Original Paper Received: January 22, 2015 Accepted: March 22, 2015 Published online: May 7, 2015
Neuroepidemiology 2015;44:166–172 DOI: 10.1159/000381807
Familial versus Sporadic Essential Tremor: What Patterns Can One Decipher in Age of Onset? Elan D. Louis a, b Lorraine N. Clark c, d Ruth Ottman e–h
a Department of Neurology, Yale School of Medicine, b Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, Conn., c Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, d Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, e GH Sergievsky Center, f Department of Neurology, College of Physicians and Surgeons, g Department of Epidemiology, Mailman School of Public Health, Columbia University, and h Division of Epidemiology, New York State Psychiatric Institute, New York, N.Y., USA
Abstract Background: Essential tremor (ET) is a very prevalent neurological disease. Although familial and sporadic ET cases are assumed to have different age at onset distributions, no detailed study of this question has been carried out. Methods: Using a carefully characterized sample of 376 ET cases (232 (61.7%) familial) enrolled in a clinical-epidemiological study, we contrasted the age of onset distributions in familial versus sporadic ET. Results: Familial ET had a lower age at onset distribution, regardless of the current age. The majority (71 (86.6%) of 82) of ET cases that appeared during childhood were familial rather than sporadic. Additionally, the onset of ET occurred after age 40 in a majority of cases (125 (53.9%) of 232 with familial ET and 118 (81.9%) of 144 with sporadic ET), and in approximately one-quarter to one-half of cases, after age 60. Conclusions: The age of onset of ET differs between familial and sporadic ET and furthermore, is variable
© 2015 S. Karger AG, Basel 0251–5350/15/0443–0166$39.50/0 E-Mail [email protected] www.karger.com/ned
within each of these groups. The onset of ET during childhood is usually familial, and the small number of identified exceptions could be due to de novo mutations. Understanding the heterogeneity in onset age will provide insights into the nature of underlying etiological and patho-biological processes about which little is presently known. © 2015 S. Karger AG, Basel
Introduction
Although essential tremor (ET) is highly heritable [1– 4], numerous ET cases do not have an identified family history [1, 2]. This observation, with many others, indicates that environmental factors are also likely to play a role in the etiology of this disease [5–9]. Surprisingly, few if any clinical differences between familial and sporadic ET have been identified. One possible exception is age at onset: the two forms of ET are commonly assumed to differ with respect to age of onset, with earlier onset in the familial than in the sporadic form [10–12]. However, no detailed study has been carried out regarding the age of Elan D. Louis, MD, MSc Department of Neurology, LCI 710 15 York Street, PO Box 208018 New Haven, CT 06520-8018 (USA) E-Mail elan.louis @ yale.edu
Downloaded by: UCONN Storrs 137.99.31.134 - 5/21/2015 10:57:24 AM
Key Words Essential tremor · Epidemiology · Genetics · Familial · Sporadic · Age of onset
Methods Participants ET cases were enrolled in a study of environmental risk factors for ET at Columbia University Medical Center (CUMC) [13]. Hence, they were not enrolled based on the presence versus absence of family history of ET. Upon enrollment, a trained tester obtained written informed consent, approved by the CUMC Institutional Review Board, from all participants. ET cases were identified from two primary sources: a computerized billing database of all ET patients who were seen at least once at the Center for Parkinson’s Disease and Other Movement Disorders at CUMC over the past 5 years, and the International Essential Tremor Foundation (IETF) [13]. IETF members who lived in the New York metropolitan area were mailed advertisements and volunteered as participants [13, 14]. All enrollees had received diagnoses of ET from their treating neurologists and lived within a 2-hour driving distance of CUMC [13, 14]. After enrollment, all diagnoses were confirmed using published diagnostic criteria, as outlined below [13, 14]. Clinical Evaluation Each case underwent an in-person evaluation that included a series of demographic and clinical questionnaires. Age at onset was defined as the self-reported age at which the individual first noted tremor. A prior study indicated that this age is reliably reported by ET cases [15]. Each patient was asked whether he or she had one or more relatives with ET or tremor and, if so, to provide additional demographic and clinical information on each affected relative. Each case also underwent a 20-minute videotaped neurological examination, which included an assessment of postural tremor, five tests of kinetic tremor, and assessments of head (neck), voice and jaw tremors [13]. Each videotaped examination was reviewed by E.D.L., who rated the severity of postural and kinetic arm tremors (range 0–3) using a reliable and valid clinical rating scale, assigning a total tremor score (range 0–36) [13]. Diagnoses of ET were reconfirmed by E.D.L. based on the available data using Washington Heights Inwood Genetic Study of Essential Tremor (WHIGET) criteria (moderate or greater amplitude kinetic tremor (tremor rating ≥2) during three or more tests or a head tremor, in the absence of Parkinson’s disease, dystonia or another cause) [13]. These diagnostic criteria for ET were developed for a populationbased genetic study and, based on data from approximately 2,000 normal (non-diseased controls), the criteria carefully specify the specific examination maneuvers during which tremor should be
