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.

Updates in essential tremor.

Essential tremor (ET) is one of the most common tremor disorders and can be disabling in its affect on daily activities. There have been major breakthroughs in the treatment of tremor and ET is the subject of important ongoing research. This review will present recent advancements in the epidemiology, genetics, pathophysiology, diagnosis, comorbidities, and imaging of ET. Current and future treatment options in the management of ET will also be reviewed. The need for continued innovation and scientific inquiry to address the unmet needs of persons of ET will be highlighted.

Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China.

BACKGROUND: Essential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown. METHOD: We investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022. RESULT: We found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions. CONCLUSION: Tremor can be the initial phenotype of certain SCA. For early-onset, familial ET patients, careful physical examinations are needed before genetic SCA screening.

Treatment patterns in essential tremor: Real-world evidence from a United Kingdom and France primary care database.

BACKGROUND AND PURPOSE: Essential tremor (ET) is one of the most common neurological disorders, but information on treatment pattern is still scant. The aim of this study was to describe the demographic and clinical characteristics, treatment patterns, and determinants of drug use in patients with newly diagnosed ET in France and the United Kingdom. METHODS: Incident cases of ET diagnosed between January 1, 2015 and December 31, 2018 with 2 years of follow-up were identified by using The Health Improvement Network (THIN®) general practice database. During the follow-up, we assessed the daily prevalence of use and potential switches from first-line to second-line treatment or other lines of treatment. Logistic regression models were conducted to assess the effect of demographic and clinical characteristics on the likelihood of receiving ET treatment. RESULTS: A total of 2957 and 3249 patients were selected in the United Kingdom and France, respectively. Among ET patients, drug use increased from 12 months to 1 month prior the date of index diagnosis (ID). After ID, nearly 40% of patients received at least one ET treatment, but during follow-up drug use decreased and at the end of the follow-up approximately 20% of patients were still on treatment. Among treated patients, ≤10% maintained the same treatment throughout the entire follow-up, nearly 20% switched, and 40%-75% interrupted any treatment. Results from the multivariate analysis revealed that, both in France and the United Kingdom, patients receiving multiple concomitant therapies and affected by psychiatric conditions were more likely to receive an ET medication. CONCLUSION: This study shows that ET is an undertreated disease with a lower-than-expected number of patients receiving and maintaining pharmacological treatment. Misclassification of ET diagnosis should be acknowledged; thus, results require cautious interpretation.

The Spectrum of Non-Parkinsonian Tremor: A Registry at a Tertiary Care Teaching Institute.

Background: Tremors other than those associated with Parkinson's disease (non-parkinsonian tremor) are commonly observed in clinical settings. However, their frequency and clinical characteristics have rarely been reported. Objectives: To classify non-parkinsonian tremors based on the consensus statement on the classification of tremors, from the task force of the International Parkinson and Movement Disorder Society published in 2018. Methods: A prospective registry at a tertiary care teaching institute. Results: A total of 475 patients with non-parkinsonian tremors were recruited for the study. 67.57% (n = 321) of our patients were male and a family history of tremor was present in 20.84% (n = 99) of patients. Dystonic tremor (DT) was the most common non-parkinsonian tremor (33.26%). 27.78% of patients fulfilled the new classification criteria for essential tremor, with 13.47% classified as pure ET (ET) and 14.31% exhibiting neurological soft signs, leading to the classification of ET plus (ETP). Patients with ETP had more family history (57.35%) [vs DT (26.48%, p = 0.00004) and ET (10.93%, p = 0.00003], longer duration of disease [mean ± standard deviation (SD) = 9.53 ± 8.64 years] [vs DT (5.60 ± 5.93, p = 0.0003) and ET (6.38 ± 5.97, p = 0.01) years], and more severe tremor as measured by the essential tremor rating assessment scale total score [mean ± SD = 27.42 ± 11.70] [vs DT (23.50 ± 8.62, p = 0.007) and ET (22.12 ± 8.19, p = 0.007)] compared with patients with DT and ET. Conclusions: DT was the most common cause of non-parkinsonian tremor in our registry followed by essential tremor syndrome. ETP was more common than ET.

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.

Odds of Medical Comorbidities in Essential Tremor: Retrospective Analysis of a Large Claims Database in the United States.

