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Abstract Objective Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs. Methods Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples. Results Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web‐based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis. Interpretation These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.

Background: Although managing symptoms is paramount for both essential tremor (ET) patients and their healthcare providers, studies of treatment satisfaction are surprisingly lacking. Objectives: We evaluated the satisfaction of patients who used a range of treatments and assessed the relation of a wide array of factors to satisfaction. Methods: One hundred four ET participants (age = 74.5 ± 10.2 years) completed a battery of self-report items. These included demographic information, measures of tremor and clinical history, psychological state, current ET treatment, and a series of questions about satisfaction with treatment. Results: Analyses of responses to the four current treatment satisfaction questions revealed that the proportion of participants who were satisfied ranged from 35.0% to 57.3% (i.e., approximately 1/3 to 1/2); conversely, the proportion who were dissatisfied ranged from 9.2% to 37.0%. The remainder were neutral. Higher satisfaction levels were observed in participants who were included in treatment selection and who had undergone deep brain stimulation surgery, p ’s

Abstract Parkinson’s disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [11C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [11C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [11C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions.

Abstract Objective Postmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have predominantly focused on cerebellar neuronal connections. Bergmann glial morphology has not yet been studied in essential tremor. Among their many roles, Bergmann glia in the cerebellar cortex ensheath Purkinje cell synapses and provide neuroprotection. Specifically, the complex radial processes and lateral appendages of Bergmann glia are structural domains that modulate Purkinje cell synaptic transmission. In this study, we investigate whether Bergmann glia morphology is altered in the essential tremor cerebellum. Methods We applied the Golgi‐Kopsch method and used computerized three‐dimensional cell reconstruction to visualize Bergmann glia in the postmortem cerebellum of 34 cases and 17 controls. We quantified morphology of terminal structures (number of terminations and lateral appendage density) and morphology of radial processes (total process length, branch length, branch order, and branch volume) in each glial cell. We quantified number of branches and volume as well. Results Essential tremor cases had a 31.9% decrease in process terminations and a 35.7% decrease in lateral appendage density in Bergmann glia. Total process length and branch length did not differ between essential tremor cases and controls. We found also a reduction in number of secondary and tertiary branches and tertiary branches volume. Interpretation These findings suggest that Bergmann glia in essential tremor cases have more alterations in their terminal structures, with a relative preservation of radial processes, and highlight a potential role for these astrocytes in the disease pathophysiology.

ObjectivesThe objective of this study was to study the interrelations of demoralization, depression, and resilience in patients with Parkinson disease, and, more specifically, to determine if higher resilience in patients with Parkinson disease is associated with lower demoralization, lower depression, or both.MethodsOutpatients with Parkinson disease (N = 95) were assessed for demoralization, depression, and resilience, as well as sociodemographic, clinical, and treatment-related variables. Bivariable associations, standard regressions, linear regression with copula correction, and correspondence analysis were used to analyze the data.ResultsAlthough the bivariable association between resilience and depression was statistically significant, the association ceased to be significant when demoralization was taken into consideration in both standard regressions and linear regression with copula correction. By contrast, the association between resilience and demoralization was significant when depression was not taken into consideration and continued to be significant when depression was taken into consideration. Correspondence analysis revealed that low resilience was strongly related to demoralization combined with depression, whereas normal resilience was closely correlated with depression without demoralization.ConclusionThese results expand our understanding of resilience by suggesting that it is a mechanism evolved to reduce or prevent demoralization and not just depression. Reducing demoralization and strengthening resilience as part of a comprehensive treatment plan are likely to improve the prognosis of Parkinson disease.

BackgroundAlthough essential tremor (ET) patients have greater odds of mild cognitive impairment (MCI) and dementia than age-matched controls, the functional consequences of these enhanced odds are unknown. We examined associations between cognitive diagnosis and the occurrence of near falls, falls, use of a walking aid or a home health aide, non-independent living, or hospitalizations within a prospective, longitudinal study of ET patients.MethodsA total of 131 ET patients (mean baseline age = 76.4 ± 9.4 years) completed a battery of neuropsychological tests and questions about life events and were assigned diagnoses of normal cognition (NC), MCI, or dementia at the baseline and at 18-, 36-, and 54-month follow-ups. Kruskall–Wallis, chi-square, and Mantel–Haenszel tests assessed whether the diagnosis was associated with the occurrence of these life events.ResultsPatients with final diagnoses of dementia were more often reported as living non-independently than NC or MCI patients and more often used walking aids than NC patients, with a p-value of MCI > NC).ConclusionCognitive diagnosis was associated with reported life events of ET patients, including the use of a mobility aid, employment of a home health aide, and removal from an independent living situation. These data provide rare insights into the important role cognitive decline plays in the experiences of ET patients.

Summary: Background: Essential tremor (ET), one of the most common neurological disorders, has a phenotypically heterogeneous presentation characterized by bilateral kinetic tremor of the arms and, in some patients, tremor involving other body regions (e.g., head, voice). Genetic studies suggest that ET is genetically heterogeneous. Methods: We analyzed whole genome sequence data (WGS) generated on 104 multi-generational white families with European ancestry affected by ET. Genome-wide parametric linkage and association scans were analyzed using adjusted logistic regression models through the application of the Pseudomarker software. To investigate the additional contribution of rare variants in familial ET, we also performed an aggregate variant non-parametric linkage (NPL) analysis using the collapsed haplotype method implemented in CHP-NPL software. Findings: Parametric linkage analysis of common variants identified several loci with significant evidence of linkage (HLOD ≥3.6). Among the gene regions within the strongest ET linkage peaks were BTC (4q13.3, HLOD=4.53), N6AMT1 (21q21.3, HLOD=4.31), PCDH9 (13q21.32, HLOD=4.21), EYA1 (8q13.3, HLOD=4.04), RBFOX1 (16p13.3, HLOD=4.02), MAPT (17q21.31, HLOD=3.99) and SCARB2 (4q21.1, HLOD=3.65). CHP-NPL analysis identified fifteen additional genes with evidence of significant linkage (LOD ≥3.8). These genes include TUBB2A, VPS33B, STEAP1B, SPINK5, ZRANB1, TBC1D3C, PDPR, NPY4R, ETS2, ZNF736, SPATA21, ARL17A, PZP, BLK and CCDC94. In one ET family contributing to the linkage peak on chromosome 16p13.3, we identified a likely pathogenic heterozygous canonical splice acceptor variant in exon 2 of RBFOX1 (ENST00000547372; c.4-2A>G), that co-segregated with the ET phenotype in the family. Interpretation: Linkage and association analyses of WGS identified several novel ET candidate genes, which are implicated in four major pathways that include 1) the epidermal growth factor receptor-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha-AKT serine/threonine kinase 1 (EGFR-PI3K-AKT) and Mitogen-activated protein Kinase 1 (ERK) pathways, 2) Reactive oxygen species (ROS) and DNA repair, 3) gamma-aminobutyric acid-ergic (GABAergic) system and 4) RNA binding and regulation of RNA processes. Our study provides evidence for a possible overlap in the genetic architecture of ET, neurological disease, cancer and aging. The genes and pathways identified can be prioritized in future genetic and functional studies. Funding: National Institutes of Health, NINDS, NS073872 (USA) and NIA AG058131(USA).

