Baseline Depressive Symptoms as a Predictor of Incident Dementia in a Prospectively Followed Cohort of Elders with Essential Tremor.

BACKGROUND: Essential tremor (ET) patients may exhibit a variety of non-motor features, including cognitive decline and depressive symptoms. Studies of several neurodegenerative diseases link depression to cognitive decline, suggesting depression is an early marker of dementia. We examined whether baseline depressive symptoms predict incident dementia in elders with ET. METHODS: 141 ET cases age 70 or older at baseline, enrolled in a prospective study of cognitive performance, took part in evaluations at baseline, and at 18, 36, 54, and 72 months. Participants completed the Geriatric Depression Scale (GDS), a 30-item self-report measure of depressive symptoms, and a battery of neuropsychological tests and functional assessments, from which we derived cognitive diagnoses at each evaluation. We calculated Cox proportional hazards regression equations to determine incident dementia risk based on participants' baseline depression scores. RESULTS: Mean baseline age was 81.5 + 6.7 years. Higher baseline GDS scores were associated with increased risk of dementia in an unadjusted model (hazards ratio [HR] = 1.11, 95% confidence interval [CI] = 1.02 - 1.20, p = 0.01), and after controlling for baseline age, education, number of medications, and tremor onset age (HR = 1.13, 95% CI = 1.02 - 1.25, p = 0.02). CONCLUSION: Baseline depression scores predicted incident dementia in elders with ET. With each one-point increase in baseline depression score, there was a 13% increase in incident dementia risk. Given the published data that reported depression may be twice as high in elders with ET compared to controls,1 this association is particularly worrisome in the ET population.

Subjective Sleep Disturbance and Lewy Pathology: Data from a Cohort of Essential Tremor Brain Donors.

INTRODUCTION: Sleep disturbances have been associated with essential tremor (ET). However, their pathophysiological underpinnings remain unknown. In this exploratory study, we examined the association between subjective sleep disturbances and the presence of Lewy pathology (LP) on postmortem brain examination in ET cases. METHODS: Fifty-two ET cases enrolled in a prospective, longitudinal study were assessed over an average period of 42 months. Cases completed the Pittsburgh Sleep Quality Index (PSQI), which yields seven component scores (e.g., sleep quality, sleep latency). For each component score, we calculated the difference between the last score and the baseline score. Brains were harvested at death. Each had a complete neuropathological assessment, including extensive α-synuclein immunostaining. We examined the associations between baseline PSQI scores and the change in PSQI scores (last - first), and LP on postmortem brain examination. RESULTS: ET cases had a mean baseline age of 87.1 ± 4.8 years. LP was observed in 12 (23.1%) of 52 cases; in 7 of these 12, LP was observed in the locus coeruleus (LC). Change in time needed to fall asleep (last - first sleep latency component score) was associated with presence of LP on postmortem brain examination - greater increase in sleep latency was associated with higher odds of LP (odds ratio = 2.98, p = 0.02). The greatest increase in sleep latency was observed in cases with LP in the LC (p = 0.04). CONCLUSION: In ET cases, increases in sleep latency over time could be a marker of underlying LP, especially in the LC.

Prevalence of and Annual Conversion Rates to Mild Cognitive Impairment and Dementia: Prospective, Longitudinal Study of an Essential Tremor Cohort.

OBJECTIVE: Despite recent attention to cognitive impairment in essential tremor, few studies examine rates of conversion to diagnoses of mild cognitive impairment and dementia. Development of dementia in essential tremor is associated with loss of functional ability and a doubling of mortality rate. This prospective, longitudinal study comprehensively reports the prevalence and incidence of, and the annual rates of conversion to, mild cognitive impairment and dementia in an essential tremor cohort. METHODS: Patients underwent detailed cognitive assessments and were assigned diagnoses of normal cognition, mild cognitive impairment, or dementia. There were 222 patients at baseline (mean age = 79.3 ± 9.7 years), and 177 patients participated in follow-up evaluations at 18, 36, 54, and 72 months (mean years of observation = 5.1 ± 1.7). Data were compared to those of historical controls and Parkinson disease patients. RESULTS: The cumulative prevalence of dementia and average annual conversion rate of mild cognitive impairment to dementia were 18.5% and 12.2%, nearly three times higher than rates in the general population, and approximately one half the magnitude of those reported for Parkinson disease patients. The cumulative prevalence of mild cognitive impairment (26.6%) was almost double that of the general population, but less than that in Parkinson disease populations. INTERPRETATION: We present the most complete exposition of the longitudinal trajectory of cognitive impairment in an essential tremor cohort yet presented. The prevalence of and conversion rates to dementia in essential tremor fall between those associated with the natural course of aging and the more pronounced rates observed in Parkinson disease. ANN NEUROL 2024;95:1193-1204.