Familial versus Sporadic ET: Patterns in Age of Onset
Table 1. Demographic and clinical features of 376 ET cases
Demographic and clinical features
Familial ET Sporadic ET All cases (n = 232) (n = 144) (n = 376)
Current age, years Median Female gender Education, years Total tremor score* Tremor duration, years* Age of tremor onset, years* Currently taking medication for tremor*
66.6±15.8 71 124 (53.4) 15.4±3.6 19.5±7.2 27.5±19.2
68.9±14.0 71 72 (50.0) 14.7±4.1 17.6±7.2 15.0±14.9
67.5±15.1 71 196 (52.1) 15.1±3.8 18.8±7.2 22.8±18.7
39.1±22.2
53.9±19.8
44.7±22.5
139 (59.9)
65 (45.1)
204 (54.3)
All values are means ± standard deviations or proportions (percentages). * p < 0.05 (familial ET vs. sporadic ET).
present and the severity of tremor that should be evident during these maneuvers to distinguish normal from ET. The WHIGET criteria have been shown to be both reliable [16] and valid [17], and have been used by tremor investigators in the United States and internationally [18–27]. Definitions Familial ET (ETF) was defined using both liberal and conservative criteria. Using liberal criteria, ETF was found to denote the presence, by the proband’s report, of at least one first- or seconddegree relative with ‘ET’ or ‘tremor’; sporadic ET (ETS) was defined as the absence of at least one such relative. Using conservative criteria, ETF was the presence, by the proband’s report, of at least one first- or second-degree relative with ‘ET’; sporadic ET (ETS) was defined as the absence of at least one such relative. Analyses Analyses were initially performed using the liberal definition for ETF and then repeated using the conservative definition of ET. As in prior studies, childhood onset ET was defined as age 18 or younger [28]. As the age of onset was not normally distributed (Kolmogorov-Smirnov test, p value
Neuroepidemiology 2015;44:166–172 DOI: 10.1159/000381807
Familial versus Sporadic Essential Tremor: What Patterns Can One Decipher in Age of Onset? Elan D. Louis a, b Lorraine N. Clark c, d Ruth Ottman e–h
a Department of Neurology, Yale School of Medicine, b Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, Conn., c Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, d Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, e GH Sergievsky Center, f Department of Neurology, College of Physicians and Surgeons, g Department of Epidemiology, Mailman School of Public Health, Columbia University, and h Division of Epidemiology, New York State Psychiatric Institute, New York, N.Y., USA
Abstract Background: Essential tremor (ET) is a very prevalent neurological disease. Although familial and sporadic ET cases are assumed to have different age at onset distributions, no detailed study of this question has been carried out. Methods: Using a carefully characterized sample of 376 ET cases (232 (61.7%) familial) enrolled in a clinical-epidemiological study, we contrasted the age of onset distributions in familial versus sporadic ET. Results: Familial ET had a lower age at onset distribution, regardless of the current age. The majority (71 (86.6%) of 82) of ET cases that appeared during childhood were familial rather than sporadic. Additionally, the onset of ET occurred after age 40 in a majority of cases (125 (53.9%) of 232 with familial ET and 118 (81.9%) of 144 with sporadic ET), and in approximately one-quarter to one-half of cases, after age 60. Conclusions: The age of onset of ET differs between familial and sporadic ET and furthermore, is variable
© 2015 S. Karger AG, Basel 0251–5350/15/0443–0166$39.50/0 E-Mail [email protected] www.karger.com/ned
within each of these groups. The onset of ET during childhood is usually familial, and the small number of identified exceptions could be due to de novo mutations. Understanding the heterogeneity in onset age will provide insights into the nature of underlying etiological and patho-biological processes about which little is presently known. © 2015 S. Karger AG, Basel
Introduction
