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Biomedical subjects

Elan D Louis

Publications and source records attributed to Elan D Louis.

At least 19 recordsLinked to original sources

Impaired motor imagery in patients with essential tremor: a case control study.

Motor imagery (MI), which refers to the process of mental representation of movements, has not been studied in patients with essential tremor (ET). We investigated the presence of impaired MI in ET patients compared with healthy controls. A group of drug-naive and nondemented ET patients and age-matched controls were studied using transcranial magnetic stimulation, while they were specifically instructed to try and imagine themselves performing two motor tasks. The various clinical and electrophysiological variables were evaluated and compared. Repeated measures ANOVA demonstrated a significant difference between ET patients and controls with respect to mean motor-evoked potential (MEP) amplitudes (F(1,38) = 31.92, P < 0.005) during MI. The process of MI effectively facilitated MEP amplitude in controls but not in ET patients, regardless of side of stimulation or motor tasks. We provide evidence to demonstrate impairment of MI in a group of ET patients compared with healthy controls. The basis for this novel finding is unclear, and further studies are warranted to determine whether it is related to cerebellar or motor cortical dysfunction.

Adult↗

Interest in participating in clinical research: A study of essential tremor patients.

Enrolling essential tremor (ET) patients in clinical research can be challenging. Investigators can maximize recruitment by targeting patient subgroups with greater interest in participation. Nothing has been published on factors that are associated with higher levels of interest in participation. The objective of this study was to identify factors associated with higher levels of interest in participating in clinical research on ET. A total of 149 ET patients were questioned about level of interest in participating in future research. Two questions were used, although one was of primary interest. Interest was rated from 0 to 10 (maximal). Data were collected on demographic factors, family history, and tremor-related disability. Tremor severity was assessed. The mean level of interest was 8.0 +/- 2.3. Level of interest was not related to age of tremor onset, tremor duration, tremor severity, extent of tremor-related disability, or use of tremor medication. Level of interest was related to family history of tremor (P < 0.05), concern that other family members might develop tremor (P < 0.05), >2 versus 0 live births in women (P < 0.05), the view that the tremor worsens with age (P < 0.05), and presence of head tremor (P = 0.05). A variety of factors were identified that were associated with greater interest in participating in clinical research. These observations should be assessed in additional patient samples. Investigators may use our observations to identify and target patients for clinical trials and other research.

Biomedical Research↗

Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells.

Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity. Astrocytes are critical for the proper functioning of the nervous system, and they play active roles in neurogenesis, synaptogenesis and synaptic neurotransmission. In this report, to help elucidate the molecular events underlying Mn neurotoxicity, we systematically identified the molecular targets of Mn in primary human astrocytes at a genome-wide level, by using microarray gene expression profiling and computational data analysis algorithms. We found that Mn altered the expression of diverse genes ranging from those encoding cytokines and transporters to signal transducers and transcriptional regulators. Particularly, 28 genes encoding proinflammatory chemokines, cytokines and related functions were up-regulated, whereas 15 genes encoding functions involved in DNA replication and repair and cell cycle checkpoint control were down-regulated. Consistent with the increased expression of proinflammatory factors, analysis of common regulators revealed that 16 targets known to be positively affected by the interferon-gamma signaling pathway were up-regulated by Mn(2+). In addition, 68 genes were found to be similarly up- or down-regulated by both Mn(2+) and hypoxia. These results from genomic analysis are further supported by data from real-time RT-PCR, Western blotting, flow cytometric and toxicological analyses. Together, these analyses show that Mn(2+) selectively affects cell cycle progression, the expression of hypoxia-responsive genes, and the expression of proinflammatory factors in primary human astrocytes. These results provide important insights into the molecular mechanisms underlying Mn neurotoxicity.

Astrocytes↗

Elderly-onset essential tremor is associated with dementia.