WHIGET and TETRAS Ratings of Action Tremor in Patients with Essential Tremor: Substantial Association and Agreement.

Background: Evaluating tremor severity is a critical component of diagnosing and clinically managing patients with essential tremor (ET). We examined the comparability of tremor severity ratings derived from two frequently used tremor rating scales: the Washington Heights-Inwood Genetic Study of Essential Tremor (WHIGET) rating scale and the Tremor Research Group Essential Tremor Rating Scale (TETRAS). Methods: A trained assistant administered and videotaped a neurological examination, including eight items assessing upper limb action tremor (arms outstretched, arms in the wingbeat position, finger-nose-finger maneuver, and drawing of Archimedes spirals). An experienced movement disorders neurologist reviewed the videos and assigned WHIGET and TETRAS ratings. We calculated associations between TETRAS and WHIGET ratings using Spearman rank order correlations. Subsequently, we collapsed these ratings into four tremor severity categories (absent, mild, moderate, severe) and then two broader tremor severity categories (absent/mild, moderate/severe). We calculated weighted Kappa coefficients to assess agreement between category assignments based on the TETRAS and the WHIGET. Results: Spearman's r' s were significant for all items (p's ≤ 0.001, mean r = 0.89). Weighted Kappa's revealed substantial to near perfect agreement for all eight items (mean k = 0.86, range = 0.64 to 1.00). Conclusion: Analyses revealed substantial strength of association and substantial to near perfect agreement between items rated with the WHIGET and TETRAS scales. These data indicated that ratings provided by each scale are highly comparable.

Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial.

Importance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. Design, Setting, and Participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. Main Outcome and Measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Conclusions and Relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02932475.

A prospective cohort study of familial versus sporadic essential tremor cases: Do clinical features evolve differently across time?

BACKGROUND: Although essential tremor (ET) is often divided into familial and sporadic cases, few data compare the evolution of clinical features in these groups over time. Leveraging data from a prospective, longitudinal study, we present analyses of the evolution of a broad range of cognitive, motor (i.e., tremor, tandem gait) and other features (e.g., disability) of ET. METHODS: Sixty-six familial and 23 sporadic ET cases completed in-home evaluations at baseline and 18, 36, and 54-month follow-ups. Assessments included detailed neuropsychological testing and videotaped neurological examinations. Analyses compared the longitudinal course of 16 clinical features in familial and sporadic cases. RESULTS: Baseline mean age was 75.2 ± 8.8 years and mean observation period was 4.7 ± 0.3 years. Tremor onset age was lower and childhood onset more common in familial than sporadic cases (p's = 0.02). Longitudinal analyses revealed no significant differences between clinical features displayed by familial and sporadic cases, or differences between the patterns of change in clinical features observed in these groups across time. Sporadic cases' daily activity skills declined significantly, whereas familial cases' did not, p's = 0.04 and 0.34, respectively; however, this finding was non-significant when controlling for false discovery rate. Several additional non-significant trends were noted. CONCLUSION: Familial and sporadic ET cases differed in onset age, and in the prevalence of childhood tremor onset. Although a number of interesting trends were observed, no significant differences in the evolution of clinical features over time in patients with and without a family history of ET were revealed.

Stigma and Social Avoidance in Adults with Essential Tremor.

Background: People with essential tremor (ET) can be subject to stigma, and some adopt avoidance behaviors. Characteristics associated with ET stigma and the relationship between perceived stigma and social dysfunction have not been studied. Objectives: To discern predictors of perceived stigma and social dysfunction in ET, and to identify potentially treatable psychological factors associated with social dysfunction. Methods: We surveyed ET patients (n = 158) on recalled stigma incidents and social dysfunction related to tremor, as well as clinical and demographic characteristics including tremor severity, and psychological constructs including anxiety, depression, mindfulness, resilience, and narcissism. Results: Worse tremor severity (Standardized beta [SB] 1.4, P < 0.001) especially among younger participants (interaction of age and tremor severity SB -0.9, P < 0.001) and presence of vocal tremor (SB 0.7, P = 0.002) predict perceived stigma. 53/157 (33.8%) participants met criteria for social dysfunction, employing maladaptive avoidance strategies. Scores for perceived stigma (Odds Ratio [OR] 1.2, P = 0.002), depression (OR 1.5, P = 0.004) and stigma psychological distress (OR 1.2, P = 0.001) as well as sex (OR 4.3 for females, P = 0.045) predicted social dysfunction. Conclusions: Depression and stigma psychological distress contribute to social dysfunction related to ET stigma. Treating these psychological factors may mitigate social avoidance behaviors prevalent among susceptible individuals: those who most perceive ET stigma, i.e. relatively younger patients with worse tremor or with vocal tremor, and in particular females who are more prone to social dysfunction than males with the same degree of perceived stigma.

