Amantadine-Induced Craniofacial Myoclonus: Distinctive Iatrogenic Dysarthria in Parkinson's Disease.

Background: Amantadine is a widely prescribed medication in Parkinson's disease (PD). A distinctive craniofacial distribution of myoclonus with speech impairment is an underrecognized iatrogenic complication in amantadine-treated patients with PD. Cases: We report 7 patients with idiopathic PD (disease duration, 6-21 years) who developed speech-induced craniofacial-predominant myoclonus with "stuttering-like" dysarthria and speech arrests days to months after amantadine initiation or dose increase. Renal insufficiency was identified as a risk factor in 4 cases. In all cases, reduction or discontinuation of amantadine markedly attenuated the myoclonus and restored speech intelligibility. Literature Review: Amantadine can induce subcortical segmental or generalized myoclonus. A report in 1996 of "vocal myoclonus" in an amantadine-treated patient with PD was the first observation of a focal distribution of myoclonus, particularly affecting speech. Since then, few cases of craniofacial myoclonus with speech impairment have been reported, none with accompanying video. With 1 exception, the craniofacial distribution was part of a generalized pattern of amantadine-induced myoclonus. Comorbid renal insufficiency is a recognized risk factor. Conclusions: Speech-induced craniofacial myoclonus, with marked "stuttering-like" dysarthria and speech arrests, is a disabling iatrogenic complication in PD that resolves upon amantadine discontinuation.

Cognition affects gait adaptation after split-belt treadmill training in Parkinson's disease.

BACKGROUND: Split-belt treadmill (SBTM) training has been proposed to improve gait symmetry and overall gait performance of patients with Parkinson's disease (PD). OBJECTIVES: To determine whether patient's baseline features affect gait adaptation to SBTM in PD with freezing of gait (FOG). METHODS: Twenty participants with idiopathic PD and treatment-resistant FOG underwent several clinical assessments including the Toronto Cognitive Assessment (TorCA) prior to treadmill training. Velocity of the treadmill was adjusted to over-ground walking speed. During SBTM training, the belt velocity on the least-affected side was reduced by 25%. RESULTS: Participants who adapted to SBTM training demonstrated cognitively intact TorCA scores (p < 0.001), particularly intact working memory (p < 0.001). After-effects correlated with normal total TorCA (p = 0.02), working memory and visuospatial (p < 0.001) function. CONCLUSIONS: Cognitive impairment, particularly impaired working memory, reduces gait adaptation and after-effects in PD with FOG. This is informative for trials studying prolonged effects of SBTM training in FOG.

Structural and Molecular Imaging for Clinically Uncertain Parkinsonism.

Neuroimaging is an important adjunct to the clinical assessment of Parkinson disease (PD). Parkinsonism can be challenging to differentiate, especially in early disease stages, when it mimics other movement disorders or when there is a poor response to dopaminergic therapies. There is also a discrepancy between the phenotypic presentation of degenerative parkinsonism and the pathological outcome. The emergence of more sophisticated and accessible neuroimaging can identify molecular mechanisms of PD, the variation between clinical phenotypes, and the compensatory mechanisms that occur with disease progression. Ultra-high-field imaging techniques have improved spatial resolution and contrast that can detect microstructural changes, disruptions in neural pathways, and metabolic and blood flow alterations. We highlight the imaging modalities that can be accessed in clinical practice and recommend an approach to the diagnosis of clinically uncertain parkinsonism.

The challenging quest of neuroimaging: From clinical to molecular-based subtyping of Parkinson disease and atypical parkinsonisms.

The current framework of Parkinson disease (PD) focuses on phenotypic classification despite its considerable heterogeneity. We argue that this method of classification has restricted therapeutic advances and therefore limited our ability to develop disease-modifying interventions in PD. Advances in neuroimaging have identified several molecular mechanisms relevant to PD, variation within and between clinical phenotypes, and potential compensatory mechanisms with disease progression. Magnetic resonance imaging (MRI) techniques can detect microstructural changes, disruptions in neural pathways, and metabolic and blood flow alterations. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging have informed the neurotransmitter, metabolic, and inflammatory dysfunctions that could potentially distinguish disease phenotypes and predict response to therapy and clinical outcomes. However, rapid advancements in imaging techniques make it challenging to assess the significance of newer studies in the context of new theoretical frameworks. As such, there needs to not only be a standardization of practice criteria in molecular imaging but also a rethinking of target approaches. In order to harness precision medicine, a coordinated shift is needed toward divergent rather than convergent diagnostic approaches that account for interindividual differences rather than similarities within an affected population, and focus on predictive patterns rather than already lost neural activity.