OBJECTIVE: To determine whether essential tremor (ET) is associated with prevalent dementia. METHODS: The authors identified all persons with dementia and ET in a population-based study in central Spain (the Neurological Disorders in Central Spain [NEDICES] Study). Dementia was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria. RESULTS: Thirty-one (11.4%) of 273 ET cases had dementia vs 204 (6.0%) of 3,382 non-ET subjects (controls) (odds ratio [OR] = 2.00, 95% CI = 1.34 to 2.98, p = 0.001). In a model that adjusted for age, stroke, and educational level, OR = 1.35, 95% CI = 0.87 to 2.18, and p = 0.17. In an adjusted model, ET cases with tremor onset after age 65 were 70% more likely to be demented than were controls (OR = 1.70, 95% CI = 1.04 to 2.76, p = 0.03), whereas ET cases with tremor onset at age < or = 65 and controls were equally likely to be demented (OR = 0.38, 95% CI = 0.09 to 1.73, p = 0.21). CONCLUSIONS: Older-onset essential tremor (ET) was associated with dementia. Prospective studies are required to elucidate the association between ET and dementia.

Age of Onset↗

Weir Mitchell's observations on sensory localization and their influence on Jacksonian neurology.

BACKGROUND: John Hughlings Jackson (1835-1911) in London was critical in advancing the concept of cerebral localization. Hughlings Jackson, however, did not work in a vacuum. Silas Weir Mitchell (1829-1914), in Philadelphia, published several clinical observations related to localization. OBJECTIVE: To examine Weir Mitchell's clinical observations on sensory localization, to determine whether they influenced Jacksonian neurology, and to elucidate the private relationship between the two men. METHODS: The authors reviewed published (fictional and scientific writings of Weir Mitchell and scientific writings of Hughlings Jackson) and archival sources (Weir Mitchell's unpublished autobiography and Hughlings Jackson's unpublished correspondence with Weir Mitchell). RESULTS: In the 1860s, Weir Mitchell, through his work on phantom limb syndrome and other nerve injuries, made oblique references to the central representation of body parts, specifically with regard to sensation. Hughlings Jackson had an interest in somatotopic representation in the nervous system and repeatedly cited Weir Mitchell's work in support of his ideas. The two shared several patients, met at least once in London, and carried on a friendly correspondence. CONCLUSIONS: Weir Mitchell's observations on sensory localization were well known to Hughlings Jackson, who cited them in seminal articles on cortical localization. Their correspondence provides an example of trans-Atlantic scientific and clinical communication at the time that neurology emerged as a distinct clinical discipline.

Cerebral Cortex↗

Organochlorine pesticide exposure in essential tremor: a case-control study using biological and occupational exposure assessments.

Essential tremor (ET) is a common neurological disorder. Its etiology and pathogenesis are not well understood and several environmental factors (i.e., toxicants) have been studied. Organochlorine pesticides (OCPs) are potent tremor-producing chemicals. These pervasive environmental contaminants have been linked with other tremor disorders (e.g., Parkinson's disease) but they have not been assessed in ET cases. Our objective was to test the hypothesis that ET is associated with OCP exposure. Serum OCP concentrations and lifetime occupational histories were assessed in ET cases and control subjects. Six serum OCP concentrations (p,p'-DDE, p,p'-DDT, beta-hexachlorocyclo-hexane, oxychlordane, trans-nonachlor, and dieldrin) were assessed. Data from a lifetime occupational history were reviewed by a blinded industrial hygienist. The six serum OCP concentrations were similar in 136 ET cases and 144 control subjects. There was no association in ET cases between the six serum OCP concentrations and total tremor score. Three (2.2%) ET cases versus 9 (6.3%) controls had past occupational exposure to OCPs (OR=0.34, 95% CI=0.09-1.28, p=0.10). Although OCPs have been associated with other tremor disorders, we were not able to find an association between the six most tremorogenic OCPs and ET. Our data suggest that these tremor-producing chemicals are not of major etiological importance in our patients with ET.

Aged↗

The neurologic content of S. Weir Mitchell's fiction.