Although essential tremor (ET) is highly heritable [1– 4], numerous ET cases do not have an identified family history [1, 2]. This observation, with many others, indicates that environmental factors are also likely to play a role in the etiology of this disease [5–9]. Surprisingly, few if any clinical differences between familial and sporadic ET have been identified. One possible exception is age at onset: the two forms of ET are commonly assumed to differ with respect to age of onset, with earlier onset in the familial than in the sporadic form [10–12]. However, no detailed study has been carried out regarding the age of Elan D. Louis, MD, MSc Department of Neurology, LCI 710 15 York Street, PO Box 208018 New Haven, CT 06520-8018 (USA) E-Mail elan.louis @ yale.edu
Downloaded by: UCONN Storrs 137.99.31.134 - 5/21/2015 10:57:24 AM
Key Words Essential tremor · Epidemiology · Genetics · Familial · Sporadic · Age of onset
Methods Participants ET cases were enrolled in a study of environmental risk factors for ET at Columbia University Medical Center (CUMC) [13]. Hence, they were not enrolled based on the presence versus absence of family history of ET. Upon enrollment, a trained tester obtained written informed consent, approved by the CUMC Institutional Review Board, from all participants. ET cases were identified from two primary sources: a computerized billing database of all ET patients who were seen at least once at the Center for Parkinson’s Disease and Other Movement Disorders at CUMC over the past 5 years, and the International Essential Tremor Foundation (IETF) [13]. IETF members who lived in the New York metropolitan area were mailed advertisements and volunteered as participants [13, 14]. All enrollees had received diagnoses of ET from their treating neurologists and lived within a 2-hour driving distance of CUMC [13, 14]. After enrollment, all diagnoses were confirmed using published diagnostic criteria, as outlined below [13, 14]. Clinical Evaluation Each case underwent an in-person evaluation that included a series of demographic and clinical questionnaires. Age at onset was defined as the self-reported age at which the individual first noted tremor. A prior study indicated that this age is reliably reported by ET cases [15]. Each patient was asked whether he or she had one or more relatives with ET or tremor and, if so, to provide additional demographic and clinical information on each affected relative. Each case also underwent a 20-minute videotaped neurological examination, which included an assessment of postural tremor, five tests of kinetic tremor, and assessments of head (neck), voice and jaw tremors [13]. Each videotaped examination was reviewed by E.D.L., who rated the severity of postural and kinetic arm tremors (range 0–3) using a reliable and valid clinical rating scale, assigning a total tremor score (range 0–36) [13]. Diagnoses of ET were reconfirmed by E.D.L. based on the available data using Washington Heights Inwood Genetic Study of Essential Tremor (WHIGET) criteria (moderate or greater amplitude kinetic tremor (tremor rating ≥2) during three or more tests or a head tremor, in the absence of Parkinson’s disease, dystonia or another cause) [13]. These diagnostic criteria for ET were developed for a populationbased genetic study and, based on data from approximately 2,000 normal (non-diseased controls), the criteria carefully specify the specific examination maneuvers during which tremor should be
Familial versus Sporadic ET: Patterns in Age of Onset
Table 1. Demographic and clinical features of 376 ET cases
Demographic and clinical features
Familial ET Sporadic ET All cases (n = 232) (n = 144) (n = 376)
Current age, years Median Female gender Education, years Total tremor score* Tremor duration, years* Age of tremor onset, years* Currently taking medication for tremor*
66.6±15.8 71 124 (53.4) 15.4±3.6 19.5±7.2 27.5±19.2
68.9±14.0 71 72 (50.0) 14.7±4.1 17.6±7.2 15.0±14.9
67.5±15.1 71 196 (52.1) 15.1±3.8 18.8±7.2 22.8±18.7
39.1±22.2
53.9±19.8
44.7±22.5
139 (59.9)
65 (45.1)
204 (54.3)
All values are means ± standard deviations or proportions (percentages). * p < 0.05 (familial ET vs. sporadic ET).
present and the severity of tremor that should be evident during these maneuvers to distinguish normal from ET. The WHIGET criteria have been shown to be both reliable [16] and valid [17], and have been used by tremor investigators in the United States and internationally [18–27]. Definitions Familial ET (ETF) was defined using both liberal and conservative criteria. Using liberal criteria, ETF was found to denote the presence, by the proband’s report, of at least one first- or seconddegree relative with ‘ET’ or ‘tremor’; sporadic ET (ETS) was defined as the absence of at least one such relative. Using conservative criteria, ETF was the presence, by the proband’s report, of at least one first- or second-degree relative with ‘ET’; sporadic ET (ETS) was defined as the absence of at least one such relative. Analyses Analyses were initially performed using the liberal definition for ETF and then repeated using the conservative definition of ET. As in prior studies, childhood onset ET was defined as age 18 or younger [28]. As the age of onset was not normally distributed (Kolmogorov-Smirnov test, p value
