Understanding the olfactory role in post-COVID cognitive and neuropsychiatric manifestations.

Introduction: Olfactory dysfunction (OD) is frequent after SARS-CoV-2 infection. The aim of this study was to examine if long-term OD is common in post-COVID condition, and the relationship between olfaction, cognition, neuropsychiatric symptoms, and disease duration in these patients. Methods: This study included 121 participants with post-COVID condition and 51 healthy controls (HC). A comprehensive neuropsychological and neuropsychiatric assessment was conducted, encompassing various domains, including general cognition, processing speed, verbal fluency, attention, verbal memory, visual memory, visuoconstructive ability, visuospatial ability, abstraction, executive functions, anxious-depressive symptoms, general health perception, fatigue level, sleep quality, and olfaction. Statistical analyses were carried out to understand the relationship of OD with cognition, and its role as moderator variable. Results: In total, 25% of the post-covid patients had a reduced smell capacity, while only 9.3% of HC presented OD. Post-COVID patients had statistically significantly worse cognitive performance and clinical status than HC. Verbal fluency (AUC = 0.85, p < 0.001), and attention (AUC = 0.82, p < 0.001) were the variables that best discriminate between groups. OD seemed to be a moderator between fatigue and cognition, and between disease duration and attention (ß = -0.04; p = 0.014). Discussion: The study highlights marked cognitive and neuropsychiatric sequelae in individuals post-COVID relative to HC. Olfactory impairment exhibits correlations with both cognitive performance and general health. Olfaction emerges as a potential prognostic marker owing to its moderating influence on disease severity indicators.

Implementation of a virtual community of practice to promote the empowerment of middle-aged people with multimorbidity: study protocol of a randomised controlled trial.

INTRODUCTION: Empowering people living with multimorbidity (multiple chronic conditions) to gain greater confidence in managing their health can enhance their quality of life. Education focused on self-management is a key tool for fostering patient empowerment and is mostly provided on an individual basis. Virtual communities of practice (VCoP) present a unique opportunity for online education in chronic condition self-management within a social context. This research aims to evaluate the effectiveness/cost-effectiveness of individualised, online self-management education compared with VCoP among middle-aged individuals living with multiple chronic conditions. METHODS AND ANALYSIS: People aged 30-60, living with ≥2 chronic conditions and receiving care in primary care (PC) centres and outpatient hospital-based clinics in Madrid and Canary Islands will enrol in an 18-month parallel-design, blinded (intervention assessment and data analysts), pragmatic (adhering to the intention-to-treat principle), individually randomised trial. The trial will compare two 12-month web-based educational offers of identical content; one delivered individually (control) and the other with online social interaction (VCoP, intervention). Using repeated measures mixed linear models, with the patient as random effect and allocation groups and time per group as fixed effects, we will estimate between-arm differences in the change in Patient Activation Measure from baseline to 12 months (primary endpoint), including measurements at 6-month and 18-month follow-up. Other outcomes will include measures of depression and anxiety, treatment burden, quality of life. In addition to a process evaluation of the VCoP, we will conduct an economic evaluation estimating the relative cost-effectiveness of the VCoP from the perspectives of both the National Health System and the Community. ETHICS AND DISSEMINATION: The trial was approved by Clinical Research Ethics Committees of Gregorio Marañón University Hospital in Madrid/Nuestra Señora Candelaria University Hospital in Santa Cruz de Tenerife. The results will be disseminated through workshops, policy briefs, peer-reviewed publications and local/international conferences. TRIAL REGISTRATION NUMBER: NCT06046326.

Perampanel: Medical Alternative for Essential Tremor?

