Eileen Rios

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.

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.

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.

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 Parkinsons disease (PD), raises the question whether jaw tremor in ET is a marker for subsequent conversion to PD.

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.

How are we doing with the treatment of essential tremor (ET)? persistence of patients with ET on medication : data from 528 patients in three settings

Background:  The pharmacological treatment of essential tremor (ET) is not optimal. There are only two first‐line medications and troublesome side effects are common. It is not uncommon for patients to simply stop taking medication. Yet, no published data substantiate or quantify this anecdotal impression.

Mirror movements in patients with essential tremor.

Mirror movements (MM), which occur in age‐related neurodegenerative diseases such as Parkinsons 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 2× 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.

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 Parkinsons 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.

Unawareness of Head Tremor in Essential Tremor: A Study of Three Samples of Essential Tremor Patients

Patients with Huntington disease may be unaware of their chorea and patients with Parkinson disease often do not recognize or endorse their medication-induced dyskinesias. 1, 2 Head tremor occurs in essential tremor (ET),3, 4 yet patients in our experience are often unaware of it. While this phenomenon is anecdotally noted, it has not been formally documented or studied systematically. To broadly sample ET in different settings, we selected cases from three settings: a tertiary-referral center (largest sample),5 a population-based study in Manhattan,6 and a brain repository.7 As expected, cases differed in several respects (Table). Using the same clinical questionnaire, each case was asked whether he/she sometimes has a head tremor. A 20 minute videotaped tremor examination was performed, which included assessments of arm and head tremors (including sitting facing the camera, sustained phonation, reading aloud, finger-nose-finger maneuver, drinking, using a spoon, stand facing camera, and walking). The videotape was reviewed (E.D.L.); arm tremors were rated using a 0 –3 scale.8 Head tremor was rated as absent (0), mild or equivocal (1), intermittent yet clearly present (2), moderate (3), or severe (4). Table Demographic and clinical features of ET cases in each of the three ET case samples In the tertiary-referral center, 119/320 (37.2%) ET cases had head tremor on examination (≥ 1); 46/119 (38.7%) did not report having head tremor. Most false negatives asked the interviewer, “do you see a head tremor now?” When told “yes”, they uniformly commented that they were unaware of this (e.g., “I don’t notice it”). By contrast to head tremor, of 298 ET cases with dominant hand tremor while writing on examination (rating ≥ 1), only 60 (20.1%) did not report having hand tremor while writing (OR 0.40, 95% CI 0.25 – 0.64; i.e., ET cases were 2.5 times less likely to report head tremor than handwriting tremor). Patients may under-report tremor because of embarrassment; however, when we restricted analyses to 129 ET cases who reported that they were not embarrassed by tremor, 21/43 (48.8%) with head tremor did not report their head tremor. When we restricted analyses to 78 ET cases who had moderate or severe head tremor on examination, approximately one-quarter (18/78 [23.1%]) did not report head tremor (as compared to only 12/150 [8.0%] cases with moderate to severe handwriting tremor who did not report their handwriting tremor, OR 3.45, 95% CI 1.56 – 7.61). Based on these findings, we consider that failure to report head tremor was not merely due to having mild head tremor. In the population-based sample, 13/106 (12.3%) cases had head tremor on examination; 7/13 (53.8%) did not report having head tremor. In the brain repository, 92/170 (54.1%) cases had head tremor on examination, but 30/92 (32.6%) did not report having head tremor. In each setting, one-third to one-half of ET cases did not report the presence of head tremor. These same cases were two to three times more likely to report their hand tremor than their head tremor. One possibility is ET cases failed to report head tremor because they were poor historians or were embarrassed. However, they reported hand tremor with reasonably high validity and, among those who were unembarrassed by their tremor, nearly one-half did not report their head tremor. A second consideration is cognitive impairment.1 This is unlikely; in our largest sample (tertiary-referral clinic), cases with cognitive impairment (Telephone Interview for Cognitive Status9 <31) were excluded. Third, even when head tremor impedes a skilled task (e.g., while shaving), patients are often unsure whether this is due to shaky hands or a shaky head. A final possibility is that cases were actually unaware of their head tremor. Indeed, when their tremor was pointed out to them, false negatives uniformly stated that they were unaware of it. A lack of internal feedback about a movement may lessen self-awareness of that movement. 1, 2 Whether, from a proprioceptive vantage point, patients have a subjective experience of head tremor, is not clear. For example, with some types of oscillatory cranial movements (e.g., patients with congenital nystagmus, who rarely experience oscillopsia10) perceptual stability (i.e., lack of awareness of nystagmus) may be achieved through a reduced sensitivity to the motion or the use of other signals to cancel the effects of the movements (i.e., a spatial constancy feedback loop).11 Whether a similar mechanism is operative in ET cases with head tremor deserves future investigation.

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.