INTRODUCTION: Essential tremor (ET) is the most common tremor disorder, estimated to affect 7 million individuals in the USA. There is little empirical evidence on comorbidities among this population beyond higher prevalence of brain-related and stress-related disorders. This study aims to examine differences in the prevalence of the 31 Elixhauser comorbidities among ET patients compared to statistically similar control patients. METHODS: An extract from Optum's de-identified Clinformatics® Data Mart Database (CDM) from 2018 to 2019 of adults aged 40-80 years with at least one claim with an ET diagnosis was propensity score matched to controls. Logistic regression was used to generate doubly robust adjusted odds ratios for each of the 31 Elixhauser comorbidities. RESULTS: In these analyses, ET patients had significantly greater adjusted odds of depression, alcohol abuse, and other neurological disorders, as well as chronic pulmonary disease, renal failure, hyperthyroidism, and cardiac arrhythmias relative to controls. They also had lower odds of uncomplicated diabetes, congestive heart failure, metastatic cancer, paralysis, peripheral vascular disease, and fluid and electrolyte disorders. CONCLUSION: A number of recent studies, including our own, suggest that psychiatric, neurologic, and stress-related disorders may be more prevalent among ET patients than controls. Additional differences in the prevalence of a range of medical comorbidities have also been variably reported across studies, suggesting that some combination of these might be more prevalent. Further studies would be of value in sorting through these associations.

Reliability of Self-Report Data on Age of Onset in Essential Tremor: Data from a Prospective, Longitudinal Cohort.

BACKGROUND: Essential tremor (ET) is a highly prevalent neurological disease. Age of onset can occur anytime between childhood and advanced age. Tremor generally starts insidiously. Age of onset is a particularly important data item in clinical and epidemiological research. In general, these data are self-reported by ET cases. A fundamental question is whether ET cases reliably report their age of onset. METHODS: In this prospective, epidemiological study of 125 ET cases, self-reported age of onset data were collected at regular 18 months intervals over four time points. RESULTS: The correlation between self-reported age of onset was high - intra-class correlation coefficient = 0.972 (95% confidence interval = 0.962-0.980, p < 0.001). However, agreement was not perfect. Approximately 20-25% of participant's reports at different time intervals differed by as much as 10 years, and approximately 10% of participant's reports differed by as much as 20 years. CONCLUSIONS: There was a robust correlation between self-reports of age of onset. Yet in a not-insignificant number of cases, there were considerable differences, some of which were substantial. These findings have broad implications for development of diagnostic algorithms, data stratification schemes, and analyses that assess correlations between biomarker data and clinical features (e.g., disease duration).

The Hidden Burden of Disease and Treatment Experiences of Patients with Essential Tremor: A Retrospective Claims Data Analysis.

INTRODUCTION: Essential tremor (ET) affects approximately 7 million people in the USA, yet public recognition of the disease and its impact remain low. METHODS: A retrospective observational study examined US claims data from 2015 to 2019 using the Compile database. ET diagnoses were captured using longitudinal data from 2015 to 2019 and for the year 2019, with diagnosis estimates extrapolated to the general US population. Confirmed ET was identified by an ET diagnosis code with at least two relevant prescriptions or by two diagnosis codes for ET and unspecified tremor at least 90 days apart. Comorbidity and treatment use data were extracted, and medication compliance and 2-year treatment persistence were assessed as measures of treatment adherence. RESULTS: A total of 1,336,183 patients with ET diagnoses codes were identified from 2015 through 2019, corresponding to 2,226,971 projected US diagnoses. In 2019, 128,263 patients had a confirmed ET diagnosis, corresponding to 213,772 projected US confirmed diagnoses. Of these, 96% had at least one comorbidity, and 64% received at least one pharmacologic treatment. Propranolol (24%) and primidone (20%) comprised the most common ET prescriptions. Two-year medication discontinuation rates were approximately 40%. CONCLUSION: Our findings revealed that 1 million people were diagnosed and sought treatment for ET in the USA from 2015 to 2019. Projected population estimates of approximately 2 million people diagnosed suggest a further 1 million remain untreated. Our findings highlight the complexity of patient care in ET, complicated by delayed diagnoses, multiple comorbidities, and lack of effective and tolerable therapies that can mitigate treatment adherence limitations.

A Bayesian approach to Essential Tremor plus: A preliminary analysis of the TITAN cohort.

BACKGROUND: The construct of Essential Tremor plus (ET-plus) refers to patients who also have rest tremor and/or mild neurologic signs of unknown significance. It is unclear whether soft signs represent confounding factors or are useful in suspecting an alternative condition. METHODS: Using a Bayesian approach to ET-plus patients recruited in The ITAlian tremor Network (TITAN), we analyzed the probability that these patients do not have ET. RESULTS: The data of 274 ET-plus patients were extracted from the TITAN database. The majority of patients (240/274; 87.5%) had a single soft sign. The post-test probability of not having ET was different according to the specific soft sign: namely, 0.64 (rest tremor); 0.46 (questionable dystonia); 0.85 (questionable bradykinesia); 0.19 (soft gait impairment); and 0.09 (questionable cognitive issues). In patients with multiple soft signs, the post-test probability of not having ET was higher than 50% for 7 out of 11 combinations, accounting for 44.1% of subjects. Overall, the post-test probability of not having ET was higher than 50% in up to 71.5% of ET-plus patients. DISCUSSION: We have here shown that: 1) the soft signs differently contribute in modulating the probability that a patient does not have ET; and 2) the effect of multiple soft signs are not always addictive. Future studies are needed to collect prevalence figures of soft signs in different neurological disorders as well as in the elderly and to calculate their value in predicting the development of an alternative tremor syndrome.