Association between cognitive diagnosis and a range of significant life events in an elderly essential tremor cohort: a longitudinal, prospective analysis.

Background: Although 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. Methods: A 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. Results: Patients 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 <0.05. Patients with a final MCI or dementia diagnosis more often employed a home health aide than NC patients, with a p-value of <0.05. Moreover, Mantel-Haenzsel tests revealed linear associations between the occurrence of these outcomes and the level of cognitive impairment, with a p-value of <0.001 (i.e., dementia > MCI > NC). Conclusion: Cognitive 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.

Medicaid coverage practices for approved gene and cell therapies: Existing barriers and proposed policy solutions.

The current Medicaid system is ill equipped to handle the anticipated approvals of new gene and cell therapy products. These advanced therapies tend to be single-dose, potentially durable options for a variety of indications spanning oncology, rare disease, and more. The up-front cost of these therapies contrasts with chronic care treatment, which may incur cost over the life of a patient. The cost of these innovative treatments, along with the anticipated larger patient pools, can limit patient access as Medicaid programs operate on limited or fixed budgets. Given the value of these therapies for diseases that may have large Medicaid populations, the system will need to grapple with the existing barriers to access to ensure equitable patient care. This review focuses on one such barrier, discrepancies between product indications and state Medicaid and Medicaid Managed Care Organization coverage policies, and it proposes federal policy solutions to this barrier to better accommodate the exponential growth of the gene and cell therapy pipeline.

Associations between cognitive function and a range of significant life events in an elderly essential tremor cohort study.

BACKGROUND: Although essential tremor (ET) is associated with cognitive decline, we know little about how specific cognitive changes predict significant events in patients' lives. We examined the relations of attention, executive function, language, memory, and visuospatial performance to the occurrence of near falls, falls, walking aid use, home health aide use, non-independent living and hospitalizations within a prospective, longitudinal study of ET cases. We expected executive function and memory to be most strongly associated with these events. METHODS: 131 ET cases (mean age at baseline = 76.4 ± 9.4 years; 109 normal cognition; 17 mild cognitive impairment, 5 demented) completed questionnaires (clinical history and occurrence of life events) and a battery of neuropsychological tests at baseline and at 18, 36, and 54 months. We assessed associations between cognitive functioning and outcomes via regression equations. RESULTS: Cases with lower baseline levels of executive function reported more near falls, p < 0.006, and were more likely to use a walking aid, p < 0.03, odds ratio (OR) = 2.89 during the follow-up period, than were other cases. Decline in executive function was associated with home health aide use during follow-up, p < 0.04, OR = 3.34. Baseline visuospatial performance also bore a marginally significant association with non-independent living arrangements during follow-up, p < 0.06, OR = 2.13. These effects were independent of age and tremor severity. CONCLUSION: These data establish the important role that cognitive decline, and executive function specifically, play in the experiences of ET patients. Moreover, these associations are of sufficient magnitude to have significant clinical implications.

Conversion Rate of Essential Tremor to Essential Tremor Parkinson Disease: Data From a Prospective Longitudinal Study.

Background and Objectives: There has been a long-standing dialog as to whether essential tremor (ET) increases the risk of developing Parkinson disease (PD). While there are relevant cross-sectional data, there are almost no longitudinal prospective data. We quantified the conversion rate from ET to ETPD in a prospective longitudinal cohort study of patients with ET. We compared the observed rate with that reported in the epidemiologic literature. Methods: We enrolled patients with ET in a prospective, longitudinal study. A senior movement disorders neurologist evaluated standardized neurologic examinations every 18 months. Results: One hundred ninety-three patients with ET (mean age = 78.1 ± 9.6 years, range = 55-96) had a mean follow-up duration of 4.1 years. Seven (3.6%) converted from ET to ETPD. The incidence of PD among patients with ET was 7/792.9 person-years (py; i.e., 882.8/100,000 py). A meta-analysis of the incidence (per 100,000 py) of PD in 14 studies from 13 countries across 4 continents reported an incidence of PD = 61.21 (men, 40 years or older) and 37.55 (women, 40 years or older). The incidence/100,000 py in men peaked in the 80- to 89-year-old age group (258.47) and in women in the 80- to 89-year-old age group (103.48 py). The abovementioned published values are 3.4-23.5 times lower than the value we observed for ET. Discussion: The incidence of PD in an ET cohort is substantially higher than that reported in historical population-based control groups across numerous countries. Additional prospective longitudinal data are needed to further explore this association.