BackgroundFew longitudinal studies assess the progression of essential tremor (ET). One unexplored issue is whether tremor severity increases across time at a uniform rate. That is, does the observed rate of change in tremor severity within a particular patient remain constant or vary across time? This question of intra-individual differences is particularly important since it reflects a primary patient concern–will the nature of change I have seen to date be what I can expect in the future?MethodsET cases were enrolled in a prospective, longitudinal study. We selected 35 cases and assessed tremor severity via Bain and Findley ratings of Archimedes spirals assigned by a senior movement disorders neurologist. After reviewing both the change in spiral scores and the rate of change in scores, we identified five mutually exclusive patterns of severity change. We calculated the prevalence of each category using two complementary sets of classification criteria.ResultsLength of follow-up was 4.5 to 16.0 years, mean=10.2 years. Mean baseline tremor severity score was 4.6, SD=1.6. Depending upon the classification criteria used, the tremor scores of one-third to one-half of cases did not increase in a uniform fashion but were better described as demonstrating jumps and/or reversals in scores across time.ConclusionsWe document the nature of changes in ET tremor severity scores across a ten-year period via expert ratings of Archimedes spiral drawings. Such natural history data are valuable to patients and clinicians who hope to better understand and predict the likely course of ET symptoms.

ObjectivesThe objective of this study was to determine whether depression and anxiety are mediators between perceived stress and demoralization via a loss of the cognitive map to get out of the predicament manifesting as subjective incompetence.MethodsNinety-five consecutive outpatients with Parkinson's disease were evaluated for perceived stress, depression, anxiety, subjective incompetence, and demoralization using reliable and valid scales. Inclusion criteria were ages 40–90, intact cognition, and no current history of substance use. The setting was a Movement Disorders Clinic at a university-affiliated hospital. The outcome variable was demoralization, selected a priori. Mediators between perceived stress and demoralization were examined using path analysis.ResultsDepression, anxiety, and subjective incompetence were mediators between perceived stress and demoralization. Among all variables, subjective incompetence was the largest contributor to demoralization. Depression connected to demoralization indirectly via subjective incompetence (β = 0.25, p < 0.001), whereas anxiety bypassed subjective incompetence (β = −0.01, p = 0.882), connecting directly to demoralization (β = 0.37, p = 0.008).ConclusionEarly treatment and reversal of subjective incompetence and anxiety could potentially prevent the escalation of demoralization and the associated disruption in health-related quality of life and eventual suicide.

Abstract Objective Orthostatic tremor (OT) is an extremely rare, misdiagnosed, and underdiagnosed disorder affecting adults in midlife. There is debate as to whether it is a different condition or a variant of essential tremor (ET), or even, if both conditions coexist. Our objective was to use data mining classification methods, using magnetic resonance imaging (MRI)‐derived brain volume and cortical thickness data, to identify morphometric measures that help to discriminate OT patients from those with ET. Methods MRI‐derived brain volume and cortical thickness were obtained from 14 OT patients and 15 age‐, sex‐, and education‐matched ET patients. Feature selection and machine learning methods were subsequently applied. Results Four MRI features alone distinguished the two, OT from ET, with 100% diagnostic accuracy. More specifically, left thalamus proper volume (normalized by the total intracranial volume), right superior parietal volume, right superior parietal thickness, and right inferior parietal roughness (i.e., the standard deviation of cortical thickness) were shown to play a key role in OT and ET characterization. Finally, the left caudal anterior cingulate thickness and the left caudal middle frontal roughness allowed us to separate with 100% diagnostic accuracy subgroups of OT patients (primary and those with mild parkinsonian signs). Conclusions A data mining approach applied to MRI‐derived brain volume and cortical thickness data may differentiate between these two types of tremor with an accuracy of 100%. Our results suggest that OT and ET are distinct conditions.

Background: A recent consensus statement introduced the term “ET plus”. Although investigators have quantified the prevalence of ET plus in cross-sectional studies, patients with ET plus have not been tracked longitudinally; hence, there is no understanding of its stability over time.Methods: We present prospective, longitudinal phenotypic data on an ET cohort that was followed regularly at 18-month intervals (T1, T2, T3, T4) for up to 64 months. We assigned an ET or ET plus diagnosis to each case at each time interval.Results: There were 201 participants at baseline. The proportion with ET plus increased from 58.7% at baseline to 72.1% at T4 (p = 0.046). Of 172 (85.6%) who received a diagnosis of ET plus at one or more time intervals, the diagnosis was unstable (e.g., with reversion) in 62 (36.0%). We also assessed the stability of the clinical features of ET plus. Rest tremor was the most unstable clinical feature of ET plus; it was present in 59 participants, among whom it reverted from present to absent in 23 (39.0%). By contrast, for “memory impairment” (i.e., either mild cognitive impairment or dementia), the proportion who reverted from present to absent was only 21.3%.Conclusion: These data support our two a priori hypotheses: (1) the prevalence of ET plus would increase progressively, as it likely represents a more advanced stage of ET, and (2) the ET plus diagnosis would not be stable over time, as cases would fluctuate with respect to their phenotypic features and their assigned diagnoses.

Abstract Objective The pathogenesis of orthostatic tremor (OT) is unknown. We investigated OT‐related white matter changes and their correlations with scores from a neuropsychological testing battery. Methods Diffusion tensor imaging measures were compared between 14 OT patients and 14 age‐ and education‐matched healthy controls, using whole‐brain tract‐based spatial statistics analysis. Correlations between altered diffusion metrics and cognitive performance in OT group were assessed. Results In all cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language), OT patients’ cognitive performance was significantly worse than that of healthy controls. OT patients demonstrated altered diffusivity metrics not only in the posterior lobe of the cerebellum (left cerebellar lobule VI) and in its efferent cerebellar fibers (left superior cerebellar peduncle), but also in medial lemniscus bilaterally (pontine tegmentum), anterior limb of the internal capsule bilaterally, right posterior limb of the internal capsule, left anterior corona radiata, right insula, and the splenium of corpus callosum. No relationship was found between diffusion measures and disease duration in OT patients. Diffusion white matter changes, mainly those located in right anterior limb of the internal capsule, were correlated with poor performance on tests of executive function, visuospatial ability, verbal memory, and visual memory in OT patients. Interpretation White matter changes were preferentially located in the cerebellum, its efferent pathways, as well as in the pontine tegmentum and key components of the frontal–thalamic–cerebellar circuit. Further work needs to be done to understand the evolution of these white matter changes and their functional consequences.

Background: Individuals with essential tremor (ET), a common movement disorder, experience functional impairment, which contributes to burden experienced by their loved ones and caregivers. Some burdened caregivers report their loved ones as seeming debilitated or prematurely old, a concept that we have called enfeeblement. Using the Essential Tremor Enfeeblement Survey (ETES), we seek to characterize enfeeblement in elders with ET and assess its contribution to caregiver burden. Methods: We administered the ETES (range = 8–40, higher scores indicating more enfeeblement) and other scales to 98 caregivers of individuals with ET. Individuals with ET were also queried regarding tremors, cognitive abilities, and overall health. We then identified demographic and clinical correlates of ETES and modeled the contribution of ETES to caregiver burden (assessed using the Zarit 12-item Burden Interview [ZBI-12]). Results: Mean ETES score was 14.2 ± 6.2 (median = 12.0, range = 8.0–32.0); 26.5% of respondents endorsed at least one of the eight ETES items. Older age, greater tremor severity and disability, more functional and gait disability, more cognitive difficulty, and more depressive symptoms were associated with higher ETES scores. ETES was the strongest contributor to caregiver burden (ZBI-12) and substantially increased the variance explained in models of caregiver burden. Discussion: Enfeeblement seems to describe a previously unexplained component of caregiver burden in elders with ET. The presence of enfeeblement may contribute to greater burden and should be factored into assessments of patient and caregiver needs.

