PSMD. OBJECTIVES: To survey current opinions and practices on the diagnosis and treatment of PSMD. METHODS: A survey was developed by the PSMD Study Group, commissioned by the International Parkinson's and Movement Disorders Society (MDS). The survey, distributed to all members, yielded a total of 529 responses, 395 (74.7%) of which came from clinicians with experience with PSMD. RESULTS: Parkinsonism (68%), hemiballismus/hemichorea (61%), tremor (58%), and dystonia (54%) were by far the most commonly endorsed presentation of PSMD, although this varied by region. Basal ganglia stroke (76% of responders), symptoms contralateral to stroke (75%), and a temporal relationship (59%) were considered important factors for the diagnosis of PSMD. Oral medication use depended on the phenomenology of the PSMD. Almost 50% of respondents considered deep brain stimulation and ablative surgeries as options for treatment. The lack of guidelines for the diagnosis and treatment was considered the most important gap to address. CONCLUSIONS: Regionally varying opinions and practices on PSMD highlight gaps in (and mistranslation of) epidemiologic and therapeutic knowledge. Multicenter registries and prospective community-based studies are needed for the creation of evidence-based guidelines to inform the diagnosis and treatment of patients with PSMD.

p.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe.

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.

The multimodal effect of circadian interventions in Parkinson's disease: A narrative review.

BACKGROUND: The circadian system and its dysfunction in persons with Parkinson's disease (PwP) has a clear impact on both motor and non-motor symptoms. Examples include circadian patterns in motor disability, with worsening of symptoms throughout the day, but also the existence of similar patterns in non-motor symptoms. OBJECTIVE: In this narrative review, we discuss the role of the circadian system, we address the role of dopamine in this system, and we summarise the evidence that supports the use of circadian system treatments for motor and non-motor symptoms in PwP. METHODS: A systematic search in PubMed and Web of Science database was performed and the final search was performed in November 2021. We included articles whose primary aim was to investigate the effect of melatonin, melatonin agonists, and light therapy in PwP. RESULTS: In total 25 articles were retrieved. Of these, 12 were related to bright light therapy and 13 to melatonin or/and melatonin agonists. Most, but not all, studies showed that melatonin and melatonin agonists and light therapy induced improvements in measures of sleep, depression, motor function, and some also cognitive function and other non-motor symptoms. For some of these outcomes, including daytime sleepiness, depressive symptoms, and some motor symptoms, there is level 2 B evidence for the use of circadian treatments in PwP. CONCLUSIONS: Treatment with bright light therapy, exogenous melatonin and melatonin agonists seems to have not only positive effects on sleep quality and depression but also on motor function in PwP. Drawbacks in earlier work include the relatively small number of participants and the heterogeneity of outcome measures. Further large and well-designed trials are needed to address these shortcomings and to confirm or refute the possible merits of the circadian system as a treatment target in PwP.

Accessibility of device-aided therapies for persons with Parkinson's disease in Poland.

Background: Access to care for people with Parkinson's disease (PD), in particular to device-aided therapies (DAT), is not equally distributed. Objectives: To analyse accessibility to DAT (deep brain stimulation; intraduodenal levodopa pump therapy; or apomorphine pump therapy) in Poland. Methods: We analysed the distribution of DAT use in Poland by determining the number of persons with PD receiving one of the three DATs during 2015-2021. Results: In 2021 the number of persons receiving DAT in Poland was 0.56% of the total PD population, having increased from 0.21% in 2015. Overall, deep brain stimulation was the preferred DAT in Poland, but strong regional differences in the use of the other DAT were present. Accessibility to DAT was negatively associated with average annual income (p<0.001). Conclusions: Access to DAT for PD in Poland is still limited and accessibility showed strong regional differences, although its general increase over the last decade is encouraging.

Morbidity and severity of COVID-19 in patients with Parkinson's disease treated with amantadine - A multicenter, retrospective, observational study.

BACKGROUND: After more than 2 years of the pandemic, effective treatment for COVID-19 is still under research. In recent months, publications hypothesized amantadine's potential beneficial effect on SARS-CoV-2 infection. OBJECTIVE: To compare the groups of Parkinson's Disease (PD) patients who were administered amantadine chronically and those who did not take this medication in the context of the incidence and severity of COVID-19 infection. METHODS: An observational, retrospective, multicenter cohort study was conducted among consecutive patients with idiopathic PD. The structured questionnaires were completed during the patient's follow-up visits at the Outpatient Clinic or during hospitalization. The questionnaire included the following informations: patient's age, duration of PD, Hoehn-Yahr (H-Y) stage, comorbidities, medications, COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR) swab test for SARS-CoV-2 with specified symptoms and their severity (home or hospital treatment). The vaccination status was verified as well. RESULTS: Five hundred fifty-two (n = 552) patients participated in the study - 329 men (60%). The mean H-Y stage was 2.44 (range: 1-4) and the mean duration of PD was 9.6 years (range: 1-34). One hundred four subjects (19%) had confirmed COVID-19 infection. Subjects over 50 years of age had a significantly lower incidence of COVID-19 (17% vs 38%, p = 0.0001) with difference also in mean H-Y stage (2.27 vs 2.49; p = 0.011) and disease duration (8.4 vs 9.9 years, p = 0.007). There were no differences between patients with and without co-morbidities. In the whole analyzed group 219 (40%) subjects were treated with amantadine. Comparing COVID-19 positive and negative patients, amantadine was used by 48/104 (46%) and 171/448 (38%) respectively. 22% of patients on amantadine vs. 17% of patients without amantadine developed COVID-19. These differences were not significant. There were no differences in morbidity and severity of COVID-19 between amantadine users and non-users as well. CONCLUSIONS: COVID-19 was less common in older (>50) with longer duration and more advanced patients. Amantadine did not affect the risk of developing COVID-19 or the severity of infection.