Single-Trajectory Multiple-Target Deep Brain Stimulation for Parkinsonian Mobility and Cognition.

BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is an emerging target to potentially treat cognitive dysfunction. OBJECTIVES: The aim of this study is to achieve feasibility and safety of globus pallidus pars interna (GPi) and NBM DBS in advanced PD with cognitive impairment. METHODS: We performed a phase-II double-blind crossover pilot trial in six participants to assess safety and cognitive measures, the acute effect of NBM stimulation on attention, motor and neuropsychological data at one year, and neuroimaging biomarkers of NBM stimulation. RESULTS: NBM DBS was well tolerated but did not improve cognition. GPi DBS improved dyskinesia and motor fluctuations (P = 0.04) at one year. NBM stimulation was associated with reduced right frontal and parietal glucose metabolism (P < 0.01) and increased low- and high-frequency power and functional connectivity. Volume of tissue activated in the left NBM was associated with stable cognition (P < 0.05). CONCLUSIONS: Simultaneous GPi and NBM stimulation is safe and improves motor complications. NBM stimulation altered neuroimaging biomarkers but without lasting cognitive improvement. © 2021 International Parkinson and Movement Disorder Society.

Incidence and prevalence of primary malignant brain tumours in Canada from 1992 to 2017: an epidemiologic study.

BACKGROUND: Primary malignant brain tumours account for more than one-third of all brain tumours and are associated with high morbidity and mortality. The purpose of this study was to estimate the incidence and prevalence of primary malignant central nervous system (CNS) tumours and trends in these rates in Canada from 1992 to 2017. METHODS: We conducted an epidemiologic study using publicly available data from the Canadian Cancer Registry from 1992 to 2017 (1994 to 2015 for prevalence) for all of Canada except Quebec (1992 to 2011). We calculated the incidence and prevalence per 100 000 person-years and the age-standardized incidence and prevalence per 100 000 person-years of primary malignant CNS tumours and stratified them by sex and age (pediatric [≥ 19 yr], adult [20-64 yr] and older adult [> 64 yr]). Our analyses assessed average disease duration, survival differences between males and females, and trends over time. RESULTS: During the study period, the average age-standardized incidence and prevalence rates of all primary malignant CNS tumours were 7.9 and 7.6 per 100 000 person-years, respectively. The incidence and prevalence increased by 37.5% and 40.5%, respectively, over the study period. Males accounted for more than half (26 085 [56.4%]) of all diagnoses and experienced decreased survival compared to females 1 year after diagnosis (p = 0.048). Children accounted for 4605 new diagnoses (10.0%), adults for 23 950 (51.7%), and older adults for 17 735 (38.3%). Age-standardized incidence and prevalence rates were highest among older adults. INTERPRETATION: Overall, the incidence of primary malignant CNS tumours increased from 1992 to 2017, and males and older adults were disproportionately affected. Increased health care resources and awareness are needed to improve identification of these tumours and deliver evidence-based care that balances safety, efficacy and preservation of quality of life for affected patients.

Predictors of survival in elderly patients undergoing surgery for glioblastoma.

BACKGROUND: Glioblastoma (GBM) has a median age of diagnosis of 64 years old and the incidence increases with age. An increasing number of elderly patients are being diagnosed with GBM and undergoing surgery. These patients often present with multiple medical comorbidities and have significantly worse outcomes compared to adult patients. The goal of this study was to determine clinical predictors of survival in elderly patients undergoing surgery for GBM. METHODS: Our brain tumor database was reviewed for all patients 65 years of age and older that underwent surgery for newly diagnosed GBM over a 14-year period from 2005 to 2018. Patient characteristics, comorbidities, complications, and treatment were collected. A total of 150 patients were included, and subdivided into two age categories; 65-74 years old and 75 years or older. RESULTS: The median OS for all patients was 9.4 months. Neither the presence nor number of medical comorbidities were associated with decreased survival (P = .9 and P = .1, respectively). Postoperative complications were associated with worse survival for all patients (HR = 2.34, P = .01) and occurred in patients in the older age category and patients with longer lengths of stay (P < .0001). CONCLUSIONS: The presence of medical comorbidities is not a reason to exclude patients with GBM from surgical consideration. Excluding EOR and adjuvant treatment, postoperative complication is the most significant predictor of survival in elderly patients. Postoperative complications are associated with a longer LOS and are more common in patients 75 years of age and older.

Advanced Therapies for the Management of Dopamine Dysregulation Syndrome in Parkinson's Disease.