OBJECTIVES: The aim of this study was to assess the safety and efficacy of perampanel in patients with refractory essential tremor (ET). METHODS: We recruited patients from our movement disorders clinic with the diagnosis of severe refractory ET, and perampanel 4 mg at night was initiated.Assessments were conducted at baseline and after 1 month of treatment with perampanel 4 mg/d. Details about tolerance and effectiveness were collected. Clinical evaluation was conducted with the Fahn-Tolosa-Marín scale, and statistical analysis was carried out with Wilcoxon matched pairs signed rank test. RESULTS: This study included 18 patients with severe ET (11 females, 7 males; mean age: 75.1 ± 12.03 years; mean duration of ET: 17.4 ± 17.03 years). Perampanel significantly improved patients' average score with refractory ET ( P ≤ 0.0001). This improvement has been occasionally quite relevant. However, a proportion of patients did not tolerate perampanel because of several adverse effects including dizziness, ataxia, irritability, and instability. CONCLUSIONS: Perampanel had a markedly positive antitremor effect in patients with ET and could be an alternative treatment. However, this drug is not devoid of adverse effects.

Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease: A Survey-Based Study.

OBJECTIVE: To characterize Parkinson's disease (PD) symptoms based on the presence, onset time, and severity of rapid eye movement sleep behavior disorder (RBD) and their association with impulse control disorders (ICD). BACKGROUND: RBD is a frequent non-motor symptom in PD, usually described as prodromal. The severity of RBD according to the start time and its relationship with ICD in PD needs further clarification. METHODS: A survey-based study was performed to determine the presence of RBD symptoms, their severity, and the temporal relationship with the PD onset. The survey included RBD1Q, the Mayo Sleep, and the RBDQ-HK questionnaires and questions about clinical characteristics, including ICD. Only PD patients with care partners spending night hours in the same room were included. RESULTS: 410 PD patients were included: 206 with RBD (50.2%) and 204 non-RBD (49.8%). The PD-RBD patients were younger and their daily levodopa dose was higher than the non-RBD group. Most of these patients developed RBD symptoms after the onset of clinical PD were younger at motor symptom onset and had higher scores in the hallucinations and psychosis subsection of MDS-UPDRS-I. RBD group had a more severe non-motor phenotype, including more ICD than those without RBD, mainly due to higher compulsive eating. CONCLUSIONS: In our study, most patients recognized RBD symptoms after the onset of the PD motor symptoms and the clinical features of PD with and without RBD were distinctive, supporting the hypothesis that PD-RBD might represent a variant pattern of neurodegeneration.

Pearls & Oy-sters: Challenges and Controversies in Wilson Disease.

Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the ATP7B gene, which are inherited in an autosomal recessive pattern. Despite all the advances made on pathogenesis, cellular biology, and genetics, to date, WD remains a diagnostic and therapeutic challenge. With this series of cases, we aim to illustrate the main challenges that clinicians may encounter when dealing with patients with WD: the difficulties with clinical diagnosis, the therapeutic management of WD and the indication for advanced therapies, management during pregnancy, and genotype-phenotype correlations.

Self-adjustment of deep brain stimulation delays optimization in Parkinson's disease.

BACKGROUND: Parkinson's Disease patients undergo time-consuming programming to refine stimulation parameters after deep brain stimulation surgery. OBJECTIVE: To assess whether the use of the advanced functions of a patient's programmer would facilitate programming of deep brain stimulation. METHODS: Thirty patients were randomly allocated to the use of advanced versus simple mode of the patient programmer in this single-centre, prospective, randomized, controlled study. Primary outcome was the number of days required to optimize the stimulation settings. RESULTS: The number of days required to optimize stimulation was significantly lower in the simple mode (88.5 ± 33.1 vs. 142.1 ± 67.4, p = 0.01). In addition, the advanced mode group had a higher number of side effects (5.4 ± 3.1 vs. 2.6 ± 1.9, p = 0.0055). CONCLUSIONS: The use of the advanced functions of patient programmer delays programming optimization and it is associated with a higher number of side effects. These findings highlight the need for other methods for faster and safer stimulation programming.

Expanding Data Collection for the MDSGene Database: X-linked Dystonia-Parkinsonism as Use Case Example.