Kinds of Harm: Animal Law Language from a Scientific Perspective.

The current language of animal welfare laws is inconsistent and unclear in the basic terms pertaining to animal sensations and potential harms. In the case of law, the exact language often plays an essential role in determining legal duties and establishing their scope. Thus, for further progress in animal law, a coherent and unified basic conceptual framework is needed. To establish such a framework, the relevant legal terminology should be discussed in a prescriptive rather than interpretive manner while drawing on the medical sciences. Here, we propose a way to clarify the relevant terms to prevent misconceptions and improve the consistency of animal law.

Personalised Approach to Diagnosing and Managing Ischemic Stroke with a Plasma-Soluble Urokinase-Type Plasminogen Activator Receptor.

BACKGROUND: The increasing incidence of ischemic stroke has led to the search for a novel biomarker to predict the course of disease and the risk of mortality. Recently, the role of the soluble urokinase plasminogen activator receptor (suPAR) as a biomarker and indicator of immune system activation has been widely examined. Therefore, the aim of the current study was to assess the dynamics of changes in serum levels of suPAR in ischemic stroke and to evaluate the prognostic value of suPAR in determining mortality risk. METHODS: Eighty patients from the Department of Neurology, diagnosed with ischemic stroke, were enrolled in the study. Residual blood was obtained from all the patients on the first, third and seventh days after their ischemic stroke and the concentrations of suPAR and C-reactive protein (CRP), as well as the number of leukocytes and National Institute of Health's Stroke Scale (NIHSS) scores, were evaluated. RESULTS: On the first day of ischemic stroke, the average suPAR concentration was 6.55 ng/mL; on the third day, it was 8.29 ng/mL; on the seventh day, it was 9.16 ng/mL. The average CRP concentration on the first day of ischemic stroke was 4.96 mg/L; on the third day, it was 11.76 mg/L; on the seventh day, it was 17.17 mg/L. The number of leukocytes on the first day of ischemic stroke was 7.32 × 103/mm3; on the third day, it was 9.27 × 103/mm3; on the seventh day, it was 10.41 × 103/mm3. Neurological condition, which was assessed via the NIHSS, on the first day of ischemic stroke, was scored at 10.71 points; on the third day, it was scored at 12.34 points; on the seventh day, it was scored at 13.75 points. An increase in the values of all the evaluated parameters on the first, third and seventh days of hospitalisation was observed. The patients with hypertension, ischemic heart disease and type 2 diabetes showed higher suPAR and CRP concentrations at the baseline as well as on subsequent days of hospitalisation. The greatest sensitivity and specificity were characterised by suPAR-3, where a value above 10.5 ng/mL resulted in a significant increase in mortality risk. Moreover, an NIHSS-1 score above 12 points and a CRP-3 concentration above 15.6 mg/L significantly increased the risk of death in the course of the disease. CONCLUSIONS: The plasma suPAR concentration after ischemic stroke is strongly related to the patient's clinical status, with a higher concentration on the first and third days of stroke resulting in a poorer prognosis at a later stage of treatment. Therefore, assessing the concentration of this parameter has important prognostic value.

Undetected ophthalmological disorders in Parkinson's disease.

BACKGROUND: Ophthalmological disorders are common and frequently disabling for people with Parkinson's disease (PD). However, details on the prevalence, severity and impact of ophthalmological disorders thus far lacking. We aimed to identify PD patients with undetected ophthalmological disorders in a large cross-sectional, observational study. METHODS: We previously delivered a screening questionnaire to detect ophthalmological symptoms (Visual impairment in PD questionnaire; VIPD-Q) to 848 patients. Here, we report on a subgroup of 102 patients who received complete ophthalmological assessment aimed at identifying clinically relevant ophthalmological diseases, which were classified as either vison-threatening or not. Impact on daily life functioning was measured using the visual functioning-25 questionnaire (VFQ-25) and fall frequency. RESULTS: Almost all patients (92%) had one or more clinically relevant ophthalmological disorders. Of those, 77% had a potentially vision-threatening disease, while 34% had a potentially treatable ophthalmological disease which impacted on quality of life. The most prevalent ophthalmological disorders were dry eyes (86%), ocular misalignment (50%) and convergence insufficiency (41%). We found a weak but significant association between clinically relevant ophthalmological diseases and both fall frequency (R2 = 0.15, p = 0.037) and VFQ-25 score (R2 = 0.15, p = 0.02). The VIPD-Q could not correctly identify patients with relevant ophthalmological disorders. CONCLUSIONS: Surprisingly, in our study sample, many participants manifested previously undetected ophthalmological diseases, most of which threatened vision, impacted on daily life functioning and were amenable to treatment. Screening for these ophthalmological disorders using a questionnaire asking about symptoms seems insufficient. Instead, episodic ophthalmological assessments should be considered for PD patients, aiming to identify vision-threatening yet treatable diseases. TRIAL REGISTRATION: Dutch Trial Registration, NL7421.