Background: The prevalence of dystonia varies worldwide. A prior report suggested a high prevalence of focal dystonia in the Faroese population, possibly reflecting a founder effect. During standardized neurological examination as part of an ongoing neuroepidemiologic study in the Faroe Islands, we noted an unusual phenomenon of thumb flexion during repetitive hand movements in a subset of subjects and sought to define its phenomenology. Methods: We requested commentary from a panel of dystonia experts regarding the phenomenology of the movements. These experts reviewed the videotaped neurological examination. Results: Among the experts, dystonia was the leading diagnosis. Alternate causes were considered, but deemed less likely. Discussion: Diagnosis of dystonia requires careful clinical assessment and consideration of associated features. We report a novel form of dystonia, not previously described to our knowledge, in this isolated population. Further studies of dystonia prevalence in the Faroe Islands are merited to characterize its burden in this population and its specific clinical characteristics.

Background: While accumulating evidence suggests that balance and gait impairments are commonly seen in patients with essential tremor (ET), questions remain regarding their prevalence, their relationship with normal aging, whether they are similar to the impairments seen in spinocerebellar ataxias, their functional consequences, and whether some ET patients carry greater susceptibility. Methods: We conducted a literature search (until December 2018) on this topic. Results: We identified 23 articles on gait or balance impairments in ET. The prevalence of balance impairment (missteps on tandem walk test) was seven times higher in ET patients than controls. Gait impairments in ET included reduced speed, increased asymmetry, and impaired dynamic balance. While balance and gait problems worsened with age, ET patients were more impaired than controls, independent of age. The pattern of impairments seen in ET was qualitatively similar to that seen in spinocerebellar ataxias. Balance and gait impairments resulted in greater number of near falls in ET patients. Factors associated with balance and gait impairments in ET included age, presence of tremor in midline structures, and cognitive dysfunction. Discussion: Accumulating evidence suggests that balance and gait impairments are common in ET patients and occur to a greater extent in controls. Thus, they represent a disease-associated feature. These impairments, which are qualitatively similar to those seen in spinocerebellar ataxias, are not merely subclinical but result in difficulty performing functional tasks and increase falls risk. A subset of patients is more susceptible to balance and gait impairments. The full spectrum of impairments remains to be characterized.

Background: Essential tremor (ET), one of the most common neurological diseases, is associated with cognitive impairment. Surprisingly, predictors of cognitive decline in ET remain largely unidentified, as longitudinal studies are rare. In the general population, however, lower physical activity has been linked to cognitive decline.Objectives: To determine whether baseline physical activity level is a predictor of cognitive decline in ET.Methods: One hundred and twenty-seven ET cases (78.1 ± 9.5 years, range = 55–95), enrolled in a prospective, longitudinal study of cognition. At baseline, each completed the Physical Activity Scale for the Elderly (PASE), a validated, self-rated assessment of physical activity. Cases underwent an extensive battery of motor-free neuropsychological testing at baseline, 1.5 years, and 3 years, which incorporated assessments of cognitive subdomains. Generalized estimating equations (GEEs) were used to assess the predictive utility of baseline physical activity for cognitive change.Results: Mean follow-up was 2.9 ± 0.4 years (range = 1.3–3.5). In cross-sectional analyses using baseline data, lower physical activity was associated with lower overall cognitive function as well as lower cognitive scores in numerous cognitive domains (memory, language, executive function, visuospatial function and attention, all p < 0.05). In adjusted GEE models, lower baseline physical activity level significantly predicted overall cognitive decline over time (p=0.047), and declines in the subdomains of memory (p = 0.001) and executive function (p = 0.03).Conclusions: We identified reduced physical activity as a predictor of greater cognitive decline in ET. The identification of risk factors often assists clinicians in determining which patients are at higher risk of cognitive decline over time. Interventional studies, to determine whether increasing physical activity could modify the risk of developing cognitive decline in ET, may be warranted.

The past 10 years has seen a remarkable advance in our understanding of the disease traditionally referred to as “essential tremor” (ET). First, the clinical phenotype of ET has been expanded from that of a bland, unidimensional, and monosymptomatic entity to one with a host of heterogeneous features. These features include a broader and more nuanced collection of tremors, non-tremor motor features (e.g., gait abnormalities) and a range of non-motor features, including cognitive, psychiatric, sleep, and other abnormalities. The natural history of these features, as well as their relationships with one another and with disease duration and severity, are better appreciated than they were previously. Studies of disease etiology have identified a number of candidate genes as well as explored several environmental determinants of disease. In addition, the decade has seen the beginnings and expansion of rigorous postmortem studies that have identified and described the postmortem changes in the brains of patients with ET. This emerging science has given rise to a new notion that the disease, in many cases, is one of cerebellar system degeneration. Across all of these studies (clinical, etiological, and pathophysiological) is the observation that there is heterogeneity across patients and that “essential tremor” is likely not a single disease but, rather, a family of diseases. The time has come to use the more appropriate terminology, “the essential tremors,” to fully describe and encapsulate what is now apparent. In this paper, the author will review the clinical, etiological, and pathophysiological findings, referred to above, and make the argument that the terminology should evolve to reflect advances in science and that “the essential tremors” is a more scientifically appropriate term.

Abstract Introduction Bradyphrenia is a key cognitive feature in Parkinson's disease (PD). There is no consensus on whether information processing speed is impaired or not beyond motor performance. Objective This study aims to explore which perceptual, motor, or cognitive components of information processing are involved in the slowdown affecting cognitive performance. Methods The study included 48 patients with PD (age: 63, 3 ± 8, 18; HY I‐III; UPDRS 15,46 ± 7,76) and 53 healthy controls (age: 60,09 ± 12,83). Five reaction time (RT) tasks were administered to all participants. The average RT in each of the tasks and the percentage of correct answers were measured. Patients with PD were in "ON state" at the time of the evaluation. Perceptual, motor, and cognitive components were isolated by means of a series of ANCOVAs. Results As expected, the motor component was slowed down in patients with PD. Moreover, while patients with PD showed slower RT than controls in all tasks, differences between groups did not exponentially increase with the increasing task complexity. ANCOVA analyses also revealed that the perceptual and sustained alert component resulted to be slowed down, with no differences being found in any of the remaining isolated cognitive components (i.e., response strategy‐inhibition, decisional, visual search, or interference control). Conclusions The results revealed that slowness of information processing in PD was mainly associated with an impaired processing speed of the motor and perceptual‐alertness components analyzed. The results may help designing new neurorehabilitation strategies, focusing on the improvement of perceptual and alertness mechanisms.