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.

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.

Sex and gender differences in movement disorders: Parkinson's disease, essential tremor, dystonia and chorea.

Sex and gender-based differences in epidemiology, clinical features and therapeutical responses are emerging in several movement disorders, even though they are still not widely recognized. In this chapter, we summarize the most relevant evidence concerning these differences in Parkinson's disease, essential tremor, dystonia and chorea. Indeed, both sex-related biological (hormonal levels fluctuations) and gender-related variables (socio-cultural and environmental factors) may differently impact symptoms manifestation and severity, phenotype and disease progression of movement disorders on men and women. Moreover, sex differences in treatment responses should be taken into account in any therapeutical planning. Physicians need to be aware of these major differences between men and women that will eventually have a major impact on better tailoring prevention, treatment, or even delaying progression of the most common movement disorders.

Differences in clinical manifestations of late-onset, compared to earlier-onset essential tremor: A scoping review.

Across the world, Essential Tremor (ET) is the most common tremor diagnosis but up to half of these diagnoses are inaccurate. The misdiagnosis rate is particularly high in late-onset ET, when tremor begins after the age of 60 years. Currently, ET is reported to affect 5.5% of those over 65 years old and 21.7% aged over 95 but there is emerging evidence that late-onset ET has associations with dementia, mortality and more rapid progression. With ageing populations, and a range of new surgical treatments for ET, there is urgent need to clarify whether the clinical manifestations of late-onset ET are the same as for earlier-onset ET. This scoping review used MEDLINE, EMBASE and CINAHL as the information sources of published peer-reviewed research articles between 2011 and 2021. Analysis was done by narrative synthesis. 14 relevant papers were retrieved from studies conducted in Denmark, India, Italy, Germany, Spain and the US and, together, they comprised 7684 participants in total. Compared to older adults with earlier-onset ET, there is evidence that late-onset ET is associated with higher risk of cognitive impairment and dementia, higher mortality rate, faster rate of progression, lack of family history, altered cortical electrical activity, prolonged pupillary responses, and less propensity to demonstrate characteristic alcohol sensitivity. There is evidence that late-onset ET has different clinical manifestations to earlier-onset ET; in particular there is higher risk of dementia and mortality. The prognosis is important for clinicians to consider when selecting candidates for deep brain stimulation surgery and also for advanced care planning.

The Pharmacotherapeutic Landscape for Essential Tremor: Quantifying the Level of Unmet Need From a Patient and Epidemiologic Perspective.

ABSTRACT: Essential tremor (ET) is one of the most common neurological diseases. Despite this high prevalence, treatment options remain limited. Recent advances in mechanistic research have led to renewed interest in developing newer pharmacotherapeutic agents. Although this is promising, there remains surprisingly little knowledge of the magnitude of the vast ET patient population who would benefit from and/or engage with such agents. This is because the vast bulk of ET patients in the population has milder tremor and does not seek medical care for their tremor. How many of these would be interested in taking a new agent? Hence, the level of unmet need, from the patient perspective and from a public health perspective, is totally unclear. In this article, the author systematically reviews peer-reviewed data on several pertinent questions that relate to this unmet need. The questions are as follows: (1) What proportion of the population of ET cases sees a health care provider for their tremor? (2) What proportion of the ET population has a tremor that is severe enough for them to want to take a medication for their tremor? (3) How do other factors such as age, sex, education, health literacy, and locale affect the receptivity to treatment in ET? (4) What is the patient use of the current ET medications? (5) Is the unmet need greater in some groups of ET cases than others? For each of these questions, available data are carefully reviewed and analyzed, and gaps in knowledge identified for further investigation.

Does essential tremor increase risk of cognitive impairment and dementia? Yes.