BACKGROUND: Dopamine Dysregulation Syndrome (DDS) is an adverse non-motor complication of dopamine replacement therapy in Parkinson's disease. The current literature on this syndrome is limited, and it remains underdiagnosed and challenging to manage. OBJECTIVE: To assess the role of advanced therapies in the management of DDS. METHODS: We performed a retrospective chart review and identified patients who fit the inclusion criteria for DDS. They were classified according to risk factors that have been identified in the literature, motor and complication scores, intervention (medical or surgical) and outcome. Multivariate analyses were performed to analyze these characteristics. RESULTS: Twenty-seven patients were identified (23 males, mean age of onset: 49 ± 8.8 years). Average levodopa equivalent daily dose was 1916.7 ± 804 mg and a history of impulse control disorders, psychiatric illness, and substance abuse was present in 89%, 70% and 3.7% of the patients, respectively. Overall 81.5% of patients had symptom resolution at follow up, on average 4.8 ± 3.5 years after management, with medication only (7/9), levodopa-carbidopa intestinal gel (1/3), deep brain stimulation of subthalamic nucleus (10/13), or globus pallidus pars interna (2/2). Reduction of medications occurred with deep brain stimulation of subthalamic nucleus (P = 0.01) but was associated with a relapse in two patients. CONCLUSION: Although the small sample size of some subgroups limits our ability to draw meaningful conclusions, our results did not suggest superiority of a single treatment option. Advanced therapies including deep brain stimulation can be considered in patients with DDS refractory to conservative measures, but outcome is variable and relapse is possible.

The neuroimaging evidence of brain abnormalities in functional movement disorders.

Neuroimaging has been pivotal in identifying and reframing our understanding of functional movement disorders. If accessible, it compensates for the limitations of the clinical exam and is especially useful where there is overlap of functional symptoms with classical presentations of disease. Imaging in functional movement disorders has increasingly identified structural and functional abnormalities that implicate hypoactivation of the cortical and subcortical motor pathways and increased modulation by the limbic system. Neurobiological theories suggest an impaired sense of agency, faulty top-down regulation of motor movement and abnormal emotional processing in these individuals. This framework challenges our traditional understanding of functional movement disorders as distinct from the deceptive term of 'organic' diseases and proposes that these conditions are not considered as mutually exclusive. This update summarizes the literature to date and explores the role of imaging in the diagnosis of functional movement disorders and in detecting its underlying molecular network.

Innovation in resident education - Description of the Neurology International Residents Videoconference and Exchange (NIRVE) program.

There is considerable heterogeneity in residency education around the world. The Neurology International Residents Videoconference and Exchange (NIRVE) program aims to deliver neurology educational content to residents across different resource settings and countries through a monthly videoconferencing platform. Its purpose is to fill gaps in didactic teaching, increase exposure to a variety of cases including various practices and delivery of neurology in multiple countries, as well as integrate global health content into neurology education. NIRVE also facilitates resident exchanges among participating sites. In this descriptive article, we report NIRVE's structure and its cumulative productivity. Since its creation, NIRVE has held more than 90 videoconference rounds and has connected 16 sites in North America, South America, Europe, Asia and Africa. We describe challenges encountered since the inception of the program eleven years ago. NIRVE also fosters a culture of long-term international connection and collaboration. During global disease outbreaks, such as the current COVID-19 pandemic, videoconference rounds serve as a sustainable alternative means to deliver education. Future goals include increasing the number of sites involved, including a focus on Africa and Asia, and fostering resident-led advocacy projects.

Global & Community Health: Acute ischemic stroke in Toronto and Manila: Bridging the gap.

The educational experience of a neurology trainee can have profound regional variations. We recount the management of a stroke code in Toronto, Canada, and Manila, Philippines, as a means to highlight the need for collaborative learning, both in terms of practicing evidence-based medicine and managing neurologic conditions in resource-limited settings. Concerted peer-led initiatives such as videoconference rounds are an easy and cost-effective means of unifying this experience.

Imaging Mild Cognitive Impairment and Dementia in Parkinson's Disease.

Cognitive dysfunction is a significant non-motor feature of Parkinson's disease, with the risk of dementia increasing with prolonged disease duration. Multiple cognitive domains are affected, and the pathophysiology cannot be explained by dopaminergic loss alone. Sophisticated neuroimaging techniques can detect the nature and extent of extra-nigral involvement by targeting neurotransmitters, abnormal protein aggregates and tissue metabolism. This review identifies the functional and anatomical imaging characteristics that predict cognitive impairment in PD, the limitations that challenge this process, and the avenues of potential research.

The Impact of Shift Work on Migraine: A Case Series and Narrative Review.

