Correlates Between Force and Postural Tremor in Older Individuals with Essential Tremor

Essential tremor (ET) is commonly associated with kinetic tremor. However, other forms of tremor, such as force and postural tremor, may occur in ET with less severity. This study objectively assessed force and postural tremor characteristics in ET with the purpose of identifying the relationships between these tremors. Ten individuals with ET (age 71?±?5 years) and ten healthy controls (age 70?±?5 years) participated in the study. Force tremor was quantified as fluctuations in index finger abduction force during isometric contractions at 10 % maximum voluntary contraction (MVC) and 60 % MVC. Postural tremor was quantified as index finger acceleration when the subjects held their entire arm unsupported, and when their arm was supported so that only the index finger could move. Time- and frequency-domain parameters were extracted from tremor data, and then correlations within, and between, tremor subtypes were examined. ET force tremor was dependent on contraction intensity whereas postural tremor was unaffected by the level of limb support. Significant correlations existed between frequency components of postural tremor and force tremor amplitude. Force tremor amplitude normalised to the level of contraction intensity correlated to the proportion of power for postural tremor. These correlations were observed for both contraction intensities and both levels of postural support. The proportion of power represents the output of central oscillators in ET patients and therefore correlated well to force tremor. Given that significant relationships existed between spectral features of postural tremor and the overall force tremor amplitude, it is clear that these tremor modalities are not completely independent in older adults with ET.     

Magnetic Resonance Spectroscopy of the Thalamus in Essential Tremor Patients

BACKGROUND AND PURPOSE: Although essential tremor (ET) is one of the most common movement disorders, its pathogenesis remains obscure. The ventral intermediate nucleus of the thalamus (VIM nucleus) is suggested to play an important role in the occurrence of disease. In this study, the authors investigated the presence of biochemical or metabolic alterations in the thalamus of patients with ET using magnetic resonance (MR) spectroscopy. METHODS: The study group included 14 patients with ET who suffered from tremor predominantly in their right arm and 9 healthy controls. All patients and controls were right handed. Following conventional cranial MR imaging, single voxel proton MR spectroscopy of the thalamus involving the VIM nuclei was performed bilaterally in both the patients with ET and controls. Metabolite peaks of choline (Cho), creatine (Cr), and Nacetylaspartate (NAA) were obtained from each spectroscopic volume of interest. The right and left thalamic NAA/Cr and Cho/ Cr ratios were compared first within the patient group and then between the control and patient groups. The differences in age and spectroscopic data between groups were assessed using the Mann-Whitney U test, whereas the comparison within groups between left thalamus and right thalamus was done by the Wilcoxon test. RESULTS: In patients with ET, the NAA/Cr ratio of the right thalamus was found to be significantly higher than the NAA/Cr ratio of the left thalamus (P= .02). However, NAA/Cr and Cho/Cr ratios were found to be similar (P> .05) when we compared the control and patient groups for the right thalamus and then the left thalamus. CONCLUSION: These data present preliminary evidence for metabolic alterations of the contralateral thalamus (namely, low NAA/Cr ratio) in ET patients with predominantly involved right arm. However, the series is small and further data are necessary to clear the subject adequately.     

Hippocampal impairment in patients with Essential Tremor

IntroductionThere is growing evidence that a proportion of patients with Essential Tremor (ET) may develop a memory impairment over time. However, no studies have evaluated whether hippocampal damage really occur in ET. This study investigated the macro and micro-structural integrity of the hippocampus in ET subjects using a multimodal MRI approach.MethodsNeuropsychological and MRI data were acquired from 110 participants (60 patients with ET and 50 age-, sex-, and education-matched healthy controls [HC]). Whole-brain T1-weighted and Diffusion Tensor Imaging (DTI) were performed to assess macro-and microstructural alterations. MRI parameters (volume; mean diffusivity [MD]; fractional anisotropy [FA]) of bilateral hippocampi were obtained. In order to evaluate the relationship between MRI alterations and neurocognitive impairment, hippocampal parameters were also correlated with cognitive test scores.ResultsCompared to controls, ET patients showed a subclinical memory impairment with significantly lower memory scores, but within the normal ranges. Despite the subclinical damage, however, ET patients showed a significant increase in MD values in the bilateral hippocampi in comparison with HC. A significant correlation was also found between MD and memory scores in ET.ConclusionThis study improves the knowledge on memory impairment in ET, as our results demonstrate for the first time the hippocampal microstructural damage related to subclinical memory impairment in ET patients. Further studies are needed before these findings can be considered predictive of a distinct ET subtype or suggestive of a co-occurent dementia.     