BACKGROUND: Silas Weir Mitchell (1829 to 1914), one of the most important neurologists in American Medicine, was known for his seminal work on the phantom limb syndrome, causalgia, and nerve injuries. He was also a prolific writer of novels and short stories. The neurologic content of this fiction has not been studied. OBJECTIVE: To assess the extent that references to neurologic topics were present in Mitchell's fiction, whether these neurologic references reflected Mitchell's scientific interests and contributions, and whether his fictional accounts of neurologic topics would precede those in his scientific writings. METHODS: The authors read Silas Weir Mitchell's novels and short stories. RESULTS: Seventeen (63.0%) of 27 fictional works contained neurologic references. Fifty-five (69.6%) of 79 references were brief (a single word or sentence). In two works, a neurologic theme was central to the plot. Some of the neurologic content was sophisticated (aphasia, brain laterality). Phantom limb syndrome, causalgia, and nerve injuries were not prominent in his fiction. Neurologic consequences of battle injuries were featured in 10 (37.0%) works. With the exception of "The Case of George Dedlow" (i.e., phantom limb syndrome), Mitchell's fictional accounts of neurologic topics followed his presentation of these topics in the scientific literature. CONCLUSIONS: The majority of Mitchell's fictional works contained references to neurologic topics but most contained brief references. The number of references to Mitchell's specific scientific interests (phantom limb syndrome, causalgia) was small, although more generally, references to the neurology of battle injuries occurred more frequently.

History, 20th Century↗

Population-based case-control study of cognitive function in essential tremor.

OBJECTIVES: To determine whether patients with essential tremor (ET) have cognitive deficits when compared with controls and whether the types of cognitive deficits reported previously are also found in this large sampling of patients with ET. METHODS: A total of 232 patients with ET and 696 matched controls age 65 years or older (median 75 years) living in central Spain (the Neurologic Diseases in Central Spain study) underwent a neuropsychological assessment, including tests of global cognitive performance, frontal executive function, verbal fluency, and memory. Subjects also were asked whether they had forgetfulness. RESULTS: Fifty-six patients with ET were previously undiagnosed; only 14 (6%) were taking medication for tremor. Adjusted for age, gender, education, premorbid intelligence, medications, and depressive symptoms, cases performed less well on most neuropsychological tests and especially tests of global cognitive performance (37-item Mini-Mental State Examination = 27.0 +/- 6.7 in cases vs 28.9 +/- 5.9 in controls, p < 0.001) and frontal executive function (Trail Making Test number of errors = 8.7 +/- 11.0 in cases vs 3.8 +/- 7.6 in controls, p < 0.001). Forgetfulness was reported in 117 (50.4%) patients with ET vs 300 (43.1%) controls (p = 0.05). CONCLUSIONS: In a population-based sample of largely untreated patients with essential tremor, cases performed more poorly on formal neuropsychological testing than did their counterparts without tremor. A complaint of forgetfulness was also marginally more common in patients with essential tremor.

Age Factors↗

Case-control study of the parkin gene in early-onset Parkinson disease.

BACKGROUND: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. OBJECTIVE: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged < or =50 years) and controls participating in a familial aggregation study. PATIENTS AND METHODS: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. RESULTS: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. CONCLUSIONS: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD.

Age of Onset↗

History of vascular disease and mild parkinsonian signs in community-dwelling elderly individuals.

