Measurement of Functional Brain Network Connectivity in People with Orthostatic Tremor.

Orthostatic tremor is a rare movement disorder characterized by a sensation of unsteadiness and leg tremor while standing. It has been hypothesized that the disorder is attributable to dysregulation of a central oscillatory network in the brain. This putative network includes primary motor cortex, supplementary motor area, cerebellum, thalamus, and pontine tegmentum. We studied this brain network by recording resting-state functional MRI data from individuals with orthostatic tremor. For each participant, we measured resting-state functional connectivity using a seed-based approach. Regions of interest included were components of the putative central oscillatory network and a primary motor thumb region (identified via transcranial magnetic stimulation). A non-central oscillatory network region of interest-posterior cingulate cortex-was included for comparative analysis of a well-characterized intrinsic network, the default mode network. Demographic information, medical history, and tremor characteristics were collected to test associations with functional connectivity. For normative context, data from the 1000 Functional Connectomes Project were analyzed using an identical approach. We observed that tremor and demographic variables were correlated with functional connectivity of central oscillatory network components. Furthermore, relative to healthy comparison participants, patients with orthostatic tremor exhibited qualitatively different patterns of cerebellar resting state functional connectivity. Our study enhances the current understanding of brain network differences related to orthostatic tremor and is consistent with a hypothesized selective decoupling of cerebellum. Additionally, associations observed between functional connectivity and factors including medical history and tremor features may suggest targets for treatment of orthostatic tremor.

Plantar Grasp sign as a screening tool for Orthostatic Tremor (OT).

Introduction: Orthostatic tremor (OT) is a rare neurological disorder characterized by a sensation of instability while standing. Very few clinical signs have been described for OT to date. Finding other symptoms and signs could prove valuable for this hard-to-recognized disease. Methods: This protocol is part of the University of Nebraska Medical Center Orthostatic Tremor longitudinal study. It was noted that OT patients flex their toes and sometimes the foot arch while standing (Plantar Grasp). They reported doing this to "grab" the floor and improve stability. This paper analyses the diagnostic test characteristics of the patient-self-reported Plantar Grasp, a new sign in OT. Results: There were 34 OT patients (88% females), and 20 controls (65% females). Eighty-eight percent of patients with OT reported the plantar grasp sign and none of the controls. The Plantar Grasp Sign was found to be very sensitive (88%), and extremely specific (100%) in our cohort. Non-weighted Negative Likelihood Ratio (NLR) was 0.12. And the 3% prevalence-weighted NLR was so low that the negative post-test probability was close to zero. Conclusion: Due to its high sensitivity, specificity, and ideal likelihood ratio, we propose that the Plantar Grasp sign could be considered to screen patients with possible OT. Further studies are needed to determine the specificity of this sign in OT versus other balance disorders.

Consensus Paper: Ataxic Gait.

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.

Effects of Fragmentation and the Case for Greater Cohesion in Neurologic Care Delivery.

GOALS: To define fragmentation in neurological care delivery; explain the positive and negative drivers in neurologic practice that contribute to fragmentation; illustrate situations that increase fragmentation risk; emphasize the costs and impact on both patients and providers; propose solutions that allow for more cohesive care. WORK GROUP: The Transforming Leaders Program (TLP) class of 2020 was tasked by American Academy of Neurology (AAN) leadership to identify the leading trends in inpatient and outpatient neurology and to predict their effects on future neurologic practice. METHODS: Research material included AAN data bases, PubMed searches, discussion with topic experts and AAN leadership. RESULTS: Trends in care delivery are driven by changes in the work force, shifts in health care delivery, care costs, changes in evidence-based care and patient factors. These trends can contribute to care fragmentation. Potential solutions to these problems are proposed based on care models developed in oncology and medicine. LIMITATIONS: This paper shares our opinions as there is a lack of evidence-based guidelines as to optimal neurological care delivery.

Electroencephalography in Orthostatic Tremor: A Prospective Study of 30 Patients.