Background: Essential tremor (ET) encompasses a variety of features, including tremor, cognitive dysfunction, and gait and balance impairments. Gait and balance impairments in ET are often mild, but they can be severe and are, in some cases, associated with functional sequelae in terms of increased fall risk and reduced balance confidence. Previous research on gait and balance in ET has been limited to cross-sectional comparisons. There have been no longitudinal studies or prospective studies. As such, our understanding of natural history and possible predictors of declines in ET-related gait and balance impairments is incomplete.Objectives: We (1) present natural history data on the change in gait and balance measures over time, (2) provide estimates of annual rate of change in each gait and balance metric, and (3) examine the relationship between baseline clinical predictors and changes in gait and balance over time.Methods: 149 ET participants (mean age 78.7 years), enrolled in a prospective, longitudinal, clinical-pathological study, underwent an extensive evaluation of cognition, tremor, and gait and balance at three distinct intervals performed every 18 months. Gait and balance measures included a combination of performance-based tests (e.g., tandem gait, tandem stance) and self-reported assessments (e.g., number of falls, use of a walking aid).Results: Between the baseline and final assessments, numerous balance and gait measures showed evidence of decline and annual rates of change were quantified for each. We examined the predictive utility of clinical variables at baseline for five gait and balance outcomes, with global cognition and executive function standing out as the most consistent predictors.Conclusions: We present a much-needed look into the course of disease for elderly patients with ET, focusing on changes observed in gait and balance and the predictors of these changes. These results also add another dimension to the relevance of cognitive impairment observed in ET; such impairment can now be viewed as predictive of poorer gait and balance over time in ET. These findings are a useful tool for clinicians, patients, and their families to better understand and plan for changing disease-features over time.

Essential tremor (ET) is among the most prevalent neurological diseases. Appreciation in recent years of a richer tremor phenomenology, additional motor and non-motor features, variability in the natural course of tremor, associations with a host of other neurological conditions, and etiological and pathophysiological heterogeneity have resulted in general awareness of the clinical richness of ET. Along with this evolving view of ET have surfaced several conundrums regarding nomenclature. One of these is whether ET should be labeled a “syndrome” or “disease.” Here, we revisit the classical definitions of “syndrome” and “disease” and discuss ET in this context. Considering the characteristics of “disease” and “syndrome” and evaluating the characteristics of ET, it seems to fit more into the “disease” construct. There are several reasons: There is considerable knowledge of the underlying etiologies and pathophysiology of ET, in numerous studies ET has been linked with other neurological conditions, the condition is progressive and deteriorative, and therapeutic approaches are grounded in an understanding of disease mechanisms and its associated neuroanatomy. Moreover, the etiological–pathological–clinical heterogeneity suggests that ET should be regarded as a “family of diseases” more appropriately termed “the essential tremors.” This nomenclatural issue is not a mere matter of words; public health implications are numerous. A condition with the label “syndrome” may not be recognized as a serious problem, may be plagued by diminished public awareness, and may not garner funds for research that a condition with the label “disease” or “diseases” would. ET should be regarded as a family of diseases.

Background: Essential tremor (ET) cases often exhibit a range of mild cerebellar signs. Their unaffected relatives have been shown in prior studies to exhibit subtle (i.e., preclinical) disease features.Objective: To quantify subtle cerebellar signs in unaffected first-degree relatives of ET cases stratified based on their tremor severity.Methods: Two hundred sixty-nine first-degree relatives of ET cases, none of whom reported tremor or a diagnosis of ET, or were diagnosed with ET based on detailed neurological examination, were stratified based on total tremor score (TTS) into two groups (lower TTS vs. higher TTS) and quartiles. Changes in gait, balance, and intention tremor were quantified on neurological examination.Results: Higher TTS performed worse on the tandem stance task (p = 0.011). When stratified into TTS quartiles, higher quartile was associated with worse performance in tandem stance (p = 0.011) and stance with feet together (p = 0.028). Similarly, intention tremor in the arms (p = 0.0002) and legs (p = 0.047) were higher in the groups with more tremor.Discussion: The links between ET and the cerebellum are multiple. These data provide intriguing evidence that subtle cerebellar signs (i.e., changes in balance and intention tremor) are more prevalent among first-degree relatives of ET cases with more tremor (i.e., those who may be themselves on the pathway to developing ET). These data contribute to a better characterization of what may be an early subclinical stage of the disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the cause of the current pandemic coronavirus disease 2019 (COVID-19), primarily targets the respiratory system. Some patients also experience neurological signs and symptoms ranging from anosmia, ageusia, headache, nausea, and vomiting to confusion, encephalitis, and stroke. Approximately 36% of those with severe COVID-19 experience neurological complications. The virus may enter the central nervous system through the olfactory nerve in the nasal cavity and damage neurons in the brainstem nuclei involved in the regulation of respiration. Patients with cerebellar ataxia (CA) are particularly vulnerable to severe outcome if they contract COVID-19 because of the complexity of their disease, the presence of comorbidities, and their use of immunosuppressive therapies. Most CA patients burdened by progressive neurologic deficits have substantially impaired mobility and other essential functions, for which they rely heavily on ambulatory services, including rehabilitation and psychosocial care. Cessation of these interventions because of isolation restrictions places the CA patient population at risk of further deterioration. This international panel of ataxia experts provides recommendations for neurologists caring for patients with CA, emphasizing a pro-active approach designed to maintain their autonomy and well-being: continue long-term medications, promote rehabilitation efforts, utilize the technology of virtual visits for regular contact with healthcare providers, and pay attention to emotional and psychosocial health. Neurologists should play an active role in decision-making in those CA cases requiring escalation to intensive care and resuscitation. Multi-disciplinary collaboration between care teams is always important, and never more so than in the context of the current pandemic.

Introduction: The diagnosis of essential tremor (ET) remains a clinical one, and diagnostic errors are common. We aimed to (1) determine precisely how frequently ET diagnoses are misapplied (i.e., what percentage of patients who have been assigned an “ET” diagnosis actually have another movement disorder), (2) determine which other movement disorders are most often misclassified as “ET,” and (3) examine the clinical features that were most associated with diagnostic errors.Methods: One hundred four consecutive patients were included who met the following criteria: (1) initial outpatient evaluation by one of the authors (EDL) between January 2015 and December 2019 and (2) pre-evaluation diagnosis of ET. Data on an extensive number of clinical features were extracted from the electronic medical record.Results: Forty-seven (45.2%) patients received a post-evaluation diagnosis of ET, 29 (27.9%) of dystonia, and 28 (26.9%) of other diagnoses including Parkinson's disease (PD) [6 (5.8%)]. Factors associated with an alternative post-evaluation diagnosis other than ET were pre-evaluation diagnosis made by a non-neurologist, shorter tremor duration, irregular tremor, abnormal limb postures, among others.Discussion: Diagnosing ET remains a challenge, with the diagnosis being over-applied and being used as a “waste basket.” More than one-half of the patients who were referred to our clinic with an intake diagnosis of ET were given an alternative post-evaluation diagnosis. While PD was reported to be the most frequently missed diagnosis in a past study, dystonia was most commonly missed in our study. Several clinical features can help to differentiate ET from other tremor disorders.

