Creutzfeldt-Jakob Disease with Initial Typical Parkinsonism Precipitated by COVID-19? A Case Report (preprint)

Background Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease caused by the accumulation of PrPSc. While COVID-19-induced sporadic CJD (sCJD) with parkinsonism as the initial symptom is extremely uncommon, this report aims to raise awareness of sCJD cases that present with parkinsonism that are not associated with genetic mutations or pathological α-synuclein (α-Syn) accumulation. Case presentation This report presents the case of a 72-year-old man with probable sporadic Creutzfeldt-Jakob disease (sCJD) who initially showed symptoms of parkinsonism, which worsened rapidly after contracting COVID-19. Despite a history of responsive tremor and bradykinesia, his condition deteriorated following the viral infection, leading to rapid consciousness decline and diffuse myoclonus. Diagnostic tests, including brain MRI, cerebrospinal fluid analysis, and EEG, pointed towards prion disease. PrPSc, a marker for CJD, was detected in both the cerebrospinal fluid and skin samples using RT-QuIC, further confirming the diagnosis. Notably, skin analysis revealed PrPSc but no pathological α-synuclein deposits, ruling out typical Parkinson's disease.  Conclussion This case underscores the importance of considering sCJD in patients with parkinsonism, especially if they experience sudden neuropsychiatric symptoms, especially if they do not exhibit pathological α-Syn accumulation or have genetic mutations.

Understanding Parkinson's Disease Conversations on Chinese Social Media: Themes, Trends, and Connections (preprint)

Parkinson's disease profoundly impacts patients' quality of life, yet public awareness is limited. As social networks reach broad audiences, they are vital platforms for health communication. This study analyzed Parkinson's disease (PD) topics on China's major social network, Weibo, to reveal public awareness and concerns. We found Parkinson's became a popular keyword due to its association with hand tremors, though this trend may impede public comprehensive understanding of this disease. Through time series analysis, marketing accounts were found to publish misinformation through concentrated posts during specific periods, but this false information had limited impact. Further analysis of communication network structures showed people focused more on mutual aid than acquiring Parkinson's disease knowledge. This indicates advanced technique should be develop to promote accurate Parkinson's knowledge through social media. Additionally, the COVID-19 pandemic over the past three years led people to pay more attention to Parkinson's, demonstrating social media's role in responding to health crises. Overall, this study details how people discuss diseases on social media, providing a basis for developing communication strategies to promote Parkinson's and other diseases, while also informing patient mutual aid systems. To our best knowledge, this is the first study revealing the communications characteristics of PD related contents on social network. The findings may also empower more effective health promotion and patient support worldwide through social networks.

Extended Duration and Intense Manifestations of COVID-19-Linked Cytotoxic Lesions of the Corpus Callosum: Case Reports and Literature Review (preprint)

While clinical instances of cytotoxic lesions of the corpus callosum (CLOCCs) are well-documented, international reports specific to COVID-19-related cases remain limited. This paper presents the case of a 40-year-old female patient admitted due to "sudden dizziness and poor limb coordination for 7 weeks following fever." She tested positive for COVID-19 and experienced symptoms like dizziness, temporary confusion, nausea, vomiting, cerebellar speech issues, and ataxia after fever onset. Later, she developed pyramidal tract symptoms and behavioral abnormalities. Head MRI revealed abnormal high signal in the splenium of the corpus callosum and abnormal signals in the left cerebellar peduncle on DWI. With no significant medical history and exclusion of other causes during treatment (including steroid therapy and two doses of intravenous immunoglobulin), a follow-up MRI after one month showed the lesions had disappeared. However, clinical recovery was slow, with residual symptoms persisting for almost a year, including involuntary tremors in the upper limbs and head. Phenytoin, gabapentin, and pregabalin showed limited effectiveness in treatment, but Arotinolol and donepezil led to slight improvement in involuntary tremors. This case suggests that COVID-19-associated CLOCCs might have a protracted course and severe symptoms, demanding differentiation from ischemic cerebrovascular diseases, particularly in early stages.