Background: Orthostatic tremor (OT) is characterized by a sensation of instability while standing, associated with high frequency (1318 Hz) tremor in the legs. Small retrospective series have reported electroencephalography (EEG) findings in OT with discordant results. Methods: We prospectively enrolled 30 OT subjects. Mean age = 68.3 (range 5487) with mean disease duration 16.3 years (range 444). A modified 1020 system EEG recording with additional midline electrodes was obtained. EMG electrodes were placed on quadricep muscles. EEG recording was performed at rest, during sleep and while standing unassisted. Results: In all subjects, EEG showed normal background, normal drowsiness and/or stage 2 sleep, and normal responses to hyperventilation and photic stimulation. These normal results persisted during stance. EEG abnormalities were found in 3 subjects (anterior-mid temporal slow activity), but were not position-dependent and were judged unlikely to be related to OT. Tremor artifact while standing was noted in all subjects, however it was measurable in 26 with frequency in the OT range in 25. When compared with EMG, the average difference in frequency was small at 1.2 Hz (range 0.52.5, p 0.46). Visual EEG analysis in OT patients did not reveal electrographic abnormalities even upon standing unassisted. Discussion: EEG was normal on this prospective, relatively large OT series. Clinicians interpreting video-EEGs should be aware of the OT artifact that can be seen in EEG and EKG leads mostly while standing.

Ataxia Prevalence in Primary Orthostatic Tremor.

Background: The exact pathophysiology of primary Orthostatic Tremor (OT) is unknown. A central oscillator is assumed, and previous imaging studies show involvement of cerebellar pathways. However, the presence of ataxia on clinical exam is disputed. We set out to study ataxia in OT prospectively. Methods: EMG-confirmed primary OT subjects and spousal controls received a neurological exam with additional semiquantitative evaluations of ataxia as part of a multinational, prospective study. These included detailed limb coordination (DLC), detailed stance and gait evaluation (DS), and the Brief Ataxia Rating Scale (BARS). Intra- and inter-rater reliability were assessed and satisfactory. Results: 34 OT subjects (mean age = 67 years, 88% female) and 21 controls (mean age = 66 years, 65% male) were enrolled. Average disease duration was 18 years (range 4-44). BARS items were abnormal in 88% of OT patients. The OT subjects were more likely to have appendicular and truncal ataxia with significant differences in DLC, DS and BARS. Ocular ataxia and dysarthria were not statistically different between the groups. Discussion: Mild-to-moderate ataxia could be more common in OT than previously thought. This is supportive of cerebellar involvement in the pathophysiology of OT. We discuss possible implications for clinical care and future research. Highlights: Previous studies of Primary Orthostatic Tremor (OT) have proposed pathophysiologic involvement of the cerebellar pathways.However, presence of ataxia has not been systematically studied in OT.This is a prospective comprehensive ataxia assessment in OT compared to controls. Mild-to-moderate appendiculo-truncal ataxia was found to be common in OT.

Development and Validation of the Orthostatic Tremor Severity and Disability Scale (OT-10).

BACKGROUND: Limited tools are available for the assessment of orthostatic tremor severity and disability. OBJECTIVES: To develop and validate a self-administered orthostatic tremor scale. METHODS: After expert consensus and literature review generating a list of 42 items, the scale was developed and modified for validation after a patient focus group, multiple rounds of Delphi panels, and cognitive interviews. Clinimetric evaluations included assessing content validity, internal consistency, measurement error and reliability, construct validity, and concurrent validity anchored on the examiner's Clinical Global Impression score. RESULTS: Eleven items ranked on a Likert scale from 0 (no disability/severity) to 5 (maximal disability/severity) were evaluated in 54 orthostatic tremor patients (16 men and 38 women; mean age: 69.17 ± 9.64 years; disease duration: 13.83 ± 11.24 years) to probe severity and disability over the preceding 1-week period. The 11-item scale showed good internal consistency (Cronbach's alpha = 0.863) and acceptable (>0.40) item-to-total correlation. However, one item was removed at the final Delphi panel because of significant floor effect, poor item-to-total correlation, and poor factor-loading, leaving the scale with 10 items (10-item Orthostatic Tremor Severity and Disability Scale). Test-retest reliability at 2 weeks was excellent (two-way random intraclass correlation coefficient > 0.90), and the individual item test-retest reliability showed good agreement, with a threshold weighted kappa >0.60 for all items. Exploratory factor analyses revealed a parsimonious two-factor construct accounting for 57.7% of the scale's variance. The 10-item Orthostatic Tremor Severity and Disability Scale scores correlated with the CGI. CONCLUSIONS: The self-administered 10-item Orthostatic Tremor Severity and Disability Scale scale is valid and reliable for capturing orthostatic tremor-related severity and disability. © 2020 International Parkinson and Movement Disorder Society.

Alarming levels of stigma toward generalized dystonia: A cross-cultural comparison.