Introduction: In many neurology residency programs, outpatient neurology subspecialties are underrepresented. Trainee exposure to these subspecialties, including movement disorders, is limited by paucity and variability of clinical experiences. We designed a structured educational tool to address this variability and allow for standardization of elements of movement disorders teaching. Methods: We designed and implemented a web-based curriculum in movement disorders for neurology housestaff, in order to improve participant knowledge. The curriculum includes an introduction with a structured framework for the description of abnormal movements and 10 interactive modules focusing on common movement disorders. The curriculum was piloted with nine neurology housestaff at Yale-New Haven Hospital. Evaluation of the curriculum was performed using pre- and post-tests, a survey, and semi-structured interviews. Results: The mean pre-test score was 0.7 (±0.19), and the mean post-test score was 0.95 (±0.05) (t = 3.27). Surveys demonstrated mean Likert values >4/5 for all questions in all categories (knowledge acquisition, quantity, enthusiasm and technical). Semi-structured interviews revealed the following themes: 1) the modules increased participant comfort with the topic, 2) the format was engaging, and 3) the curriculum accommodated different learning styles. All participants remarked that the structured framework was a particular strength. Conclusion: We have created, implemented, and evaluated a foundational curriculum in movement disorders for neurology trainees, using readily-available technology. Housestaff responded positively to the curriculum, both in terms of content and format. This curriculum can be implemented in a variety of educational settings, as a central component of a standardized approach to movement disorders teaching.

Introduction: Deficits in goal-directed behavior are common in individuals with Parkinson's disease (PD) and have been ascribed to apathy. In addition to apathy, individuals' beliefs in their competence (self-efficacy) and capacity to regulate emotions, thoughts, and actions (self-regulation) are critical skills for goal-directed behavior. We investigated these skills and their relationship to motor and non-motor symptoms in individuals with PD. We also examined the neural correlates of these skills using functional magnetic resonance imaging (fMRI). Methods: We enrolled 35 subjects with mild PD (Hoehn and Yahr stage ≤2.5) and used the new general self-efficacy (NGSES) and self-regulation scales (SRS). We correlated the scores on these scales with measures of cognition, anxiety, depression, apathy, fatigue, quality of life, and disease burden using stepwise regression analyses. We collected resting-state fMRI data in a 3-Tesla scanner and computed the pairwise functional connectivity among nodes of major networks. We correlated the connectivity maps with the NGSES and SRS scores. Results: Our PD cohort demonstrated intact NGSES and SRS scores compared with respective population data. These scores showed significant negative correlation with apathy and disease burden. Stronger connectivity in the salience network and decoupling from the default mode network supported self-efficacy and self-regulation. Conclusions: Self-efficacy and self-regulation capacity seems preserved, but vulnerable to disease-related factors in individuals with mild PD. Educational programs cultivating this capacity could improve the coping skills of these individuals. Functional connectivity changes in salience and default mode networks may serve as neurobiological markers to demonstrate the effectiveness of such interventions.

Background: The search for essential tremor (ET) genes is active, and it is only a matter of time before genetic tests become available. Genetic testing preferences in families have been studied in numerous other neurological disorders but there are no published data about ET. Methods: We surveyed 34 ET probands and their relatives (43 affected, 28 unaffected) enrolled in our Family Study of Essential Tremor to assess their interest in genetic testing. We examined whether clinical factors influenced their interest in testing. Clinical utility (“Your physician will be able to use the information obtained to improve your care”) and penetrance (“How likely an individual who carries an ET gene is to develop ET”) were defined for participants. Results: Interest in genetic testing was high in ET families (90/105 [85.7%]). There was a significant difference between affected (including probands and affected relatives) and unaffected relatives in terms of their interest in genetic testing, with the former being more interested (70/77 [90.9%] vs. 20/28 [71.4%] p = 0.04). Participants were more likely to want testing in the scenarios with high clinical utility; disease penetrance was not a determining factor (all p < 0.05). Sixteen hypothetical factors were identified that might influence a participant’s decision to undergo genetic testing for ET. Discussion: Interest in genetic testing was high in ET families. While genetic testing is not currently available for ET, the hunt for ET genes is ongoing, and this is a highly familial disorder. Understanding genetic testing preferences will greatly aid clinicians once a genetic test becomes available.

Background: Physical examination findings of dystonia are often underrecognized, especially in the setting of other movement disorders such as essential tremor (ET). Phenomenology Shown: A patient with ET exhibited numerous textbook features of cervical dystonia, which were misattributed to ET by a primary care physician and two neurologists. Educational Value: To provide a clear and unmistakable visual example of the clinically significant characteristics of cervical dystonia in the setting of concomitant ET.

Background: Research studies have shown an association between essential tremor (ET) and dementia, although dementia in ET is not often regarded as a clinically important issue. Phenomenology Shown: We present three tangible visual records of patients with ET who have developed concurrent, comorbid dementia. Educational Value: ET is a risk factor for dementia. This non-motor feature of the disease has substantial effects on the lives of patients and their families.

Background: Although the motor and non-motor features of essential tremor (ET) have been characterized in detail, it is not known whether ET patients suffer psychologically and whether those who are close to them consider them to be suffering in this way. Methods: Fifty ET patients and 50 “close others” (COs), identified by patients “as someone who knows you well and sees you often” and who can “provide a different perspective on your well-being”, reported their own depressive symptoms, daily stress, and perceptions of patient psychological suffering and patient overall suffering with validated scales. ET patients’ tremor severity, duration, disability, cognition, and number of medications were also assessed. Results: ET patients reported levels of psychological suffering within the range documented in arthritis and dementia patients from previous studies, and COs perceived significantly more psychological suffering in patients than patients reported themselves. Regression models, controlling for tremor severity, duration, and disability revealed that patients’ greater psychological suffering was associated with greater patient depression. The greater perceptions of COs of patient psychological and overall suffering were associated with greater CO depression and daily stress. Sensitivity analysis showed that patients’ cognitive status or number of medications did not affect the results. Discussion: Multidisciplinary teams caring for ET patients should look beyond simple clinical ET indicators. They should be aware of patient experiences and perceptions of COs of psychological and overall suffering. This will help guide the development of evidence-based, supportive interventions that improve communication about the needs of ET patients and those who are close to them.

Abstract Diffusion tensor imaging (DTI) studies have detected white matter microstructural changes in essential tremor (ET). However, it is still unclear whether these changes are related to cognitive deficits, which have been described in ET patients. DTI-derived fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity measures were compared between 23 ET patients and 23 age-, gender-, and education-matched healthy individuals, using whole-brain tract-based spatial statistics. Correlations of white matter changes with scores obtained from a detailed neuropsychological assessment were subsequently examined. ET patients demonstrated increases in MD in the bilateral posterior corona radiata, bilateral superior longitudinal fasciculus, bilateral fornix (cres)/stria terminalis, genu and splenium of the corpus callosum, bilateral anterior and posterior limbs of internal capsule, bilateral retrolenticular region part of internal capsule, and left posterior thalamic radiation. Except for the genu of the corpus callosum, an increase in AD values was also found in these same tracts. Furthermore, increased MD and AD values in different white matter areas was negatively correlated with performance on language and verbal memory and positively with visuospatial ability. These correlations suggest that white matter changes might be involved in the pathogenesis of cognitive deficits in ET.

