Tandem gait performance in essential tremor: clinical correlates and association with midline tremors.

Gait difficulty has been reported in essential tremor (ET) although it has been the subject of a limited number of studies. We broadly assessed these clinical correlates, including the association of gait difficulty with a variety of midline tremors (jaw, voice, neck). Tandem gait (10 steps) was assessed in 122 ET cases. Cranial tremor score (0-3) was the number of locations (neck, jaw, voice) in which tremor was present. Number of tandem mis-steps positively correlated with age (P < 0.001), age of tremor onset (P = 0.001), and presence of neck (P < 0.001), jaw (P = 0.001), and voice tremors (P = 0.047). Number of tandem mis-steps increased markedly with cranial tremor score: 0 (0.8 +/- 1.2), 1 (1.1 +/- 1.6), 2 (2.3 +/- 3.0), 3 (3.7 +/- 1.6) (P < 0.001). It was not correlated with severity of arm or leg tremors. ET patients with cranial tremors (neck, jaw, voice), those with older age of onset, and those of current older age are more likely to manifest tandem gait difficulty. Tandem gait difficulty was not correlated with severity of limb tremors. Tandem gait difficulty and cranial tremors in ET may both be symptomatic of the same underlying pathophysiology, a disturbance of cerebellar regulation of the midline, which is distinct from its regulation of the limbs.

Mirror movements in patients with essential tremor.

Mirror movements (MM), which occur in age-related neurodegenerative diseases such as Parkinson's disease (PD), have never been studied in essential tremor (ET). The objective of this work is to study the prevalence and clinical correlates of MM in ET cases and controls. In a clinical-epidemiological study in New York, participants performed repetitive motor tasks; MM (hands and feet) were rated. MM occurred in 35/107 (32.7%) ET cases versus 23/97 (23.7%) controls (OR 1.56, P = 0.16). Total MM score was 2x higher in cases (3.9 +/- 7.7 vs. 1.9 +/- 3.9, P = 0.02). MM (hands) occurred in 16 (15.0%) cases versus 5 (5.2%) controls (OR 3.24, P = 0.03) and total hand MM score was three to four times higher in ET cases (1.4 +/- 4.5 vs. 0.4 +/- 2.0, P = 0.03). MMs were not correlated with age, tremor duration, or severity and were most severe in cases with rest tremor. Thus, it was concluded that MM occurred in 1/3 of ET cases. These results further expand the spectrum of nontremor, motor phenomenology seen in ET. Whether, as in PD, MMs in ET represent a failure of subcortical structures to support the cortical network involved with the initiation of unilateral motor activity, requires future neurophysiological investigation.

Older onset essential tremor: More rapid progression and more degenerative pathology.

There are few data on rate of progression in essential tremor (ET). To quantify the rate of tremor progression in a cross-sectional sample of 348 ET cases in an epidemiological study; characterize the relationship between age of tremor onset and rate of tremor progression in that sample; and characterize the relationship between age of tremor onset, rate of tremor progression, and severity of underlying brain changes in 9 cases from a brain repository. Rate of tremor progression was defined as tremor severity / duration. The degeneration index = number of torpedoes per section / Purkinje cell linear density. In the epidemiological study, older age of tremor onset was associated with faster rate of tremor progression (P < 0.001). In the brain repository, older age of tremor onset was associated with higher degeneration index (P = 0.037), and higher degeneration index was associated with faster rate of tremor progression (P = 0.018). In a large clinical sample, older age of onset was associated with more rapid tremor progression. In a brain bank, older age of onset was associated with more degenerative pathology in the cerebellum. As in several neurodegenerative disorders, in older onset cases, it is possible that the disease advances more rapidly.

Cancer and blood concentrations of the comutagen harmane in essential tremor.

Blood concentrations of harmane, a tremor-producing neurotoxin, are elevated in essential tremor (ET). Harmane is also a comutagen. Using a case-control design, we compared the prevalence of cancer in ET cases vs. controls, and determined whether blood harmane concentrations are elevated among ET cases with cancer. 66/267 (24.7%) ET cases vs. 55/331 (16.6%) controls had cancer (adjusted OR 1.52, 95% CI 1.01-2.30, P = 0.04). Among specific cancer types, colon cancer was more prevalent in ET cases than controls (2.6% vs. 0.6%, P = 0.04). Log blood harmane concentration was higher in ET cases vs. controls (P = 0.02) and in participants with vs. without cancer (P = 0.02). Log blood harmane concentration was highest in ET cases with cancer when compared with other groups (P = 0.009). These links between cancer and ET and between high blood harmane and cancer in ET deserve further study.

Dietary epidemiology of essential tremor: meat consumption and meat cooking practices.