DualAttNet: Synergistic Fusion of Image-level and Fine-Grained Disease Attention for Multi-Label Lesion Detection in Chest X-rays (preprint)

Chest radiographs are the most commonly performed radiological examinations for lesion detection. Recent advances in deep learning have led to encouraging results in various thoracic disease detection tasks. Particularly, the architecture with feature pyramid network performs the ability to recognise targets with different sizes. However, such networks are difficult to focus on lesion regions in chest X-rays due to their high resemblance in vision. In this paper, we propose a dual attention supervised module for multi-label lesion detection in chest radiographs, named DualAttNet. It efficiently fuses global and local lesion classification information based on an image-level attention block and a fine-grained disease attention algorithm. A binary cross entropy loss function is used to calculate the difference between the attention map and ground truth at image level. The generated gradient flow is leveraged to refine pyramid representations and highlight lesion-related features. We evaluate the proposed model on VinDr-CXR, ChestX-ray8 and COVID-19 datasets. The experimental results show that DualAttNet surpasses baselines by 0.6% to 2.7% mAP and 1.4% to 4.7% AP50 with different detection architectures. The code for our work and more technical details can be found at https://github.com/xq141839/DualAttNet.

Internal tremors and vibrations in long COVID: a cross-sectional study (preprint)

Background: Internal tremors and vibrations symptoms have been described as part of neurologic disorders but have not been fully described as a part of long COVID. We compared demographics, socioeconomic characteristics, pre-pandemic comorbidities, and new-onset conditions between people with internal tremors and vibrations as part of their long COVID symptoms and people with long COVID but without these symptoms. Methods: A cross-sectional study, Listen to Immune, Symptom and Treatment Experiences Now (LISTEN), collected data from adults with long COVID. The study sample included 423 participants enrolled between May 2022 and June 2023. Results: The 423 participants had a median age of 46 years (interquartile range, 38-56), 74% were female, 87% were Non-Hispanic White, and 158 (37%) reported "internal tremors, or buzzing/vibration" as a long COVID symptom. Before long COVID, the groups had similar comorbidities. Post-COVID, participants with internal tremors and vibrations had significantly worse health as measured by the Euro-QoL visual analogue scale (median: 40 vs. 50 points, P = 0.007), higher rates of financial difficulties caused by the pandemic and housing insecurity (P < 0.001 for each), and were significantly more likely to have new-onset conditions of mast cell disorders (11% vs. 2.6%), neurologic conditions (22% vs. 8.3%), anxiety (20% vs. 8.7%), and trauma- or stress-related mental health disorders (12% vs. 3.4%) compared with those without internal tremors (Bonferroni-adjusted P < 0.05 for each). Participants with internal tremors also reported significantly higher rates of cardiovascular, gastrointestinal, integumentary, and neurologic long COVID symptoms compared with those without internal tremors (Bonferroni-adjusted P < 0.05 for each). Conclusions and Relevance: Among people with long COVID, those with internal tremors and vibrations have more associated symptoms and worse health status, suggesting it may be associated with a severe phenotype of the condition.

Water treatment-free intermittent hemodialysis: a new approach for kidney replacement therapy in the ICU setting. A retrospective study (preprint)

The optimal modalities of kidney replacement therapy (KRT) in the ICU remain debated. Intermittent hemodialysis (IHD) and continuous veno-venous hemofiltration (CVVH) are the two main methods. Intermittent hemodialysis requires a water treatment system that may not be available in all jurisdictions. We report the experience of an innovative strategy of intermittent KRT without water treatment system. During the COVID epidemics, the shortage of KRT machines and the transient impossibility of our water treatment system led us to use the Fresenius MultiFiltrate Pro® monitor to achieve IHD in a particular setting. Based on the manufacturer’s recommendations, the dialysate flow during "CVVHDF post" (post-dilution continuous veno-venous hemodiafiltration) mode was increased by connecting the substitution pump in parallel with the dialysate pump using a Y-connector. This allowed doubling the flow rate of dialysate, allowing for 9000 mL/h during intermittent KRT sessions with a blood flow rate of 250 mL/min. We called this technic “water treatment-free intermittent hemodialysis” or WTF-IHD. We report our experience in 18 patients who underwent 88 WTF-IHD sessions (median duration 5 hours (IQR [4;6]) between August 2019 and May 2020. The median urea reduction ratio was 38% (IQR [29;49]). Hypotension occurred during 21.6% of sessions. Hypokalemia or hypophosphatemia occurred in less than 5% of sessions. In conclusion, WTF-IHD represents an attractive alternative to conventional IHD when a water treatment system is not available. Despite its lower efficacy compared with IHD, it may have substantial organizational and economic impact.