MDSGene is an online database on movement disorders that collates genetic and clinical knowledge using a standardized published literature abstraction strategy. This review is dedicated to X-linked dystonia-parkinsonism (XDP). We screened 233 citations and curated phenotypic and genotypic data for 414 cases. To reduce data missingness, we (1) contacted authors and engaged the research community to provide additional clinical and genetic information, and (2) revisited previously unpublished data from a cohort of XDP patients seen at our institution. Using these approaches, we expanded the cohort to 577 cases and increased information available for important clinical and genetic features such as age at onset, initial manifestation, predominant motor symptoms, functional impairments, and repeat size information. We established the use of mining unpublished data to expand the MDSGene workflow and present an up-to-date description of the phenomenology of XDP using an extensive collection of previously reported and unreported data. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Patient-adjusted deep-brain stimulation programming is time saving in dystonia patients.

BACKGROUND: Deep-brain stimulation (DBS) programming for dystonia patients is a complex and time-consuming task. OBJECTIVE: To analyze whether programming a programming paradigm based on patient's self-adjustment is practical, effective and time saving in dystonia. METHODS: We retrospectively compared dystonia rating scales as well as the time necessary to optimize programming and the number of in-hospital visits in all patients (n = 102) operated at our center who used simple mode (SM) or advanced mode (AM) programming; the latter uses groups of different stimulation parameters and allows the patient and their caregiver to change stimulation groups at home, using the patient remote control. RESULTS: Both AM- and SM-allocated patients improved clinically to the same extent after DBS, as assessed by the Burke-Fahn-Marsden (BFM) and the Toronto Western Spasmodic Torticollis (TWSTRS) dystonia rating scales. All subscores improved after DBS without statistically significant differences in improvement between AM and SM (BFM: - 43% vs. - 53%, p = 0.569; TWSTRS: - 63% vs. - 72%, p = 0.781). AM and SM patients reached optimization within a similar median time [5.5 months (95% CI 4.6-6.3) for AM vs. 6.2 months (4.2-7.6) for SM, p = 0.674) but patients on advanced programming needed fewer in-hospital visits to achieve the same improvement [median of 5 visits (95% CI 4-7) for AM vs. 8 visits (7-9) for SM, p = 0.008]. CONCLUSIONS: Advanced DBS programming based on patient's self-adjustment under the supervision of the treating physician is feasible, practical and significantly reduces consultation time in dystonia patients.

Seizures and movement disorders: phenomenology, diagnostic challenges and therapeutic approaches.

Seizures and movement disorders (MDs) are distinct neurological conditions presenting with abnormal movements. Despite sharing an overlap in phenomenology, these movements have different origins. In order to explore the overlaps and the narrow boundaries between these two conditions, we performed a review of the literature to explore the risk of seizures in MDs. We discussed the mimics and chameleons including MDs that look like seizure (eg, paroxysmal dyskinesia, status dystonicus) and seizures that look like MDs (eg, epilepsia partialis continua, nocturnal frontal lobe epilepsy). Additionally, we examined the therapeutic challenges as well as the anatomical and chemical pathways relevant in the interplay between epilepsy and MDs. Finally, we proposed an algorithm to guide clinicians towards the final diagnosis of conditions characterised by the co-occurrence of MDs and seizures.

Diagnostic delay in Parkinson's disease caused by PRKN mutations.

OBJECTIVE: To confirm that there is a diagnostic delay in Parkin-related Parkinson Disease and to explore possible factors causing such a delay. METHODS: We retrospectively analyzed our patients with mutations in the parkin RBR E3 ubiquitin protein ligase gene (PRKN). We collected a total of 34 patients and focused on 18 cases (14 homozygous, 4 compound heterozygous). An arbitrary cut-off of 10 years from disease onset to diagnosis was considered to define patients with delayed diagnosis. RESULTS: Eight of 18 cases had a significant delay in their diagnosis (25.3 ±â€¯17 years). By comparing patients with and without a delayed diagnosis and subsequently, comparing these groups to a group of young onset PD negative for mutations of PRKN, SNCA, DJ1, PINK1, LRRK2, GBA, and ATP13A2, we identified a specific phenotype associated with a diagnostic delay: young age, lack of tremor, and involvement of lower limbs (particularly dystonia affecting gait) at the time of disease onset. CONCLUSIONS: Our findings emphasize the diverse phenotypes associated with PRKN mutations and the related diagnostic challenges they present.