BACKGROUND/AIM: Harmane [1-methyl-9H-pyrido(3,4-b)indole] is a tremor-producing neurotoxin. Blood harmane concentrations are elevated in essential tremor (ET) patients for unclear reasons. Potential mechanisms include increased dietary harmane intake (especially through well-cooked meat) or genetic-metabolic factors. We tested the hypothesis that meat consumption and level of meat doneness are higher in ET cases than in controls. METHODS: Detailed data were collected using the Lawrence Livermore National Laboratory Meat Questionnaire. RESULTS: Total current meat consumption was greater in men with than without ET (135.3 +/- 71.1 vs. 110.6 +/- 80.4 g/day, p = 0.03) but not in women with versus without ET (80.6 +/- 50.0 vs. 79.3 +/- 51.0 g/day, p = 0.76). In an adjusted logistic regression analysis in males, higher total current meat consumption was associated with ET (OR = 1.006, p = 0.04, i.e., with 10 additional g/day of meat, odds of ET increased by 6%). Male cases had higher odds of being in the highest than lowest quartile of total current meat consumption (adjusted OR = 21.36, p = 0.001). Meat doneness level was similar in cases and controls. CONCLUSION: This study provides evidence of a dietary difference between male ET cases and male controls. The etiological ramifications of these results warrant additional investigation.

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor.

Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high-performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3+/-15.5 vs. 65.5+/-14.2 years, p=0.94). Mean log blood harmane concentration was approximately 50% higher in cases than controls (0.50+/-0.54g(-10)/ml vs. 0.35+/-0.62g(-10)/ml, p=0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (OR(adjusted) 1.56, 95% CI 1.01-2.42, p=0.04), and odds of ET was 1.90 (95% CI 1.07-3.39, p=0.029) in the highest versus lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53+/-0.57g(-10)/ml), intermediate in cases with sporadic ET (0.43+/-0.45g(-10)/ml) and lowest in controls (0.35+/-0.62g(-10)/ml) (test for trend, p=0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors.

Higher blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations correlate with lower olfactory scores in essential tremor.

BACKGROUND: Harmane (1-methyl-9H-pyrido[3,4-b]indole), a neurotoxin, may be an environmental risk factor for essential tremor (ET). Harmane and related chemicals are toxic to the cerebellum. Whether it is through this mechanism (cerebellar toxicity) that harmane leads to ET is unknown. Impaired olfaction may be a feature of cerebellar disease. OBJECTIVE: To determine whether blood harmane concentrations correlate with olfactory test scores in patients with ET. METHODS: Blood harmane concentrations were quantified using high performance liquid chromatography. Odor identification testing was performed with the University of Pennsylvania Smell Identification Test (UPSIT). RESULTS: In 83 ET cases, higher log blood harmane concentration was correlated with lower UPSIT score (rho=-0.46, p<0.001). 25/40 (62.5%) cases with high log blood harmane concentration (based on a median split) had low UPSIT scores (based on a median split) vs. 12/43 (27.9%) ET cases with low log blood harmane concentration (adjusted odd ratios (OR) 4.04, 95% confidence intervals (CI) 1.42-11.50, p=0.009). When compared with the low log blood harmane tertile, the odds of olfactory dysfunction were 2.64 times higher in cases in the middle tertile and 10.95 times higher in cases in the high tertile. In 69 control subjects, higher log blood harmane concentration was not correlated with lower UPSIT score (rho=0.12, p=0.32). CONCLUSIONS: Blood harmane concentrations were correlated with UPSIT scores in ET cases but not controls. These analyses set the stage for postmortem studies to further explore the role of harmane as a cerebellar toxin in ET.

ICD-9 CM code 333.1 as an identifier of patients with essential tremor: a study of the positive predictive value of this code.

BACKGROUND/AIMS: Health outcomes research often uses administrative databases. Patients with the diseases of interest are identified using International Classification of Diseases (ICD-9 CM) codes. The utility of the code for essential tremor (ET), 333.1, remains untested. We determined the positive predictive value (PPV) of the code 333.1. METHODS: Patients with the ICD-9 CM code 333.1 were identified from billing records at the Neurological Institute of New York. Their medical records were reviewed to determine whether they met Consensus Criteria for ET. RESULTS: Of 964 patients who carried the code 333.1, only 472 met diagnostic criteria for ET (i.e. PPV = 49.0%). The additional use of ICD 9-CM codes for parkinsonism and dystonia (as exclusionary criteria) only marginally improved this value (57.8%). Common diagnoses among the false positives were Parkinson's disease, dystonia, enhanced physiological tremor, drug-induced tremor, orthostatic tremor, and psychogenic tremor. Patients seen by general neurologists (vs. movement disorder specialists) were half as likely to meet diagnostic criteria for ET (34.6 vs. 51.9%, OR 0.50, 95% CI 0.23-0.70, p < 0.001). CONCLUSION: The code 333.1 performed poorly when attempting to identify ET cases. Given the very high prevalence of ET, a unique diagnostic code would seem to be in order.

Replication of the LINGO1 gene association with essential tremor in a North American population.