Continuing vocational training in times of economic uncertainty - An event-study analysis in real time (preprint)

Continuing vocational training (CVT) is a key channel for employees to adapt their skills to changing requirements in the labor market due to structural changes and digitization. The COVID-19 pandemic and the energy crisis in consequence of the war in Ukraine may have accelerated these developments. Yet, it is unclear how the economic impacts of these crises affect individuals’ occupational preferences. In detail, we want to investigate how demand for CVT changes in times of economic uncertainty. We use Google Trends data for Germany and apply an event study analysis to examine how interest in CVT developed with the onset of the COVID-19 pandemic and the Russian attack on Ukraine. We find that the interest in CVT strongly declined during the first wave of the pandemic regardless of how severely a region was affected. During the second lockdown, the decline in CVT interest was more pronounced in the eastern German states where we find a general decline in search intensity since March 2020. Overall, we show that the search intensity for CVT decreased on average by 12 to 19 percent during the first 2.5 years of the pandemic, whereas the search intensity for online CVT increased by 39 to 45 percent. We also see a decrease in the search intensity for CVT at the beginning of the energy crisis. JEL Codes: I18, J24

Refraining from interaction can decrease fear of physical closeness during COVID-19.

Perception of peripersonal space (PPS) and interpersonal distance (IPD) has been shown to be modified by external factors such as perceived danger, the use of tools, and social factors. Especially in times of social distancing in the context of the COVID-19 pandemic, it is vital to study factors that modify PPS and IPD. The present work addresses the question of whether wearing a face mask as a protection tool and social interaction impact the perception of IPD. We tested estimated IPD in pictures at three distances: 50 cm, 90 cm, and 150 cm in both social interaction (shaking hands) and without interaction and when the two people in the pictures wore a face mask or not. Data from 60 subjects were analyzed in a linear mixed model (on both difference in distance estimation to the depicted distance and in absolute distance estimation) and in a 3 (distance: 50, 90, 150) × 2 (interaction: no interaction, shake hands), × 2 face mask (no mask, mask) rmANOVA on distance estimation difference. All analyses showed that at a distance of 50 and 90 cm, participants generally underestimated the IPD while at an IPD of 150 cm, participants overestimated the distance. This could be grounded in perceived danger and avoidance behavior at closer distances, while the wider distance between persons was not perceived as dangerous. Our findings at an IPD of 90 cm show that social interaction has the largest effect at the border of our PPS, while the face mask did not affect social interaction at either distance. In addition, the ANOVA results indicate that when no social interaction was displayed, participants felt less unsafe when depicted persons wore a face mask at distances of 90 and 150 cm. This shows that participants are on the one hand aware of the given safety measures and internalized them; on the other hand, that refraining from physical social interaction helps to get close to other persons.

Subclavian Steal Syndrome Caused by Thrombosis Associated with COVID-19: a Case Report.

Background: Thromboembolic complications are a frequent occurrence during COVID-19. This report presents a patient with signs of subclavian steal syndrome (SSS) caused by a thrombus in the initial part of the right subclavian artery. Pathological occlusive changes, such as thrombosis, are four times more common on the left subclavian. Thrombosis of the subclavian artery occurs in about 1% of the population, but atherosclerotic changes are common and usually asymptomatic. Objective: The aim of this report is to present a patient with signs of subclavian steal syndrome (SSS) caused by a thrombus in the initial part of the right subclavian artery associated with symptoms of COVID-19. Case report: A 56-year-old female patient presented with tremor, numbness and prickling in the right hand, tinnitus, blurred vision, vertigo, syncope, trismus and headaches. The formation of a thrombus caused neurological symptoms in the right hand with a stronger pronounced tremor, headache and syncopal episodes. Routine CT with angiography did not reveal significant subocclusions of the neck arteries or significant ischemic changes in the brain. The patient was treated as Parkinsonismus (disease) with syncopal and collapsing episodes. Due to worsening subjective complaints, CT angiography of the neck and head blood vessels was repeated with iterative 3D reconstruction. The examination, as mentioned above, revealed atherosclerotic changes with thrombosis and stronger subocclusion of the right subclavian artery (RSA) proximal to the origin of the arteria vertebralis. Both vertebral arteries, as well as arteria basilaris, had a normal appearance. During physical exertion of the right arm doppler examination of neck blood vessels revealed the presence of reverse blood flow in the right vertebral artery. Haematological tests and high D-dimer also confirmed the diagnosis. After anticoagulant therapy, the thrombotic mass on the mural calcified RSA plaque disappeared. With the reduced physical strain on the right hand and a lifestyle change, syncopal conditions and headaches stopped. There was a reduction in tremors and tingling in the right hand as well. Conclusion: We reported a case of subclavian steal syndrome caused by thrombosis associated with OVID-19. Thromboembolic complications are common in the course of this disease. The diagnosis was confirmed with advanced diagnostic tools (CTA with 3D reconstruction), laboratory tests (D-dimer) and doppler ultrasound. When routine CT angiography is not completely clear, 3D reconstruction is necessary.