Abstract Essential tremor (ET) is one of the most prevalent movement disorders. Being that it is a common disorder, its diagnosis is considered routine. However, misdiagnoses may occur regularly. Over the past decade, several studies have identified brain morphometric changes in ET, but these changes remain poorly understood. Here, we tested the informativeness of measuring cortical thickness for the purposes of ET diagnosis, applying feature selection and machine learning methods to a study sample of 18 patients with ET and 18 age- and sex-matched healthy control subjects. We found that cortical thickness features alone distinguished the two, ET from controls, with 81% diagnostic accuracy. More specifically, roughness (i.e., the standard deviation of cortical thickness) of the right inferior parietal and right fusiform areas was shown to play a key role in ET characterization. Moreover, these features allowed us to identify subgroups of ET patients as well as healthy subjects at risk for ET. Since treatment of tremors is disease specific, accurate and early diagnosis plays an important role in tremor management. Supporting the clinical diagnosis with novel computer approaches based on the objective evaluation of neuroimage data, like the one presented here, may represent a significant step in this direction.

Abstract Objectives In screening studies of Western patients with cerebellar dysfunction, FMR1 premutations have been detected. A screening study of East Asian patients with presumed essential tremor (ET) did not detect these mutations, possibly because the ET patients did not closely mimic the phenotype of fragile X‐associated tremor/ataxia syndrome (FXTAS). The aim of this study was to estimate the prevalence of FMR1 premutations in a carefully recruited group of ET patients with additional phenotypic features of FXTAS. Materials and Methods From April 2014 to April 2018, we prospectively recruited patients with ET diagnoses from three tertiary care centers. Demographic and clinical data were collected, as well as data on presence of cerebellar signs and extrapyramidal signs (EPS). Tremor, cerebellar signs, and EPS were evaluated using appropriate clinical rating scales. For ET patients with additional cerebellar signs or EPS, FMR1 mutation analysis and brain magnetic resonance imaging were performed. Results Six hundred and three ET patients were recruited. Cerebellar signs or EPS were present in 168 (27.9%) of 603. FMR1 CGG repeat analysis was performed in 74 of 168 patients. Fifty‐two of 74 had cerebellar signs only, three had EPS only, and 19 had both neurologic abnormalities. Two patients had a FMR1 premutation and fulfiled both clinical and radiological criteria of FXTAS. Conclusions Two (2.7%) of 74 patients with presumed ET and additional neurological features were discovered to have FXTAS. The possibility of FXTAS should be considered in patients with ET who exhibit mild cerebellar signs or EPS.

Objective: We (1) report whether a companion (i.e., spouse, relative, aide) accompanied our consecutive outpatients with a range of movement disorders, (2) identified the set of patient characteristics that was associated with the need for a visit companion, and (3) characterized the role(s) of these companions during the visit. Our overarching goals were to further understand patient needs and the extent of their support networks, and to enrich the clinician-patient interface.Methods: Two-hundred consecutive patients were enrolled from the Movement Disorders Clinic at Yale School of Medicine. We noted whether patients were accompanied by another person during the visit and documented the role of the visit companion during the encounter.Results: One-hundred-twenty-eight of 200 patients (64.0%) brought a companion, with these being spouses (44.8%), adult children (24.1%) or an aide, nurse or social worker (14.5%). Patients who were unemployed (odds ratio [OR] = 5.32, p = 0.019), had a diagnosis of Parkinson's disease or other Parkinsonian syndromes (OR = 10.61, p = 0.001), or were dependent in any instrumental activities of daily living (iADLs) (OR = 4.99, p = 0.005) or basic activities of daily living (bADLs) (OR = 5.81, p = 0.02), had increased odds of presenting to the clinical visit with a visit companion. Visit companions' main roles involved communication (86.7%) and transportation (84.4%).Conclusion: Visit companions were commonly present during movement disorders outpatient visits–two-thirds of patients were accompanied. A number of factors increased the odds of requiring such a companion by 4- or 5-fold.

Objective: Essential tremor (ET) is among the most common neurologic diseases. Although in the past it was considered a benign condition, recent research has demonstrated increased risk of mortality. To date, however, no studies have examined predictors of mortality in ET.Methods: In a longitudinal, prospective study of 141 elders with ET, we used Cox proportional-hazards models to estimate hazard ratios (HRs) for death.Results: The mean baseline age was 81.1 ± 8.8 years. During the follow-up interval, 27 (19.1%) died. Average time from baseline to death was 12.3 ± 8.7 months (range = 0.3–31.2). In univariate Cox regression models, older age (HR = 1.16, p < 0.001), lower Montreal Cognitive Assessment score (HR = 0.88, p = 0.004), higher Clinical Dementia Rating (CDR) score (HR = 4.53, p < 0.001), higher score on the Geriatric Depression scale (GDS) (HR = 1.07, p = 0.048), less balance confidence (HR = 0.98, p = 0.006), more falls (HR = 1.11, p = 0.003), and more tandem mis-steps (HR = 1.53, p = 0.004) were associated with increased risk of mortality. In the final multivariate Cox model, older age (HR = 1.14, p = 0.005), higher CDR score (HR = 3.80, p = 0.002) and higher GDS (HR = 1.11, p = 0.01) were independently associated with increased risk of mortality.Conclusions: This study highlights several independent predictors of mortality in elderly ET; clinicians should consider screening for depressive symptoms, assessing cognition and tracking CDR scores, and assessing balance while evaluating patients with ET.

Intentional movement is an internally driven process that requires the integration of motivational and sensory cues with motor preparedness. In addition to the motor cortical-basal ganglia circuits, the limbic circuits are also involved in the integration of these cues. Individuals with Parkinson’s disease (PD) have a particular difficulty with internally generating intentional movements and maintaining the speed, size, and vigor of movements. This difficulty improves when they are provided with external cues suggesting that there is a problem with the internal motivation of movement in PD. The prevailing view attributes this difficulty in PD to the dysfunction of motor cortical-basal ganglia circuits. First, we argue that the standard cortical-basal ganglia circuit model of motor dysfunction in PD needs to be expanded to include the insula which is a major hub within the limbic circuits. We propose a neural circuit model highlighting the interaction between the insula and dorsomedial frontal cortex which is involved in generating intentional movements. The insula processes a wide range of sensory signals arising from the body and integrates them with the emotional and motivational context. In doing so, it provides the impetus to the dorsomedial frontal cortex to initiate and sustain movement. Second, we present the results of our proof-of-concept experiment demonstrating that the functional connectivity of the insula-dorsomedial frontal cortex circuit can be enhanced with neurofeedback-guided kinesthetic motor imagery using functional magnetic resonance imaging in subjects with PD. Specifically, we found that the intensity and quality of body sensations evoked during motor imagery and the emotional and motivational context of motor imagery determined the direction (i.e., negative or positive) of the insula-dorsomedial frontal cortex functional connectivity. After 10–12 neurofeedback sessions and “off-line” practice of the successful motor imagery strategies all subjects showed a significant increase in the insula-dorsomedial frontal cortex functional connectivity. Finally, we discuss the implications of these results regarding motor function in patients with PD and propose suggestions for future studies.