INTRODUCTION: Although stigma has been linked to poor quality of life, studies examining its prevalence in dystonia are lacking. Our objective was to determine prevalence and predictors of stigma against generalized dystonia in diverse cultural settings. METHOD: Participants were 273 (65.9% female) patients and visitors approached at primary care clinics from three populations: León, Nicaragua (92 participants); a mostly-Hispanic Clinic in Omaha, NE USA (85 participants); and a mostly-non-Hispanic population in Omaha, Nebraska (96 participants). Participants learned about generalized dystonia, epilepsy and schizophrenia through reading a small vignette and viewing videos, followed by a questionnaire designed to identify stigma. We compared levels of stigma between dystonia and other conditions at different sites and measured variables that could affect them. RESULTS: Prevalence of stigma was high toward dystonia (33.00%), similar to epilepsy and lower than schizophrenia. The results showed a complex relationship between the studied variables and level of stigma, especially with age. Female gender predicted more stigmatizing answers. Country of origin, level of education and self-identification of Hispanic ethnicity did not affect stigma. Learning more personal information about the dystonia patient decreased dystonia, a proof that unjustified preliminary negative judgment was present. CONCLUSIONS: Stigma against generalized dystonia was very prevalent across all the communities studied. Demographic and socio-cultural variables had different correlations to level of stigma, underlying the complexity of this problem. The alarming levels of stigma against dystonia justify further studies on how to minimize its impact on our patients.

The use of smartphone in measuring stance and gait patterns in patients with orthostatic tremor.

Orthostatic tremor (OT) is a rare movement disorder characterized by a fast tremor (13-18 Hz) in the lower extremities during stance. Patients with OT typically complain of instability while standing/walking. However, due to the geographical limitation, the standing instability or gait problems in patients with OT cannot be assessed and monitored frequently. The increasing popularity of using smartphone-based accelerometers could be a solution to eliminate this limitation. This study examined the feasibility of using smartphone-based accelerometers to identify the changes in body movement in different standing and locomotor tasks. Twenty patients with OT and seven healthy controls were consented to participate in this study. Subjects stood with eyes open or eyes closed for 20 seconds. They also performed four different locomotor tasks (normal walking, tandem walk, walking on an elevated surface, and obstacle negotiation). When performed different locomotor tasks, patients with OT had a larger acceleration of body movement than controls in the medial-lateral direction (tandem walk: p = 0.026, walking on an elevated surface: p = 0.002, and stepping over the obstacle: p = 0.028). Patients with OT had smaller acceleration of body movement than controls while standing with eyes open in the vertical direction (p = 0.012), in the anterior-posterior direction (p = 0.013) and in the medial-lateral direction (p = 0.011). This study provides objective evidence of balance instability in patients with OT not only while standing but also during different challenging locomotor tasks by using smartphone-based accelerometers.

A dozen years of evolution of neurology clerkships in the United States: Looking up.

OBJECTIVE: To report a 2017 survey of all US medical school neurology clerkship directors (CDs) and to compare the results to similar surveys conducted in 2005 and 2012. METHODS: An American Academy of Neurology (AAN) Consortium of Neurology Clerkship Directors (CNCD) workgroup developed the survey that was sent to all neurology CDs listed in the AAN CNCD database. Comparisons were made to similar 2005 and 2012 surveys. RESULTS: The response rate was 92 of 146 programs (63%). Among the responding institutions, neurology is required in 94% of schools and is 4 weeks in length in 75%. From 2005 to 2017, clerkships shifted out of a fourth-year-only rotation (p = 0.035) to earlier curricular time points. CD protected time averages 0.24 full-time equivalent (FTE), with 31% of CDs reporting 0.26 to 0.50 FTE support, a >4-fold increase from prior surveys (p < 0.001). CD service of >12 years increased from 9% in 2005 to 23% in 2017. Twenty-seven percent also serve as division chief/director, and 22% direct a preclinical neuroscience course. Forty-nine percent of CDs are very satisfied in their role, increased from 34% in 2012 (p = 0.046). The majority of CDs identify as white and male, with none identifying as black/African American. CONCLUSION: Changes since 2005 and 2012 include shifting of the neurology clerkship to earlier in the medical school curriculum and an increase in CD salary support. CDs are more satisfied than reflected in previous surveys and stay in the role longer. There is a lack of racial diversity among neurology CDs.

Orthostatic Tremor: Pathophysiology Guiding Treatment.