Hyperkinetic movement disorders following SARS-CoV-2 infection and vaccination - an update.

The aim of this review was to summarise current knowledge regarding hyperkinetic movement disorders related to SARS-CoV-2 infection and vaccination in terms of phenomenology, epidemiology, pathogenesis and treatment. After a thorough review of the PubMed and Google Scholar databases (2020-2022), we identified myoclonus and ataxia sometimes accompanied by opsoclonus (AMS) as the two most frequent COVID-19 sequelae, with chorea, tremor and dystonia being very rare. The pathogenesis seems to be variable, but in the majority of AMS cases it was autoimmunological, with good response and recovery after corticosteroids or intravenous immunoglobulins infusions. Vaccination may be complicated by hyperkinetic movement disorders (e.g. tremor, dystonia), but this is very rare. Patients with Deep Brain Simulation depletion should not be postponed due to lockdowns as this may result in fatal outcomes.

Chronic inflammatory demyelinating polyradiculoneuropathy-associated tremor: Phenotype and pathogenesis.

BACKGROUND AND PURPOSE: Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP-related tremor is more variable than other tremor disorders. METHODS: Consecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross-sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and t-test was used for comparisons between groups. RESULTS: Twenty-four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high-frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F-wave latency and median nerve sensory amplitude. TSI (2.3 ± 0.1) was significantly higher than essential tremor. CONCLUSIONS: Postural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat-to-beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor.

COVID19-associated new-onset movement disorders: a follow-up study.

BACKGROUND: Neurological symptoms are common manifestation in acute COVID-19. This includes hyper- and hypokinetic movement disorders. Data on their outcome, however, is limited. METHODS: Cases with new-onset COVID-19-associated movement disorders were identified by searching the literature. Authors were contacted for outcome data which were reviewed and analyzed. RESULTS: Movement disorders began 12.6 days on average after the initial onset of COVID-19. 92% of patients required hospital admission (mean duration 23 days). In a fraction of patients (6 of 27; 22%; 4 males/2 females, mean age 66.8 years) the movement disorder (ataxia, myoclonus, tremor, parkinsonism) was still present after a follow-up period of 7.5 ± 3 weeks. Severe COVID-19 in general and development of encephalopathy were risk factors, albeit not strong predictors, for the persistence. CONCLUSIONS: The prognosis of new-onset COVID-19-associated movement disorder appears to be generally good. The majority recovered without residual symptoms within several weeks or months. Permanent cases may be due to unmasking of a previous subclinical movement disorder or due to vascular/demyelinating damage. Given the relatively low response rate of one third only and the heterogeneity of mechanisms firm conclusions on the (long-term) outome cannot, however, be drawn.

When brain devices go wrong: a patient with a malfunctioning deep brain stimulator (DBS) presents to the emergency department.

A man in his 50s attended the emergency department with an acute deterioration in his Parkinson's symptoms, presenting with limb rigidity, widespread tremor, choreiform dyskinesia, dysarthria, intense sadness and a severe occipital headache. After excluding common differentials for sudden-onset parkinsonism (eg, infection, medication change), an error on the patient's deep brain stimulator was noted. The patient's symptoms only resolved once he was transferred to the specialist centre so that the programmer could reset the device settings. Due to COVID-19-related bed pressures on the ward, there was a delay in the patient receiving specialist attention-highlighting the need for non-specialist training in the emergency management of device errors.