Disorders of Balance and Gait in Essential Tremor Are Associated with Midline Tremor and Age

Disorders of balance and gait have been observed in patients with essential tremor (ET), but their association with tremor severity remains unclear. This study aimed to evaluate postural instability and gait changes in ET patients and to investigate their relationship to tremor characteristics with regard to cerebellar dysfunction as a possible common pathogenetic mechanism in ET. Thirty ET patients (8F, mean (SD) age 55.8 (17.8), range 19–81 years) and 25 normal controls (7F, 53.0 (17.7), 19–81) were tested with the scales of Activities-specific Balance Confidence (ABC), Fullerton Advanced Balance (FAB), and International Cooperative Ataxia Rating Scale (ICARS). Posturography and gait were assessed using a Footscan® system. Tremor was evaluated by the Fahn–Tolosa–Marin Tremor Rating Scale (TRS) and accelerometry in five upper limb positions. A mean (SD) TRS sum score of 27.0 (13.2) corresponded to mild to moderate tremor severity in most patients. In comparison with controls, ET subjects exhibited lower tandem gait velocity (0.21 vs. 0.26 m/s, P?=?0.028), more missteps (0.57 vs. 0.12, P?=?0.039), and increased postural sway in tandem stance (sway area 301.1 vs. 202.9 mm², P?=?0.045). In normal gait, step width increased with the midline tremor subscore of TRS (Pearson r?=?0.60, P?=?0.046). Moreover, significant correlations were found between age and quantitative measures of normal and tandem gait in ET patients but not in controls. ABC, FAB, and ICARS scores did not significantly differ between patients and controls. In conclusion, gait and balance alterations in ET patients occur even without subjective complaints. Their relationship with midline tremor and dependence on age suggest a connection with cerebellar dysfunction.     

Matching Asymmetry of Tremor with Asymmetry of Postmortem Cerebellar Hemispheric Changes in Essential Tremor

Although the number of postmortem studies in essential tremor (ET) has grown in recent years, clinical-pathological correlations remain limited. We are unaware of a study that has assessed whether the pathological changes in ET, if asymmetric, lateralize to the cerebellar hemisphere that is ipsilateral to the arm with more severe action tremor, as one would predict if the lesions were tremor producing. We compared postmortem changes in the right vs. left cerebellar hemispheres in ET and examined how these correlated with asymmetry of tremor on neurological examination. Action tremor in each arm was quantified using a reliable and valid clinical rating scale. Cases were divided into three clinical groups: tremor more severe on right, tremor more severe on left, and tremor symmetric. Calbindin D_28k immunohistochemistry was performed on 100 μm vibrotome sections from a standard tissue block of both right and left neocerebellums to quantify Purkinje cell linear density, torpedo counts, and a group of previously described changes in Purkinje cell axonal shape (thickened axonal profiles) and connectivity (axon recurrent collaterals, axonal branching, terminal axonal sprouting, arciform axons, extent of recurrent collateral plexus). ET cases were divided into three postmortem groups: findings greatest on right, findings greatest on left, and findings symmetric. In 18 (72.0 %) of 25 ET cases, clinical and pathological features were concordant (i.e., both clinically and pathologically right-predominant (one case), both clinically and pathologically left-predominant (five cases), or both clinically and pathologically symmetric (12 cases), p?=?0.007). In the remaining seven (28.0 %) ET cases, clinical and pathological data were not concordant, and in none were they completely discordant (i.e., tremor was more severe on the right, and postmortem cerebellar changes were paradoxically more severe on the left or vice versa). Among the seven ET cases with >20 % side-to-side difference in tremor severity, six cases (85.7 %) had the expected pathological asymmetry, with quantified postmortem cerebellar changes more marked ipsilateral to the more clinically affected side. We also created continuous measures of asymmetry. For the entire sample, there was a positive correlation between the clinical asymmetry index and the pathological asymmetry index?=?0.52, p?=?0.01 (i.e., the right-left difference in clinical asymmetry was correlated with the right-left difference in postmortem changes). For the seven ET cases with clear clinical asymmetry, the correlation was even more robust (r?=?0.78, p?=?0.039). Clinical-pathological correlations are important in terms of understanding the significance of observed pathological changes. The correlation between clinical laterality or symmetry of tremor and pathological changes in the majority of ET cases provides additional evidence that the pathological changes in the cerebellum in ET are of patho-mechanistic importance.     