BACKGROUND: Mild parkinsonian signs (MPS) are commonly found during the clinical examination of older people. These signs could reflect the accumulation of vascular pathological changes in the brain. If the etiology were vascular, one could hypothesize that individuals with MPS would be more likely to have systemic vascular disease than would their counterparts without these signs. OBJECTIVES: To examine whether MPS are associated with a history of vascular disease and whether certain MPS (rigidity, changes in axial function) are more strongly associated with a history of vascular disease than are other MPS (tremor). METHODS: Evaluation of older people without dementia in Washington Heights-Inwood, northern Manhattan, NY. The presence of vascular diseases was assessed with a structured health interview. RESULTS: Mild parkinsonian signs were present in 375 (16.4%) of 2286 participants without dementia. Diabetes mellitus, heart disease, peripheral vascular disease, and stroke were more prevalent in participants with MPS than without MPS, whereas nonvascular diseases (cancer, thyroid disease) were not. In a logistic regression analysis that adjusted for age, sex, education, and depressive symptoms, the number of vascular diseases was associated with MPS (odds ratio, 1.31 [95% confidence interval, 1.18-1.46]; P<.001). The combination of diabetes mellitus and heart disease increased the odds of MPS by 70% and the combination of these with stroke increased the odds by 332%. CONCLUSIONS: The presence of MPS in elderly individuals might reflect, in part, the accumulation of vascular pathological changes in the basal ganglia or white matter regions caused by preventable vascular diseases. Prospective and pathological studies are needed to further explore this finding.

Aged↗

Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study.

BACKGROUND: Testosterone deficiency has been reported in patients with Parkinson disease (PD), Alzheimer disease, and Huntington disease. It is not known whether testosterone therapy (TT) in men with borderline hypogonadism and neurodegenerative diseases will be of substantial benefit. Previously, we reported that testosterone deficiency is more common in patients with PD compared with age-matched control subjects, and we also reported in 2 small open-label studies that some nonmotor symptoms responded favorably to TT. OBJECTIVE: To define the effects of TT on nonmotor and motor symptoms in men with PD and probable testosterone deficiency. DESIGN: Double-masked, placebo-controlled, parallel-group, single-center trial. PATIENTS: Two experimental groups: patients with PD who were receiving either TT or placebo. INTERVENTIONS: Participants received either the study drug by intramuscular injection (200 mg/mL of testosterone enanthate every 2 weeks for 8 weeks) or placebo (isotonic sodium chloride solution injections). In patients in each group, the testosterone serum concentration was obtained at each study visit. During 2 study visits, testosterone levels were blindly evaluated and the intramuscular testosterone dose was increased by 200 mg/mL if the free testosterone value failed to double from the baseline value. MAIN OUTCOME MEASURES: The primary outcome variable was the St Louis Testosterone Deficiency Questionnaire, and secondary outcome measures included measures of mood, cognition, fatigue, motor function, and frequency of adverse events. At the end of the double-blind phase, all patients were offered open-label TT and were followed up after 3 and 6 months. RESULTS: Fifteen patients in the placebo group (mean age, 69.9 years), receiving a mean total levodopa equivalent dose of 924 mg/d, had a baseline free testosterone level of 47.91 pg/mL, compared with 15 patients in the TT group (mean age, 66.7 years), receiving an average total levodopa equivalent dose of 734 mg/d, who had a baseline free testosterone level of 63.49 pg/mL. Testosterone was generally well tolerated. More subjects in the TT group experienced lower extremity edema (40% vs 20%). In 2 patients, 1 in each group, prostate-specific antigen levels were elevated from baseline. The improvement in the TT group compared with the placebo group (1.7 vs 1.1) on the St Louis Testosterone Deficiency Scale was not statistically significant. In addition, there were no significant differences in motor and nonmotor features of PD between the 2 groups, although a few subscales showed improvements (Hopkins Verbal Learning Test, P<.04; and Backward Visual Span subtrial, P<.03). However, long-term open-label TT resulted in delayed but sustained improvement in subjects in the TT group who continued to receive treatment (n = 6) compared with subjects in the placebo group who elected not to receive TT (n = 3). CONCLUSIONS: Testosterone therapy was generally well tolerated in elderly men with PD and probable testosterone deficiency. While there was no significant difference in the motor and nonmotor scales between the TT and placebo groups at the end of 8 weeks compared with baseline, this may be due to several study limitations, including small sample size, a strong placebo effect with intramuscular therapy, and short follow-up that did not allow measurement of delayed effects of TT in some subjects. Until more definitive studies are reported, practitioners should be particularly cautious in treatment of low testosterone concentrations in men with PD and borderline testosterone deficiency, and careful consideration should be given to the risks vs the benefits of TT.