Expanding Community Health Worker decision space: impacts of a Participatory Action Research training intervention in a rural South African district (preprint)

BACKGROUND While recognised in policy and strategy, in practice, Community Health Workers (CHWs) in South Africa experience many challenges. Since the COVID-19 pandemic, CHW roles have expanded, shifting from communities to clinics. The objective was to assess a community-based training intervention to support functionality and local decision-making of CHWs in rural South Africa, aiding CHWs to undertake new, expanded roles during the COVID-19 pandemic.  METHODS: CHWs from three rural villages were recruited and trained in rapid Participatory Action Research (PAR) methods via a series of workshops with community stakeholders. Training was designed to support CHWs to convene community groups, raise and/or respond to health concerns, understand concerns from different perspectives, and facilitate and monitor action in communities, health, and other public services. Narrative data from in-depth interviews with CHWs before and after the intervention were thematically analysed using the decision space framework to examine functionality in devolved decision-making.  RESULTS: CHWs reported experiencing multiple, intersecting challenges: lack of financial, logistical and health systems support, poor role clarity, precarious employment, low and no pay, unstable organizational capacity, and fragile accountability mechanisms. CHWs had considerable commitment and resilience in the face of COVID-19 in terms of increased workloads, increased risk of infection and death, low job security and poor remuneration. The training intervention addressed some resourcing issues, increased management capacity, gave CHWs greater role clarity, improved community mobilisation skills and forged new community and facility-based relationships and alliances. Through regular spaces and processes for cooperative learning and collective action, the intervention supported CHWs to rework their agency in more empowered ways with communities, clinic staff and health managers, and among peers. The training thus served as an implementation support strategy for primary healthcare (PHC).  CONCLUSION: The analysis revealed fundamental issues of recognition of CHWs as a permanent, central feature in PHC. The training intervention was positively impactful in widening decision space for CHWs, supporting functionality and agency for local decision-making. The intervention has been recommended for scale-up by the local health authority. Further support for and analysis of how to sustain expansion of CHW decision space is warranted.

Delayed encephalopathy after COVID-19: A case series of six patients.

RATIONALE: Acute encephalopathy is a severe neurological complication of coronavirus disease 2019 (COVID-19). Most cases of acute encephalopathy associated with COVID-19 occur within several weeks of COVID-19 onset. We describe a case series of 6 patients who developed delayed encephalopathy (DE) after COVID-19. PATIENT CONCERNS AND DIAGNOSES: We evaluated patients who recovered from COVID-19 and showed acute disturbance of consciousness or focal neurological deficits without recurrence of pneumonitis. Six patients, 2 females and 4 males, with ages ranging from 65 to 83 years were included. Durations of hospitalization due to COVID-19 were between 25 and 44 days. The severity of COVID-19 was moderate in 5 and severe in 1 patient. Patients were rehospitalized for acute disturbance of consciousness concomitant with postural tremor and, abnormal behavior, hemiplegia, aphasia, or apraxia between 34 and 67 days after the onset of COVID-19. Chest computed tomography showed no exacerbation of pneumonitis. Brain magnetic resonance imaging showed no specific findings except in 1 patient with an acute lacunar infarction. Electroencephalogram demonstrated diffuse slowing in all patients. Repeat electroencephalogram after recovery from encephalopathy demonstrated normal in all patients. One of the 6 patients had cerebrospinal fluid (CSF) pleocytosis. CSF protein levels were elevated in all patients, ranging from 51 to 115 mg/dL. CSF interleukin-6 levels ranged from 2.9 to 10.9 pg/mL. The immunoglobulin index was 0.39 to 0.44. Qlim(alb) < QAlb indicating dysfunction of the blood-brain barrier was observed in all patients. Severe acute respiratory syndrome coronavirus 2 reverse transcription polymerase chain reaction of CSF was negative in all patients. Neuronal autoantibodies were absent in serum and CSF. INTERVENTIONS AND OUTCOMES: Immunotherapy including steroid pulses was administered to 3 patients; however, symptoms of encephalopathy resolved within several days in all patients, regardless of treatment with immunotherapy, and their consciousness levels were recovered fully. Notably, postural tremor remained for 2 weeks to 7 months. LESSONS: In our patients, DE after COVID-19 was characterized by symptoms of acute encephalopathy accompanied with tremor in the absence of worsening pneumonitis after the fourth week of COVID-19 onset. Our findings indicate blood-brain barrier dysfunction may contribute to the pathogenesis of DE after COVID-19.

Development and Assessment of a Movement Disorder Simulator Based on Inertial Data.