Background: Mild and transient head tremor may sometimes be observed in otherwise tremor-free relatives of essential tremor (ET) cases, although its prevalence is unclear. A diagnostic question is whether this transient, isolated head tremor, often observed as no more than a wobble, is an early manifestation of ET or whether it is a normal finding. A direct comparison with controls is needed.Methods: Two hundred and forty-one first-degree relatives of ET cases (FD-ET) and 77 spousal controls (Co) were enrolled in a study of ET. Each underwent a detailed evaluation that included a tremor history and videotaped neurological examination. None of the enrollees reported tremor, had a prior diagnosis of ET, or had significant tremor on screening spirals. All videotaped examinations were initially reviewed by a movement disorder neurologist blinded to subject type, and among those with head tremor on examination, co-reviewed by two additional movement disorders neurologists.Results: Twenty-six (10.8, 95% Confidence interval [CI] = 7.5–15.3%) of 241 FD-ET vs. 2 (2.6, 95% CI = 0.7–9.0%) of 77 Co had isolated, transient head tremor (odds ratio = 4.54, 95% CI = 1.05–19.57, p = 0.04). No enrollee had significant upper extremity tremor and none met inclusion criteria for ET based on the presence of upper extremity tremor. With one exception, head tremor occurred during or after phonation. It was always transient (generally a single back and forth wobble) and rare (observed briefly on one or two occasions during the videotaped examination) and had a faster frequency, lower amplitude and a different quality than voluntary head shaking.Conclusion: The basis for the observed isolated head tremor is unknown, but it could be an early feature of ET in ET families.Indeed, one-in-ten otherwise unaffected first-degree relatives of ET cases exhibited such tremor. To a far lesser extent it was also observed in “unaffected” controls. In both, it is likely a sign of early, emerging, undiagnosed ET, although follow-up studies are needed to confirm this. If it were ET, it would indicate that the prevalence of ET may be considerably higher than previously suspected.

Objective: To investigate the prevalence of index finger pointing (IFP) while walking, which is likely a subtle form of hand dystonia, in cranio-cervical focal dystonia syndromes, Parkinson's disease (PD), essential tremor (ET), and controls.Methods: We recruited patients with an established diagnosis of PD, dystonia, or ET and healthy controls. All participants were videotaped while walking. Videotapes were evaluated by the authors, blinded to diagnosis, to assess the presence or absence of IFP.Results: Two-hundred-fifty participants included 50 dystonia, 50 PD, 80 ET and 70 controls. IFP was present in 29/250 (11.6%) participants: 10 dystonia (20.0%), 8 PD (16.0%), 8 ET (10.0%), and 3 controls (3.8%) (p = 0.03). There was a significant evidence of a trend in the odds of having this sign among disorders with higher risk of dystonic features (dystonia>PD>ET>control; test for trend = 0.004). Among the 180 patients (dystonia, PD, and ET, i.e., excluding the 70 controls), IFP was present in 26 (14.4% prevalence).Conclusion: IFP during gait, likely a subtle form of hand dystonia, was observed in 14.4% of movement disorder patients. The highest prevalence was in dystonia, the second highest in a disease that is often accompanied by dystonia (PD), a lower prevalence among individuals with a disease that is rarely accompanied by dystonia (ET), and the lowest in controls.

BackgroundEssential tremor (ET) is among the most common neurological diseases and it often runs in families. How knowledgeable ET patients and their families are about their disease has been the subject of surprisingly little scholarship.MethodsTo fill this gap in knowledge, we administered a comprehensive 32-item survey (i.e., questions about etiology, pathophysiology, symptoms and signs, natural history, and treatments) to 427 participants, including 76 ET probands, 74 affected relatives (AFRs), 238 unaffected relatives, and 39 spouses of unaffected relatives, all of whom were participating in two ET family studies. We hypothesized that there would be gaps in knowledge about ET and furthermore, that probands and AFRs would be the most knowledgeable, followed by unaffected relatives and then spouses of unaffected relatives, who would be the least knowledgeable.ResultsOverall, ET patients lacked knowledge about their disease. Nearly one-third of probands answered “yes” or “do not know” to the question, “is ET the same or different from the type of tremor that many normal people can get when they become old and frail?” A similar proportion did not know whether children could get ET or they responded “no.” Nearly one-fourth of affecteds (i.e., probands and AFRs) did not know whether or to what degree (e.g., very well, moderately well, not well) the symptoms of ET could be medically controlled, and 38.0% either reported that there was no brain surgery for ET or reported that they did not know. Nearly 17% of affecteds did not endorse genes as a cause for ET, which was surprising given the fact that this was a family study of ET. Probands and AFRs were the most knowledgeable, followed by unaffected relatives. Spouses of unaffected relatives were the least knowledgeable.ConclusionWe targeted a large group of ET patients and their families, as this group is perhaps most likely to be informed about the disease. ET patients and their AFRs were more knowledgeable about the features of ET than their family members without ET. Overall, however, knowledge of ET was very limited and this lack of knowledge encompassed all aspects of the disease including its underlying causes, the nature of the symptoms and signs, its natural history and its treatment. Further ET awareness education and programs targeting both families of ET patients and the public would help alleviate this gap in knowledge.

Background: Essential tremor (ET) can be profoundly disabling in severe cases; however, such cases may not often be encountered by general practitioners, primary care physicians, or general neurologists, leading to misdiagnosis. Phenomenology shown: Severe kinetic, postural, and intention tremors in patients with ET. Educational value: To provide visual examples of severe, long-standing ET for general practitioners, primary care clinicians, and general neurologists.

Background: The diagnosis of dystonia can be clinically challenging due to its heterogeneous presentation; essential tremor (ET) is a more common neurological disorder, but may be mimicked by other movement disorders, including dystonia, leading to misdiagnosis. Phenomenology Shown: In three patients with hand tremor, two with prior diagnoses of ET, we present examples of “spooning” of the hands, characterized by wrist flexion and metacarpophalangeal hyperextension. Educational value: Subtle dystonic features such as “spooning” may be present during the evaluation of patients with tremor and aid in the diagnosis of dystonia.

Background: Orthostatic tremor (OT), a rare and complex movement disorder, is characterized by rapid tremor of both legs and the trunk while standing. These disappear while the patient is either lying down or walking. OT may be idiopathic/primary or it may coexist with several neurological conditions (secondary OT/OT plus). Primary OT remains an enigmatic movement disorder and its pathogenesis and neural correlates are not fully understood.Methods: A PubMed search was conducted in July 2017 to identify articles for this review.Results: Structural and functional neuroimaging studies of OT suggest possible alterations in the cerebello-thalamo-cortical network. As with essential tremor, the presence of a central oscillator has been postulated for OT; however, the location of the oscillator within the tremor network remains elusive. Studies have speculated a possible dopaminergic deficit in the pathogenesis of primary OT; however, the evidence in favor of this concept is not particularly robust. There is also limited evidence favoring the concept that primary OT is a neurodegenerative disorder, as a magnetic resonance spectroscopic imaging study revealed significant reduction in cerebral and cerebellar N-acetyl aspartate (NAA) levels, a marker of neuronal compromise or loss.Discussion: Based on the above, it is clear that the pathogenesis of primary OT still remains unclear. However, the available evidence most strongly favors the existence of a central oscillatory network, and involvement of the cerebellum and its connections.