Affect↗

Common misdiagnosis of a common neurological disorder: how are we misdiagnosing essential tremor?

BACKGROUND: As a common neurological disorder, the diagnosis of essential tremor (ET) is considered routine. Despite this, previous work suggests that misdiagnoses may be common. Among other things, these misdiagnoses can lead to treatment errors. OBJECTIVES: To estimate how often other tremor disorders are misdiagnosed as ET and to identify factors that increase the odds of misdiagnosing ET and to precisely quantify the extent to which they do so. DESIGN: Seventy-one consecutive patients underwent an evaluation at the Neurological Institute of New York, New York, between January 1, 2000, and December 31, 2005; these patients had a pre-evaluation diagnosis of ET. The criteria for ET were adapted from the consensus statement of the Movement Disorder Society. RESULTS: Twenty-six patients (37%) were misdiagnosed as having ET ("false ET"). Their true diagnoses were Parkinson disease (11 patients [15%]), dystonia (6 patients [8%]), Parkinson disease with ET (5 patients [7%]), and other disorders (4 patients [6%]). Factors associated with misdiagnosed ET included unilateral arm tremor (odds ratio, 10.5; 95% confidence interval, 1.2-95.4; P=.02), spooning of the hands and other dystonic postures (odds ratio, 16.3; 95% confidence interval, 4.0-66.4; P<.001), and other unusual features (isolated thumb tremor, isolated leg tremor, and non-rhythmic tremor) (odds ratio, 49.4; 95% confidence interval, 2.7-895.0; P<.001). CONCLUSIONS: About 1 in 3 patients with tremor was misdiagnosed as having ET, with the most frequent false diagnoses being Parkinson disease and dystonia. Several factors that increased the odds of misdiagnosing ET were identified. These factors could be incorporated into improved diagnostic algorithms.

Adult↗

Essential tremor associated with pathologic changes in the cerebellum.

BACKGROUND: Although essential tremor (ET) is one of the most common neurologic disorders, there have been few postmortem studies. We recently reported postmortem changes (torpedoes and Bergmann gliosis) in the cerebellar cortex in a few ET cases. OBJECTIVE: To describe more extensive postmortem changes in the cerebellum in another ET case. DESIGN: Case report. RESULTS: A 90-year-old woman had a 30-year history of ET. At postmortem examination, there was segmental loss of Purkinje cells, presence of torpedoes, and Bergmann gliosis in the cerebellar cortex. Moreover, there were extensive changes in the dentate nucleus, in the form of neuronal loss, neuronal atrophy, microglial clusters, and reduction in the number of efferent fibers (ie, pallor of the hilum). CONCLUSIONS: The brain in the current case exhibited more marked cerebellar pathologic features than noted in previously reported ET cases and thereby extends the described cerebellar findings in this common, yet pathologically poorly characterized, neurologic disorder.

Aged, 80 and over↗

Functional correlates of mild parkinsonian signs in the community-dwelling elderly: poor balance and inability to ambulate independently.

Mild tremor, rigidity, and bradykinesia (mild parkinsonian signs, MPS) are commonly detected during the clinical examination of elderly people without known neurological disease. The functional correlates of these incidental findings are not well understood. Balance and ability to ambulate independently are important functions in the elderly. The objective of this study is to examine whether MPS were associated with impaired balance. Balance was assessed using a subjective measure (complaint of poor balance) and a functional measure (the need to use a walker, cane, or wheelchair). Our methods included the neurological evaluation of nondemented older people in Washington Heights-Inwood, NY. Of 2,251 participants, 527 (23.4%) complained of poor balance; 538 (23.9%) required a cane, walker, or wheelchair; and 363 (16.1%) had MPS. In adjusted logistic regression analyses, MPS were associated with a complaint of poor balance (OR=1.5, 95% CI=1.1-2.0) and the need to use a cane, walker, or wheelchair (OR=1.9, 95% CI=1.4-2.6). The need to use a cane, walker, or wheelchair was associated with changes in axial function (OR=5.5, 95% CI=2.6-11.6) as well as rigidity (OR=1.5, 95% CI=1.07-2.2). Although they are incidental and subtle, signs of bradykinesia, rigidity, and tremor are associated with impaired function. The elderly in whom these signs have been detected are 50% more likely to complain of poor balance and 90% more likely to require a cane, walker, or wheelchair than are their counterparts without these signs.