Cognitive Performance as a Function of MAPT Haplotype: A Prospective Longitudinal Study of an Essential Tremor Cohort.

Background: Cognitive impairment is a feature of essential tremor (ET). There are no studies of the genetic drivers of this association. We examined whether the microtubule-associated protein tau (MAPT) H1 haplotype is associated with cognitive performance in ET. Methods: ET cases genotyped for the MAPT H1 and H2 haplotypes completed a battery of neuropsychological tests at baseline and four follow-up evaluations. Chi-square, t-tests, and analyses of covariance examined associations between the presence of the MAPT H1 haplotype, cognitive diagnoses of normal, mild cognitive impairment (MCI), and dementia, and performance in specific cognitive domains. Results: We observed no evidence of cognitive differences as a function of the presence of the MAPT H1 haplotype. Specifically, cases with (n = 57) and without (n = 42) this haplotype did not differ with respect to the prevalence of diagnoses of MCI or dementia, p ≥ 0.87. Moreover, cases with vs without this haplotype did not differ in either the age or point in the disease course at which observed conversions to MCI or dementia occurred, p's ≥ 0.51. Finally, no haplotype-related differences were observed in performance in the cognitive domains of attention, executive function, language, memory, visuospatial or global ability, p's ≥ 0.21, or in changes in performance in these domains across time, p's ≥ 0.08. Discussion: The study in an ET cohort revealed no influence of MAPT haplotypes on cognitive performance. This study serves as a valuable foundation for future studies to expand our understanding of the genetic drivers of cognitive impairment in ET. Highlights: This study found no evidence of cognitive differences between individuals with and without the MAPT H1 haplotype. Our work provides a valuable foundation for future work to expand our knowledge of the genetic drivers of cognitive impairment in ET.

Limb positioning and magnitude of postural tremor ratings: A study of 100 essential tremor cases.

BACKGROUND: Essential tremor (ET) is a highly prevalent movement disorder. As the diagnosis is purely clinical, it is important for clinicians to develop a reliable taxonomy of signs and symptoms of ET. Here, we investigate two common clinical maneuvers for determining the presence and severity of postural tremor in ET cases: the evaluation of tremor observed when arms are held in the outstretched and wing posture positions. METHODS: Two movement disorders neurologists assessed tremor severity from videotaped neurological evaluations of 100 ET cases displaying outstretched and wing posture positions. These raters also completed a forced choice measure indicating whether upper limb tremor was more severe in the outstretched position, the wing posture position, or equivalent in the two positions. RESULTS: Our raters judged tremor observed in the wing posture position to be more severe than tremor observed in the outstretched position (average ratings of 1.17 and 1.03, respectively, p's <0.05). This finding replicated across the two independent neurologists' ratings of tremor severity. Analyses of the forced choice measure revealed parallel results, with tremor observed in the wing posture position more often identified as more severe than tremor observed in the outstretched position (37.5% versus 14.5%, respectively, p < 0.05). CONCLUSION: Our data reveal that ET cases generally display more severe upper limb tremor in the wing posture position than in the outstretched position. These findings having potential clinical and research implications, suggesting that postural tremor in ET may be more easily identified from observations of the wing posture than the outstretched position.

Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Brain Donation Decisions as Disease Specific Behaviors: An Elucidation of the Donation Process in the Context of Essential Tremor.

Brain donation is a challenging process, comprising four sequential stages: (1) the brain donation decision, (2) pre-mortem arrangements and follow up, (3) specimen collection and (4) tissue processing. It is important to understand the factors that are pertinent to each stage. Currently, there is extensive information on factors that involve donor's personal and cultural backgrounds and how these could affect the process. However, little is known about disease-specific factors that influence the process. The Essential Tremor Centralized Brain Repository was established in 2003, and after nearly 20 years of collecting essential tremor (ET) brain tissue, we are well-positioned to discuss the brain donation process from a disease-specific standpoint. In the current manuscript, we discuss ET disease-specific factors that influence the first two stages of the brain donation process. We center our discussion around three points: (1) factors that influence the patient's decision to donate, (2) the involvement of next of kin in the donation, and (3) the rationale for enrolling patients prospectively and evaluating them longitudinally before the anatomical gift takes place. This discussion shares our understanding of the background from which our repository operates and may be of value for other brain banks that study similar neurodegenerative diseases.