Background: Essential tremor (ET) is the most common tremor disorder. In addition to its hallmark feature, kinetic tremor of the upper limbs, patients may have a number of non-motor symptoms and signs (NMS). Several lines of evidence suggest that ET is a neurodegenerative disorder and certain NMS may antedate the onset of tremor. This article comprehensively reviews the evidence for the existence of a "premotor phase" of ET, and discusses plausible biological explanations and implications.Methods: A PubMed search in May 2017 identified articles for this review.Results: The existence of a premotor phase of ET gains support primarily from longitudinal data. In individuals who develop incident ET, baseline (i.e., premotor) evaluations reveal greater cognitive dysfunction, a faster rate of cognitive decline, and the presence of a protective effect of education against dementia. In addition, baseline evaluations also reveal more self-reported depression, antidepressant medication use, and shorter sleep duration in individuals who eventually develop incident ET. In cross-sectional studies, certain personality traits and NMS (e.g., olfactory dysfunction) also suggest the existence of a premotor phase.Discussion: There is preliminary evidence supporting the existence of a premotor phase of ET. The mechanisms are unclear; however, the presence of Lewy bodies in some ET brains in autopsy studies and involvement of multiple neural networks in ET as evident from the neuroimaging studies, are possible contributors. Most evidence is from a longitudinal cohort (Neurological Disorders of Central Spain: NEDICES); additional longitudinal studies are warranted to gain better insights into the premotor phase of ET.

BackgroundEssential tremor (ET) is associated with physical and cognitive impairments, as well as embarrassment, avoidance of social settings, and related difficulties that negatively impact the lives of patients. In similar disease contexts, burden on friends and relatives acting as caregivers has been noted and has well-documented implications. There has been no study examining caregiver burden related to ET.MethodsData were gathered from 55 ET participants enrolled in a clinical study and their caregivers. The Zarit Burden Interview was used to assess caregiver burden. To assess clinical features that may be associated with burden, we collected several variables including the Montreal Cognitive Assessment, self-reported tremor disability, a videotaped neurological examination, questionnaires assessing ET participants’ suffering, caregivers’ perceptions of that suffering, and both caregiver and ET participant depressive symptoms. Spearman’s correlations were performed between caregiver burden and clinical features, and we created a multivariate linear regression model predicting caregiver burden.ResultsMany ET caregivers provide little to no care and experience little to no burden. However, some caregivers (11%) provide over 25 h of care/week, and 13% experience high levels of burden. Caregivers most commonly provided assistance with writing and cooking. Increased burden was associated with the ET participants’ decreased cognition, more caregiving tasks, more hours/week of caregiving activities, a longer duration of care, more ET participant falls/year, more medications taken by the ET participant, and more depressive symptoms in both the ET participant and the caregiver (all p

Background: Although essential tremor (ET) is the most common tremor disorder, its pathogenesis is not fully understood. The traditional model of ET, proposed in the early 1970s, posited that the inferior olivary nucleus (ION) was the prime generator of tremor in ET and that ET is a disorder of electrophysiological derangement, much like epilepsy. This article comprehensively reviews the origin and basis of this model, its merits and problems, and discusses whether it is time to lay this model to rest. Methods: A PubMed search was performed in March 2017 to identify articles for this review. Results: The olivary model gains support from the recognition of neurons with pacemaker property in the ION and the harmaline-induced tremor models (as the ION is the prime target of harmaline). However, the olivary model is problematic, as neurons with pacemaker property are not specific to the ION and the harmaline model does not completely represent the human disease ET. In addition, a large number of neuroimaging studies in ET have not detected structural or functional changes in the ION; rather, abnormalities have been reported in structures related to the cerebello-thalamo-cortical network. Moreover, a post-mortem study of microscopic changes in the ION did not detect any differences between ET cases and controls. Discussion: The olivary model largely remains a physiological construct. Numerous observations have cast considerable doubt as to the validity of this model in ET. Given the limitations of the model, we conclude that it is time now to lay this model to rest.

BackgroundEssential tremor (ET) is not exclusively a tremor disorder; it is also associated with cognitive and gait dysfunction. However, a gap in knowledge is that the relationship between cognitive and gait dysfunction has not been studied in detail in ET. We examined the relationship between cognition and balance and falls in ET and hypothesized that cognitive dysfunction in ET patients would be associated with greater problems with balance and more falls.MethodsET cases were recruited into the Clinical–pathological Study of Cognition in ET. A comprehensive cognitive assessment was performed. This included the Montreal Cognitive Assessment (MoCA) to measure global cognition, multiple motor-free tests comprehensively assessing performance in each cognitive domain, and an assignment of Clinical Dementia Rating (CDR) scores. We collected data on the number of reported falls in the past year, and balance confidence was assessed using the 6-item Activities of Balance Confidence Scale. These cross-sectional analyses utilized baseline data.ResultsThere were 199 ET cases (mean age 78.6 years). In linear regression models that considered the effects of numerous confounding variables, lower global cognition (poorer cognition) was associated with greater number of falls and reduced balance confidence (p

Background: Tourette syndrome (TS) has been described as peaking in adolescence with subsequent regression. We report patients who were diagnosed with TS during childhood who experienced a latent period (significant reduction in or absence of tics) followed by tic re-emergence in adulthood.Methods: We performed a retrospective chart review of outpatients over age 21 seen at the Yale neurology clinic between January 2012 and July 2016 who were diagnosed with childhood-onset tics, and who experienced a latent period of greater than 1 year followed by an exacerbation.Results: Sixteen patients were identified. The mean latent period was 16 years. Ten patients (62.5%) identified an exacerbation trigger, most commonly changes in substance use (five patients). Seven patients (43.8%) reported worsening of tics since childhood. Six patients (37.5%) had received pharmacological intervention for tics as children, and 15 patients (93.8%) as adults. Six of 15 patients (40.0%) had an effective response from those pharmacological intervention(s).Discussion: Our study demonstrates that the decline in symptoms as patients age may represent temporary improvement. The latent period lasted years in our patients, different from the more rapid waxing and waning in children. A change in substance use was an important trigger. Requests for pharmacological intervention were not necessarily correlated with worsening tic severity.

Background: Classically, the onset of head tremor in essential tremor (ET) patients follows that of hand tremor, such that there is a somatotopic spread of involved areas. Here we present a series of seven self-reportedly “unaffected” relatives of ET cases. These seven were clinically asymptomatic and had normal levels of arm tremor on examination, yet each evidenced a transient head wobble on examination. We estimate the prevalence of this phenotype within the two studies from which cases were ascertained.Methods: ET cases and their self-reportedly affected and unaffected relatives, enrolled in two family studies, underwent a medical history and videotaped neurological examination.Results: In seven self-reportedly “unaffected” relatives, a transient and subtle head wobble was seen, always during sustained phonation, speech, or reading aloud. Total tremor score (a measure of arm tremor) ranged from 5 to 12 (i.e., mild tremor within the range of normal). The prevalence of this phenotype of early head tremor was 3.7% in one study and 23.1% in the other.Discussion: We present a series of seven individuals who had early head tremor in an evolving transition state from normal to ET. These cases raise a number of broad clinical, phenotypic, and pathophysiological issues about ET.