ADCK3-related Coenzyme Q10 Deficiency: A Potentially Treatable Genetic Disease.

BACKGROUND: Disorders related to dysfunction of coenzyme (CoQ10) metabolism, including AarF domain containing kinase 3 gene (ADCK3) mutations, have received attention due to the potential for response to CoQ10 supplementation. METHODS: We describe two new cases of neurological syndromes due to ADCK3 mutations that obtained striking benefit from CoQ10, and a third who did not. We also review 20 cases from the literature in which responses to CoQ10 were documented out of all 38 previously reported cases. RESULTS: Despite the remarkable responses in some cases with ataxia and movement disorders (myoclonus, dystonia, tremor), overall, we were not able to identify variables that predicted response to CoQ10 supplementation. CONCLUSIONS: Based on our experience and data from the literature, we recommend a minimum of 10 mg/kg/day of ubiquinone with titration up to 15 mg/kg/day, maintained at least for 6 months in order to obtain or exclude potential benefit from therapy.

Rethinking status dystonicus.

Status dystonicus is a movement disorder emergency that has been a source of controversy in terms of terminology, phenomenology, and management since it was first described in 1982. Here we argue that the current use of the term status dystonicus falls well short of the precision needed for either clinical or academic use. We performed a critical review on this topic, describing possible pathophysiological mechanisms and areas of uncertainties. This review also addresses the problems derived by the extreme clinical heterogeneity of this condition, as the lack of an objective criterion useful for the definition, or the fact that status dystonicus may present not only in the context of a known dystonic syndrome. We propose a new possible definition that includes not only dystonia but also other hyperkinetic movements in the wide range of movement disorders that can be seen during an episode. The new definition keeps the term status dystonicus and highlights the fact that this is a medical emergency based on the impairment of bulbar and/or respiratory function requiring hospital admission as the principal feature. Furthermore, the new definition should not consider as necessary unspecific features as patient's condition at baseline, the distribution of dystonia, occurrence of systemic symptoms such as fever or laboratory findings. We hope that this proposal will stimulate the debate on this subject among our peers, further developing a clinical and pathophysiological understanding of status dystonicus. © 2017 International Parkinson and Movement Disorder Society.

Novel Levodopa Formulations for Parkinson's Disease.

Levodopa remains the most effective treatment for Parkinson's disease and is considered the gold standard therapy. However, disease progression and changes in the gastrointestinal tract result in a declining window of treatment response in a majority of patients. Efforts have been made recently to improve levodopa bioavailability either by developing more effective oral formulations or by innovating routes of administration (intestinal infusion, transcutaneous or inhaled levodopa). IPX066 is a novel levodopa-carbidopa (LD/CD) oral formulation combining immediate-release (IR) and extended-release (ER) LD/CD recently approved in the USA and the EU. Levodopa-carbidopa intestinal gel (LCIG) is an approved therapy consisting of a suspension of levodopa and carbidopa infused directly into the proximal jejunum via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube through a portable infusion pump. Ongoing studies are evaluating the 'accordion pill' (AP09004), an ER LD/CD formulation with gastroretentive properties. ND0612 is a proprietary liquid formulation of LD/CD that enables subcutaneous administration via a small patch-pump device, and CVT-301 is a levodopa inhalation powder with rapid onset of action; both are currently in active studies. Other novel formulations have been discontinued, including DM-1992, which is a bilayer formulation containing an IR LD/CD layer and an ER LD/CD layer with gastroretentive properties, and XP21279, a novel oral levodopa prodrug that is absorbed from the small and large intestine by high-capacity nutrient transporters expressed throughout the gastrointestinal system. ODM-101 is a new oral formulation of levodopa/carbidopa/entacapone that contains a higher amount of carbidopa (65 or 105 mg), but no active studies are underway. The current review aims to summarize the pharmacokinetic aspects, clinical efficacy, and potential adverse events of novel levodopa formulations currently available or under development.