The detection analysis of neurodegenerative diseases by means of low-cost sensors and suitable classification algorithms is a key part of the widely spreading telemedicine techniques. The choice of suitable sensors and the tuning of analysis algorithms require a large amount of data, which could be derived from a large experimental measurement campaign involving voluntary patients. This process requires a prior approval phase for the processing and the use of sensitive data in order to respect patient privacy and ethical aspects. To obtain clearance from an ethics committee, it is necessary to submit a protocol describing tests and wait for approval, which can take place after a typical period of six months. An alternative consists of structuring, implementing, validating, and adopting a software simulator at most for the initial stage of the research. To this end, the paper proposes the development, validation, and usage of a software simulator able to generate movement disorders-related data, for both healthy and pathological conditions, based on raw inertial measurement data, and give tri-axial acceleration and angular velocity as output. To present a possible operating scenario of the developed software, this work focuses on a specific case study, i.e., the Parkinson's disease-related tremor, one of the main disorders of the homonym pathology. The full framework is reported, from raw data availability to pathological data generation, along with a common machine learning method implementation to evaluate data suitability to be distinguished and classified. Due to the development of a flexible and easy-to-use simulator, the paper also analyses and discusses the data quality, described with typical measurement features, as a metric to allow accurate classification under a low-performance sensing device. The simulator's validation results show a correlation coefficient greater than 0.94 for angular velocity and 0.93 regarding acceleration data. Classification performance on Parkinson's disease tremor was greater than 98% in the best test conditions.

Assessment of Risk Factors and Early Presentations of Parkinson Disease in Primary Care in a Diverse UK Population.

IMPORTANCE: Early features of Parkinson disease (PD) have been described through population-based studies that overrepresent White, affluent groups and may not be generalizable. OBJECTIVE: To investigate the association between risk factors and prediagnostic presentations of PD in an ethnically diverse UK population with high socioeconomic deprivation but universal access to health care. DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study was conducted using electronic health care records on 1 016 277 individuals from primary care practices in East London to extract clinical information recorded between 1990 and February 6, 2018. The data were analyzed between September 3, 2020, and September 3, 2021. Individuals with a diagnosis of PD were compared with controls without PD or other major neurological conditions. MAIN OUTCOMES AND MEASURES: A matched analysis (10 controls matched for each patient with PD according to age and sex) and an unmatched analysis (adjusted for age and sex) were undertaken using multivariable logistic regression to determine associations between risk factors and prediagnostic presentations to primary care with subsequent diagnosis of PD. Three time periods (<2, 2-<5, and 5-10 years before diagnosis) were analyzed separately and together. RESULTS: Of 1 016 277 individuals included in the data set, 5699 were excluded and 1055 patients with PD and 1 009 523 controls were included in the analysis. Patients with PD were older than controls (mean [SD], 72.9 [11.3] vs 40.3 [15.2] years), and more were male (632 [59.9%] vs 516 862 [51.2%]). In the matched analysis (1055 individuals with PD and 10 550 controls), associations were found for tremor (odds ratio [OR], 145.96; 95% CI, 90.55-235.28) and memory symptoms (OR, 8.60; 95% CI, 5.91-12.49) less than 2 years before the PD diagnosis. The associations were also found up to 10 years before PD diagnosis for tremor and 5 years for memory symptoms. Among midlife risk factors, hypertension (OR, 1.36; 95% CI, 1.19-1.55) and type 2 diabetes (OR, 1.39; 95% CI, 1.19-1.62) were associated with subsequent diagnosis of PD. Associations with early nonmotor features, including hypotension (OR, 6.84; 95% CI, 3.38-13.85), constipation (OR, 3.29; 95% CI, 2.32-4.66), and depression (OR, 4.69; 95% CI, 2.88-7.63), were also noted. Associations were found for epilepsy (OR, 2.5; 95% CI, 1.63-3.83) and hearing loss (OR, 1.66; 95% CI, 1.06-2.58), which have not previously been well reported. These findings were replicated using data from the UK Biobank. No association with future PD diagnosis was found for ethnicity or deprivation index level. CONCLUSIONS AND RELEVANCE: This study provides data suggesting that a range of comorbidities and symptoms are encountered in primary care settings before PD diagnosis in an ethnically diverse and deprived population. Novel temporal associations were observed for epilepsy and hearing loss with subsequent development of PD. The prominence of memory symptoms suggests an excess of cognitive dysfunction in early PD in this population or difficulty in correctly ascertaining symptoms in traditionally underrepresented groups.