Essential Tremor (ET), by definition, is a disorder of movement. Yet over the years, epidemiologic, clinical, pathologic, and neuroimaging studies have converged to reveal a cognitive side of ET. The cognitive symptoms in ET are heterogeneous and are likely to reflect heterogeneous underlying mechanisms. In this chapter, we review and synthesize a diverse set of studies from both population-based settings to cohorts with more detailed investigations into cognition to consider the various mechanisms by which cognitive symptoms may emerge in a subset of individuals with ET. As part of our analysis, we consider questions surrounding ET diagnosis and the possibility of comorbid disease as potential factors that, upon closer examination, appear to strengthen the argument in favor of ET as a risk factor for dementia. Importantly, we also consider the clinical relevance of cognitive impairment in ET. While ET is not universally characterized by significant cognitive deficits, the data from epidemiological, cognitive, neuroimaging, and postmortem neuropathologic studies converge to reveal an increased risk for cognitive impairment and dementia among individuals with ET. We conclude by offering directions for future research, and a neurocognitive framework with which to consider existing findings and to use in the design of novel studies dedicated to clarifying the basis, nature, and course of cognitive impairments in ET.

Does essential tremor increase the risk of dementia? No.

Essential tremor (ET) is the most common neurological cause of tremor affecting adult humans affecting about 6% of those over age 65 years. In the United States, dementia has a prevalence of 15% in those age 68 and older. Overlap of the two conditions is therefore not surprising. Several studies report mild subclinical cognitive dysfunction in non-demented people with ET, likely related to overactivity of fronto-cerebellar circuitry involved in tremor pathophysiology. Frontal/executive dysfunction is often though not exclusively noted, and some studies have even shown areas of cognitive strengths. Mild cognitive impairment (MCI) is impairment which a person is aware of but does not interfere significantly with daily activities. While MCI has been considered to presage dementia this is not necessarily the case, as some persons with MCI revert to normal cognition in follow-up. Dementia is a clinical syndrome with cognitive impairment interfering with daily activities. Population-based and clinic-based studies have shown mixed results regarding rates of MCI in ET. A handful of studies have looked at development of dementia in ET with differing results. Brain pathology studies in ET and dementia or investigating Alzheimer-type pathology have thus far been unrevealing. There is evidence by some investigators supporting a greater risk of dementia for those having older onset tremor, while those having ET at a younger age faring at least as well as controls regarding risk of cognitive impairment and dementia. At present the evidence is inconclusive that ET as a group are at a greater risk of developing dementia.

Epidemiology of Pediatric Essential Tremor in the United States: A Systematic Literature Review from 2010 to 2020.

Background: Essential tremor (ET) is one of the most common movement disorders worldwide, yet the size of the pediatric ET population is not well understood. The objective of this review was to identify, evaluate, and synthesize evidence describing the epidemiology of pediatric ET in the United States published between 2010 and 2020. Methods: The authors searched MEDLINE, Embase, and the Cochrane Database of Systematic Reviews using terms related to ET, epidemiology, and pediatric patients. Eligibility criteria included observational studies that reported primary data on pediatric prevalence or incidence of ET or age of onset/diagnosis of ET. A total of 562 unique articles were identified for screening. Results: The review did not identify any studies that reported information on pediatric prevalence or incidence of ET, or age of ET diagnosis among nonpediatric patients. A total of 10 samples were identified, all of which described age of ET onset that ranged from 27.0 years to 56.7 years among 9 adult populations (weighted mean of 41.6 years) and 9.7 years in a single pediatric sample. One adult sample reported that 13% of all ET cases reported onset by age 14, and 21.8% of all ET cases reported onset by age 18. Discussion: There is a notable lack of recent data describing the incidence and prevalence of pediatric ET in the United States. Many children who present with symptoms of ET may not be diagnosed until later in life, and an increased awareness of pediatric ET could allow for early identification and monitoring of these patients.

The differences in clinical characteristics and natural history between essential tremor and essential tremor plus.

The diverse clinical manifestation of essential tremor (ET) has led to the question whether the different phenotypes may affect the clinical outcome and progression. This study aimed to estimate the clinical characteristics and natural history of ET and ET-plus. A total of 221 patients with ET were included, 117 (52.9%) reclassified as ET and 104 (47.1%) as ET-plus. Patients with ET-plus were significantly older in age at onset (P < 0.001); had a higher frequency of cranial tremors (P < 0.001), neurological comorbidities (P < 0.001) and psychiatric comorbidities (P = 0.025); more tremor progression (P < 0.001); and poorer response to medical treatment (P < 0.001) compared to ET patients. Regression analysis revealed that late-onset tremor (OR 11.02, 95% CI 2.79-43.53), neurological comorbidities (OR 3.38, 95% CI 1.56-7.31), psychiatric comorbidities (OR 4.29, 95% CI 1.48-12.44), cranial tremors (OR 2.10, 95% CI 1.02-4.30), and poor response to medical treatment (OR 3.67, 95% CI 1.87-7.19) were associated with ET-plus diagnosis. ET and ET-plus differ in the age of onset, tremor distribution, comorbidities, treatment response rate, and progression. Identifying the ET phenotypes may increase the clinical value in therapeutic strategies and clinical research in the future.