A cluster-randomised clinical trial comparing two cardiovascular health education strategies in a child population: the Savinghearts project.

BACKGROUND: This paper describes a methodology for comparing the effects of an eduentertainment strategy involving a music concert, and a participatory class experience involving the description and making of a healthy breakfast, as educational vehicles for delivering obesity-preventing/cardiovascular health messages to children aged 7-8 years. METHODS/DESIGN: This study will involve a cluster-randomised trial with blinded assessment. The study subjects will be children aged 7-8 years of both sexes attending public primary schools in the Madrid Region. The participating schools (n=30) will be randomly assigned to one of two groups: 1) Group MC, in which the children will attend a music concert that delivers obesity-preventing/cardiovascular health messages, or 2) Group HB, in which the children will attend a participatory class providing the same information but involving the description and making of a healthy breakfast. The main outcome measured will be the increase in the number of correct answers scored on a knowledge questionnaire and in an attitudes test administered before and after the above interventions. The secondary outcome recorded will be the reduction in BMI percentile among children deemed overweight/obese prior to the interventions. The required sample size (number of children) was calculated for a comparison of proportions with an α of 0.05 and a ß of 0.20, assuming that the Group MC subjects would show values for the measured variables at least 10% higher than those recorded for the subjects of Group HB. Corrections were made for the design effect and assuming a loss to follow-up of 10%. The maximum sample size required will be 2107 children. Data will be analysed using summary measurements for each cluster, both for making estimates and for hypothesis testing. All analyses will be made on an intention-to-treat basis. DISCUSSION: The intervention providing the best results could be recommended as part of health education for young schoolchildren. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01418872.

Efficacy of a strategy for implementing a guideline for the control of cardiovascular risk in a primary healthcare setting: the SIRVA2 study a controlled, blinded community intervention trial randomised by clusters.

UNLABELLED: This work describes the methodology used to assess a strategy for implementing clinical practice guidelines (CPG) for cardiovascular risk control in a health area of Madrid. BACKGROUND: The results on clinical practice of introducing CPGs have been little studied in Spain. The strategy used to implement a CPG is known to influence its final use. Strategies based on the involvement of opinion leaders and that are easily executed appear to be among the most successful. AIM: The main aim of the present work was to compare the effectiveness of two strategies for implementing a CPG designed to reduce cardiovascular risk in the primary healthcare setting, measured in terms of improvements in the recording of calculated cardiovascular risk or specific risk factors in patients' medical records, the control of cardiovascular risk factors, and the incidence of cardiovascular events. METHODS: This study involved a controlled, blinded community intervention in which the 21 health centres of the Number 2 Health Area of Madrid were randomly assigned by clusters to be involved in either a proposed CPG implementation strategy to reduce cardiovascular risk, or the normal dissemination strategy. The study subjects were patients ≥ 45 years of age whose health cards showed them to belong to the studied health area. The main variable examined was the proportion of patients whose medical histories included the calculation of their cardiovascular risk or that explicitly mentioned the presence of variables necessary for its calculation. The sample size was calculated for a comparison of proportions with alpha = 0.05 and beta = 0.20, and assuming that the intervention would lead to a 15% increase in the measured variables. Corrections were made for the design effect, assigning a sample size to each cluster proportional to the size of the population served by the corresponding health centre, and assuming losses of 20%. This demanded a final sample size of 620 patients. Data were analysed using summary measures for each cluster, both in making estimates and for hypothesis testing. Analysis of the variables was made on an intention-to-treat basis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01270022.