Clozapine Use in a Movement Disorder Clinic.

BACKGROUND: Clozapine is an effective antipsychotic for Parkinson's disease (PD) that does not worsen motor function and can improve tremor. It is approved for PD psychosis in Europe and Australia. OBJECTIVE: The aim of this study was to report on the use of clozapine in a movement disorder clinic. METHODS: We report on patients monitored during the COVID-19 pandemic in clinic over a 7-month period. RESULTS: Sixty-five patients were seen, of whom 50 had PD. Thirty-one were treated for psychosis, 18 for refractory tremor and 1 for levodopa dyskinesias. The remainder had psychotic symptoms with dementia with Lewy bodies (n = 2) or other movement disorders. Four had clozapine discontinued because of sedation and 1 for agranulocytosis. Three had clozapine temporarily halted because of granulocytopenia but were rechallenged successfully. CONCLUSIONS: When comparing clozapine use in this clinic as compared with others, we deduce that clozapine is likely significantly underutilized in the United States.

A 62-Year-Old Man Presenting with Bilateral Tremor of the Upper Limb After a Diagnosis of COVID-19 with Confirmed Volumetric Brain Loss.

BACKGROUND The SARS-CoV-2 viral infection is associated with respiratory and multi-organ systemic disease. It has been shown to affect the central nervous system and produce varied neurological symptoms, including ischemic strokes, seizures, and encephalitis. Neurological manifestations of this viral infection are thought to be due to neurotropic reactions on the central nervous system or post-infectious immune-mediated damage. This report presents a case of bilateral tremor of the upper limbs more than 6 weeks after a diagnosis of COVID-19, with confirmed volumetric brain loss shown by follow-up brain magnetic resonance imaging (MRI) combined with 3-dimensional volumetric NeuroQuant image analysis. CASE REPORT We report a case of new-onset tremors in a 62-year-old man after SARS-CoV-2 infection. MRI of the brain was performed shortly after the onset of tremors, and a follow-up MRI after 2 months showed evidence of rapid parenchymal volume, loss of midbrain substance, and increased cerebrospinal fluid volume within 2 months of the initial examination. CONCLUSIONS This case report shows central neurological effects of COVID-19, which can be evaluated by quantitative volumetric MRI analysis, although further studies are warranted to determine how this type of brain imaging can be used to evaluate the effects of SARS-CoV-2 infection over time.

Directed stimulation of the dentato-rubro-thalamic tract for deep brain stimulation in essential tremor: a blinded clinical trial.

OBJECTIVE: Observational studies utilising diffusion tractography have suggested a common mechanism for tremor alleviation in deep brain stimulation for essential tremor: the decussating portion of the dentato-rubro-thalamic tract. We hypothesised that directional stimulation of the dentato-rubro-thalamic tract would result in greater tremor improvement compared to sham programming, as well as comparable improvement as more tedious standard-of-care programming. METHODS: A prospective, blinded crossover trial was performed to assess the feasibility, safety and outcomes of programming based solely on dentato-rubro-thalamic tract anatomy. Using magnetic resonance imaging diffusion-tractography, the dentato-rubro-thalamic tract was identified and a connectivity-based treatment setting was derived by modelling a volume of tissue activated using directional current steering oriented towards the dentato-rubro-thalamic tract centre. A sham setting was created at approximately 180° opposite the connectivity-based treatment. Standard-of-care programming at 3 months was compared to connectivity-based treatment and sham settings that were blinded to the programmer. The primary outcome measure was percentage improvement in the Fahn-Tolosa-Marín tremor rating score compared to the preoperative baseline. RESULTS: Among the six patients, tremor rating scores differed significantly among the three experimental conditions (P=0.030). The mean tremor rating score improvement was greater with the connectivity-based treatment settings (64.6% ± 14.3%) than with sham (44.8% ± 18.6%; P=0.031) and standard-of-care programming (50.7% ± 19.2%; P=0.062). The distance between the centre of the dentato-rubro-thalamic tract and the volume of tissue activated inversely correlated with the percentage improvement in the tremor rating score (R2=0.24; P=0.04). No significant adverse events were encountered. CONCLUSIONS: Using a blinded, crossover trial design, we have shown the technical feasibility, safety and potential efficacy of connectivity-based stimulation settings in deep brain stimulation for treatment of essential tremor.