Aged↗

Jaw tremor: prevalence and clinical correlates in three essential tremor case samples.

The spectrum of involuntary movements seen in essential tremor (ET) is limited. Jaw tremor is one such movement. The prevalence and clinical correlates of jaw tremor have not been studied in detail. The objective of this study was to estimate the prevalence and examine the clinical correlates of jaw tremor in ET using ET cases from three distinct settings (population, tertiary-referral center, brain repository). All ET cases underwent a videotaped tremor examination in which tremors (including limb, head, voice, and jaw) were assessed. The prevalence [95% confidence interval (CI)] of jaw tremor was lowest in the population sample (7.5%; 3.9%-14.2%), intermediate in the tertiary-referral center (10.1%; 6.8%-14.7%), and highest in the brain repository (18.0%; 12.3%-25.5%; P = 0.03). Jaw tremor was associated with older age (P < 0.001), more severe action tremor of the arms (P < 0.001), and presence of head and voice tremor (P < 0.001). Jaw tremor was present in 4/14 (28.6%) ET cases with consistent rest tremor vs. 15/193 (7.8%) cases without rest tremor (odds ratio = 4.8; 95% CI = 1.3-7.0; P = 0.009). The prevalence of jaw tremor was 7.5% to 18.0% and was dependent on the mode of ascertainment, being least prevalent in a population-based sample. ET cases with jaw tremor had a more clinically severe and more topographically widespread disorder. The association in our study between jaw tremor and rest tremor, along with the published observation that jaw tremor can occur in Parkinson's disease (PD), raises the question whether jaw tremor in ET is a marker for subsequent conversion to PD.

Age Factors↗

Intention tremor of the head in patients with essential tremor.

Patients with essential tremor (ET) have kinetic arm tremor; this tremor can also have an intentional component. We are unaware of reports of intention tremor of the head in ET. Our aims were to describe, provide electrophysiological data and video documentation of, and estimate the prevalence of intention tremor of the head in our sample. Ten (9.0%; 95% confidence interval = 4.7%-14.3%) of 111 patients had intention tremor of the head; in 7 it involved the neck and in 3 the chin. These patients trended toward having more severe kinetic arm tremor and they had more severe intention tremor of the arms. These observations provide further support for the evolving view that the cerebellum may be involved in ET.

Aged↗

Study of possible factors associated with age of onset in essential tremor.

Factors associated with the age of onset of essential tremor (ET) have not been studied in detail. Identification of modifiable factors could lead to strategies to delay disease onset and identification of nonmodifiable factors would be useful while counseling at risk individuals. The objective of this study was to identify factors associated with age of onset of tremor in ET. One hundred ninety-five ET cases were enrolled in an environmental epidemiological study. Clinical questionnaires included questions on age of onset, demographics (age, sex, race, education), early-life exposures (birth order, childhood household size), exposures prior to tremor onset (head trauma, well water, rural living, estrogen replacement therapy), and family history. In unadjusted analyses, age of onset was associated with family history of tremor (40.9 +/- 22.0 years for cases with a family history of tremor vs. 57.3 +/- 18.4 years for cases without a history; P < 0.001), history of head trauma, younger current age, greater tremor severity, and white race. Ninety-one percent of cases with onset before age 20 years had a family history of tremor. Age ofonset was not associated with other variables of interest (e.g., sex, well water, rural living). In an adjusted linear regression model, age of tremor onset was strongly associated with family history of tremor (P < 0.001). The familial form of ET is characterized by an earlier age of onset than the sporadic form. This study did not detect any other exposures that modified the age of onset of ET. Follow-up studies are needed to examine additional factors of potential interest.

Adolescent↗