Prospective, longitudinal analysis of medication use in a cohort of elderly essential tremor cases.

BACKGROUND: There are no prospective, longitudinal studies investigating patterns of medication use among essential tremor (ET) patients. Our goal was to fill this knowledge gap. We also had a unique opportunity to examine medication use patterns primarily among elders with longstanding ET. We hypothesized that by the time ET patients reach advanced ages, medication changes would be uncommon - that is, they may have reached some kind of equipoise. METHODS: A prospective, longitudinal cohort of ET cases was evaluated across three time points. Cases were not ascertained from a treatment setting, thereby removing important selection biases. Each reported current medications and dosages of each. RESULTS: There were 144 cases (mean baseline age = 76.1 ± 9.4 years). The mean observation period = 2.9 ± 0.2 years. Primidone and propranolol were the most commonly used medications, although almost one-half of cases (44.4%) reported using neither during this period. A third of primidone users (33.3%) and a quarter of propranolol users (24.6%) reported changes in use vs. nonuse during the observation period. The majority of our cases made some change in their daily medication dosage during the course of the study - 73.3% of primidone users and 57.9% of propranolol users. CONCLUSION: In this prospective, longitudinal study, use vs. nonuse and daily dosage of both primidone and propranolol fluctuated across time for a sizable proportion of ET cases. Even among elders with chronic, longstanding ET, there is considerable ongoing medication adjustment, underscoring the need to improve the medication situation for ET patients.

Distribution of rest tremor in patients with Essential Tremor: Does it lateralize with simple kinetic, postural, or intention tremors?

BACKGROUND: Essential tremor (ET) is characterized by action tremor, although rest tremor may also occur. Despite this, rest tremor has not been studied extensively. A dearth of studies compare the relationship of rest tremor to other types of tremors in ET. METHODS: Two-hundred-and-thirteen ET cases underwent detailed neurological examination, including evaluations of rest, simple kinetic, postural, and intention tremors. A movement disorders neurologist assessed the prevalence of each type of tremor. Each instance of tremor was classified as either symmetrical (present and equally severe on both sides of the body) or asymmetrical (only present on or more severe on one side of the body). Asymmetrical rest tremor that co-occurred with other types of asymmetrical tremors in a given case was further classified as either concordant (i.e., asymmetry on the same side of the body) or discordant (i.e., asymmetry on opposite sides of the body). Chi-square analyses examined the prevalence of concordant versus discordant pairings. RESULTS: Sixty-two cases (29.2%) had rest tremor while seated. Fifteen (7.4%) had rest tremor while standing. Among asymmetric tremor pairings, concordant pairings occurred 2-2.7 times more frequently than discordant pairings - for pairings involving rest tremor while seated, 73.2% were concordant and 26.8% discordant (p < 0.001); for pairings involving rest tremor while standing, 66.7% were concordant and 33.3% were discordant (p = 0.25). CONCLUSIONS: Rest tremor often lateralized with other tremor types. These data add to our knowledge of the phenotypic manifestations of ET.

Lack of Familial Aggregation of the "Essential Tremor-Plus" Phenotype in Familial Essential Tremor.

BACKGROUND: Essential tremor (ET) is a highly prevalent neurological disease that frequently runs in families. A recent and controversial proposal is to separate ET patients into two distinct groups - ET versus ET-plus. If this were a valid construct, one would expect in familial aggregation studies to observe that ET-plus would cluster in some families yet be absent in others, rather than being randomly distributed across families. We examined whether there is evidence of familial aggregation of ET-plus. METHODS: Probands (n = 84 [56 ET-plus and 28 ET]) and their first- and second-degree relatives (n = 182 and 48) enrolled in a genetics study. χ2 and generalized estimating equations (GEE) tested associations between probands' ET-plus status and the ET-plus status of their relatives. RESULTS: χ2 analyses revealed that ET-plus was no more prevalent in relatives of probands diagnosed with ET-plus than in relatives of probands diagnosed with ET, p > 0.05. Restricting relatives to first-degree relatives similarly did not detect a significant association (p = 0.88). GEE yielded similar results (respective p's = 0.39 and 0.81). CONCLUSION: The data demonstrate that ET-plus does not seem to aggregate in families. As such, they do not lend support to the notion that ET-plus is a valid biological construct.

Longitudinal Progression of Essential Tremor: Do Tremor Severity Scores Increase at a Uniform Rate?

Background: Few 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? Methods: ET 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. Results: Length 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. Conclusions: We 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.