A marker in the LINGO1 gene, rs9652490, showing significant genome-wide association with essential tremor (ET), was recently reported in an Icelandic population. To replicate this association in an independent population from North America, we genotyped 15 SNPs in the LINGO1 gene in 257 Caucasian ET cases ('definite,' 'probable' or 'possible') and 265 controls enrolled in an epidemiological study at Columbia University. We observed a marginally significant association with allele G of the marker rs9652490 (P=0.0569, odds ratio (OR)=1.33). However, for 'definite' or 'probable' ET, rs9652490 was significantly associated with ET (P=0.03, OR=1.41). Our subsequent analysis of early-onset ET (age at onset <40 years) revealed that three SNPs, rs177008, rs13313467 and rs8028808, were significantly associated with ET (P=0.028, OR=1.52; P=0.0238, OR=1.54; and P=0.0391, OR=1.55, respectively). These three SNPs represent a 2.3 kb haplotype. Finally, a meta-analysis of three published studies confirms allelic association with rs9652490 and two adjacent SNPs. Our study independently confirms that the LINGO1 gene is a risk factor for ET in a Caucasian population in North America, and further shows that those with early-onset ET are likely to be at high risk.

Mutations in the Parkinson's disease genes, Leucine Rich Repeat Kinase 2 (LRRK2) and Glucocerebrosidase (GBA), are not associated with essential tremor.

We evaluated an association between essential tremor (ET) and the Parkinson's disease (PD) genes, Leucine Rich Repeat Kinase 2 (LRRK2) and Glucocerebrosidase (GBA). Clinical studies demonstrate an association between ET and PD, suggesting possible shared pathophysiologies, yet LRRK2 has rarely been studied in ET, and GBA, not at all. ET cases (n = 275, including 42 with rest tremor) and controls (n = 289) were enrolled in an epidemiological study (Columbia University). Post-mortem brain tissue samples were obtained on 24 additional ET cases, including 3 with brainstem Lewy bodies. We performed a comprehensive analysis of the LRRK2 gene by genotyping 4 LRRK2 mutations (G2019S, I2020T, R1441C and Y1699C), 2 rare LRRK2 variants (L1114L and I1122V) and 19 LRRK2 SNPs. All GBA exons were sequenced in a subset of 93 Ashkenazi Jewish (AJ) cases, 62 AJ controls and 24 ET brains. LRRK2 mutations were not found in any ET cases or ET brains and none of the LRRK2 SNPs was associated with ET. GBA mutations were found in 7.5% (7/93) of AJ ET cases and 4.8% (3/62) of AJ controls (p = 0.75). 8.3% (2/24) of ET brains carried a GBA mutation. Four different heterozygous mutations were identified, including 3 previously reported mutations (N370S, R496H, and E326K) and 1 new missense variant (R44C). As suggested by several smaller prior reports, the known mutations for the LRRK2 gene are not risk factors for ET. Furthermore, a similar frequency of GBA mutations in AJ ET cases and controls suggests that GBA is not a common cause of ET either.

Embarrassment in essential tremor: prevalence, clinical correlates and therapeutic implications.

BACKGROUND: Embarrassment is a commonly described feature of essential tremor (ET) but has not been the focus of clinical research. OBJECTIVE: To estimate the prevalence, identify susceptible patient groups, and quantify the therapeutic correlates of reported embarrassment. METHODS: A total of 106 ET cases from a population-based sample and 349 ET cases from a clinical sample were asked, "Does your tremor often embarrass you?" RESULTS: In the clinical sample, the prevalence of embarrassment was high (58.2%). Even in those ET cases with no head tremor and mild arm tremor, nearly one-half (29/61 [47.5%]) reported embarrassment. While the prevalence of embarrassment was lower in the population-based sample, it was not negligible (18.9%). Embarrassment was associated with younger age of onset (p=0.003) and women were nearly twice as likely as men to report embarrassment (OR=1.85, p=0.01). Independent of tremor severity, embarrassment nearly doubled the odds of using tremor medication (OR=1.86, p=0.01). CONCLUSIONS: Embarrassment may be a source of disability in ET. Even among clinic patients with mild tremor, nearly one-half reported embarrassment. We identified a number of patient characteristics linked to embarrassment. Embarrassment alone (i.e., independent of tremor severity) was responsible for a doubling of tremor medication usage. The majority of clinical trials do not assess the therapeutic effects of medication on embarrassment. These trials may benefit from scaled assessments of level of embarrassment.

Action tremor of the legs in essential tremor: prevalence, clinical correlates, and comparison with age-matched controls.

The hallmark feature of essential tremor (ET) is action tremor of the arms. Leg tremor may also occur yet it has not been the central focus of previous studies. Its prevalence has only rarely been reported, its clinical correlates have yet to be explored. Our aims were to report the prevalence and analyze the clinical correlates of leg action tremor in patients with ET and, given the propensity for normal elderly individuals to manifest mild limb tremors, compare the prevalence with that in age-matched controls. Kinetic leg tremor rated > or =1 occurred in 28/63 (44.4%) ET cases and in only 9/63 (14.3%) controls (p<0.001); moderate leg tremor occurred in 14.3% of cases. Leg tremor severity modestly correlated with disease duration (r=0.31, p=0.02). However, the severity and laterality of leg tremor did not correlate with those of arm tremor. The pathophysiological implications of this finding deserve further exploration.

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.

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.