OBJECTIVE: We present a case report of 2 migraine patients engaged in shift work, followed by a narrative review, to assess whether shift work influences headache-related disability and chronification of migraine. BACKGROUND: Numerous modifiable factors can lead to chronification of migraine and to higher headache-related disability. These include, among others, obesity, depression, overuse of acute medications, ineffective acute treatments, and stressful life events. Sleep disruptions and disorders are also felt to increase the risk of transitioning from episodic to chronic migraine. We hypothesize that shift work, which by definition leads to atypical or irregular sleep cycles, along with poor quality sleep, is a risk factor for chronification of migraine. METHODS: We present the case histories of 2 shift workers with migraine as per International Classification of Headache Disorders 3 criteria, seen at a large, busy academic headache center, followed by a narrative review of the literature. RESULTS: Previous literature regarding the relationship between shift work and migraine is sparse and conflicting, with more recent studies suggesting that shift work may be a risk factor for migraine-related disability. In our case series, both patients initially reported severe migraine headache-related disability and both patients had noted a worsening of their headaches after beginning night shift work. Both improved when switched back to day shifts, then worsened upon being put back on night shifts. Their headache patterns finally reverted from chronic to episodic migraine after eliminating night shifts completely and maintaining a good sleep routine. CONCLUSIONS: In the 2 cases presented, shift work appeared to be associated with chronification of migraine and higher headache-related disability despite optimal headache management and good patient adherence. A switch to only day shifts promoted transition to an episodic, less disabling pattern of migraine. It is clinically important to take a detailed sleep history in headache patients, and when appropriate, provide support for workplace accommodations. Further larger-scale, rigorous studies are needed to more clearly delineate the relationship between shift work and migraine.

Implementation of the Current Dystonia Classification from 2013 to 2018.

BACKGROUND: There is a discrepancy in the way dystonia is classified in the literature, as articles continue to reference the old criteria or fail to use the 2013 criteria correctly. METHODS: We performed a systematic review of the dystonia literature and distinguished between studies that use the new classification correctly, made errors in implementing the new classification, or continued to use the old classification methods. RESULTS: Of the 990 articles included in the study, 59.8% used the classification correctly, 31.3% used mixed terminology, and 8.9% continued to use the old classification. Articles relating to surgery were significantly less likely to use the new classification correctly. There is an upward trend in the annual rate of articles properly referencing the new classification. CONCLUSIONS: The 2013 classification has been well received in scientific literature, and more studies are adapting to its use.

Nucleus basalis of Meynert neuronal activity in Parkinson's disease.

OBJECTIVE: Neuronal loss within the cholinergic nucleus basalis of Meynert (nbM) correlates with cognitive decline in dementing disorders such as Alzheimer's disease and Parkinson's disease (PD). In nonhuman primates, the nbM firing pattern (5-40 Hz) has also been correlated with working memory and sustained attention. In this study, authors performed microelectrode recordings of the globus pallidus pars interna (GPi) and the nbM immediately prior to the implantation of bilateral deep brain stimulation (DBS) electrodes in PD patients to treat motor symptoms and cognitive impairment, respectively. Here, the authors evaluate the electrophysiological properties of the nbM in patients with PD. METHODS: Five patients (4 male, mean age 66 ± 4 years) with PD and mild cognitive impairment underwent bilateral GPi and nbM DBS lead implantation. Microelectrode recordings were performed through the GPi and nbM along a single trajectory. Firing rates and burst indices were characterized for each neuronal population with the patient at rest and performing a sustained-attention auditory oddball task. Action potential (AP) depolarization and repolarization widths were measured for each neuronal population at rest. RESULTS: In PD patients off medication, the authors identified neuronal discharge rates that were specific to each area populated by GPi cells (92.6 ± 46.1 Hz), border cells (34 ± 21 Hz), and nbM cells (13 ± 10 Hz). During the oddball task, firing rates of nbM cells decreased (2.9 ± 0.9 to 2.0 ± 1.1 Hz, p < 0.05). During baseline recordings, the burst index for nbM cells (1.7 ± 0.6) was significantly greater than those for GPi cells (1.2 ± 0.2, p < 0.05) and border cells (1.1 ± 0.1, p < 0.05). There was no significant difference in the nbM burst index during the oddball task relative to baseline (3.4 ± 1.7, p = 0.20). With the patient at rest, the width of the depolarization phase of APs did not differ among the GPi cells, border cells, and nbM cells (p = 0.60); however, during the repolarization phase, the nbM spikes were significantly longer than those for GPi high-frequency discharge cells (p < 0.05) but not the border cells (p = 0.20). CONCLUSIONS: Neurons along the trajectory through the GPi and nbM have distinct firing patterns. The profile of nbM activity is similar to that observed in nonhuman primates and is altered during a cognitive task associated with cholinergic activation. These findings will serve to identify these targets intraoperatively and form the basis for further research to characterize the role of the nbM in cognition.