PURPOSE OF REVIEW: Orthostatic tremor (OT) is a rare disorder characterized by tremor and a feeling of unsteadiness while standing that resolve upon walking or sitting. A pathognomonic 13-18 Hz tremor is seen on surface EMG while standing. Though its clinical features have been better defined over time, much of its pathophysiology remains unknown and treatment options are limited. We review here recent developments in both of these areas. RECENT FINDINGS: Several recent studies have furthered our understanding of the central oscillatory network involved in OT. fMRI and 18F-FDG-PET studies have identified a ponto-cerebello-thalamo-cortical network underlying OT, though the nature of its dysfunction remains unknown. Randomized trials of treatments for OT are few, so most data are from case reports or small case series. Clonazepam and gabapentin are likely the most effective medical therapies, while bilateral ventral intermediate nucleus deep brain stimulation shows promise for refractory cases. Though much about OT remains unknown, our understanding of its pathophysiology has improved through recent studies. Treatment benefit is overall modest and inconsistent, though better understanding of the disease could lead to new avenues for treatment.

Role of the Personal KinetiGraph in the routine clinical assessment of Parkinson's disease: recommendations from an expert panel.

INTRODUCTION: Evaluation of people with Parkinson's disease (PD) is often complex due to heterogeneity of symptoms and disease course, including the variability of motor fluctuations and dyskinesia. Routine clinical evaluations may be incomplete, may not accurately capture important symptoms, and may not reflect day-to-day variability. While significant advances have been made in wearable ambulatory continuous objective monitoring (COM) technologies, many clinicians remain uncertain of how to incorporate them in clinical practice, including the value to clinical decision-making. The Personal KinetiGraph™ (PKG) has FDA clearance in the United States, and has recently been used in several clinical studies. Areas covered: An expert group of movement disorders neurologists convened to discuss the clinical utility of the PKG in the routine assessment of people with PD. Based on their experience, the group identified clinical scenarios where objective information gained from review of PKG reports can provide useful information to improve clinical management. Expert commentary: PKG provides clinically meaningful data in patients with PD that can aid the clinician in evaluating patients and optimizing their pharmacologic therapy. Early clinical experience and expert opinion suggest that utilization of COM technologies such as the PKG have the potential to improve medical care in people with PD.

Bilateral chorea/ballismus: detection and management of a rare complication of non-ketotic hyperglycaemia.

Non-ketotic hyperglycaemia (NKH) is the most common metabolic cause of hemichorea-hemiballismus (HC-HB) and an often-reversible condition. A 68-year-old man presented to the emergency department with a severe hyperglycaemic episode and altered mental status. He was treated appropriately and discharged home after his blood glucose levels were normal with an improvement of mental status. Four weeks after the discharge, he returned with flailing movements of bilateral upper and lower limbs. MRI of the brain revealed hyperintensities of the bilateral putamen on T1-weighted imaging. The patient's symptoms improved with a combination of amantadine, clonazepam and tetrabenazine. Several hypotheses involving gemistocytes, calcification and petechial haemorrhage were proposed in support of imaging abnormalities in the striatum. Dopamine-depleting agents and neuroleptics are used in the treatment of chorea. It is recommended to try a dose of tetrabenazine in patients with NKH-induced HC-HB if no improvement is appreciated with initial treatment of glycaemic control.

Hyperbaric oxygen for late sequelae of carbon monoxide poisoning enhances neurological recovery: case report.

Neuropsychiatric sequelae have been reported in 15%-45% of survivors of carbon monoxide (CO) poisoning. Hyperbaric oxygen (HBO2) therapy reduces the incidence of cognitive and neurological a dysfunction. The efficacy of providing HBO2 beyond the first one to two days after initial insult is unknown. However, some evidence exists for the benefit of this treatment. We report on treating a patient 14 months after CO injury, who responded with markedly improved neurologic status. A 27-year-old scholar was found comatose due to CO poisoning (carboxyhemoglobin = 31.7%). He received five acute HBO2 treatments. After discharge, he developed chorea, Parkinsonism, dystonia, memory loss, slowed processing speed and verbal fluency, leaving him disabled. After the patient reached a clinical plateau, HBO2 was tried again at 90 minutes at 2.4 ATA plus air breaks. Neuropsychological testing was performed at baseline and after each 20 HBO2 cycles, five of which were performed during the period from 14-22 months after CO exposure. After the first 20 treatments, Parkinsonism and dystonia improved. After 40 sessions, further improvements were seen on mental speed, verbal fluency, and fine motor movements. The outcome following 100 treatments was that the patient regained independence, including the ability to drive and to become gainfully employed. Our case calls into question the concept that HBO2 therapy has no role during the chronic phase of CO brain injury. Randomized clinical trials should be considered to evaluate the therapeutic efficacy of HBO2 in patients with neurological sequelae following CO injury.