磁共振测量特发性震颤和帕金森病患者基底节区核团体积的研究

目的：利用磁共振体积测量技术评价特发性震颤（ET）,帕金森病（PD）患者基底节区核团体积的变化及互相间的差异。方法：采用1．5T磁共振机测量9例ET患者、5例PD患者和8例年龄匹配正常人全脑体积、尾状核和壳核体积。比较各组之间感兴趣区体积的差异。结果：PD组双侧尾状核标化体积之和、双侧壳核标化体积之和较正常人缩小（P〈0．05）。ET组双侧尾状核标化体积,双侧壳核标化体积与正常对照组无差别。结论：PD患者存在尾状核和壳核体积的缩小,而ET患者无明显尾状核和壳核体积变化。     

Verbal Fluency in Essential Tremor Patients: The Effects of Deep Brain Stimulation

ObjectiveTo assess the effects of different frequencies of thalamic Deep-Brain-Stimulation (DBS) on cognitive performance of patients suffering from Essential Tremor (ET).MethodsIn 17 ET-patients with thalamic-DBS, Tremor-Rating-Scale (TRS), standardized phonemic and semantic verbal fluency (VF), Stroop-Color-Word-Test and Digit-span-test were investigated in three randomized stimulation-settings: i) high-frequency stimulation (HFS), ii) low-frequency stimulation (LFS) and iii) OFF-stimulation (DBS-OFF). Paired-samples t-test for TRS and one-way repeated measures analysis of variance for cognitive performance were calculated.ResultsTremor was reduced during HFS (Mean_TRS-HFS = 12.9 ± 9.6) compared to DBS-OFF (Mean_TRS-OFF = 44.4 ± 19.8, P < .001) and to LFS (Mean_TRS-10Hz = 50.0 ± 24.2; P < .001). While performance of Stroop-task and digit-span remained unaffected by stimulation-settings (P > .05), phonemic and semantic VF differed significantly between the three conditions (F_Pvf = 5.28, F_Svf = 3.41, both P < .05). Post-hoc comparisons revealed significant differences for both phonemic and semantic VF between LFS (Mean_Pvf-10Hz = 54.6 ± 9.2, Mean_Svf-10Hz = 56.4 ± 7.9) and HFS (Mean_Pvf-ON = 48.3 ± 11.4, Mean_Svf-ON = 51.1 ± 11.0, both P < .05), while DBS-OFF (Mean_Pvf-OFF = 51.2 ± 9.3, Mean_Svf-OFF = 53.6 ± 12.9) and HFS and DBS-OFF and LFS did not differ significantly (P > .05).ConclusionsHFS compared to LFS or DBS-OFF significantly reduced tremor but simultaneously worsened VF while working memory and cognitive inhibition remained unaffected. In contrast, LFS enhanced VF but did not ameliorate tremor. The data emphasize the relevance of thalamocortical loops for verbal fluency but also suggest that more sophisticated DBS-regimes in ET may improve both motor and cognitive performance.     

Balance and Motor Speech Impairment in Essential Tremor

The pathogenesis of essential tremor (ET) is still under debate. Several lines of evidence indicate that ET is associated with cerebellar dysfunction. The aim of the present study was to find corroborating evidence for this claim by investigating balance and speech impairments in patients with ET. In addition, the effect of deep brain stimulation (DBS) on balance and speech function was studied. A group of 25 ET patients including 18 with postural and/or simple kinetic tremor (ETpt) and seven ET patients with additional clinical signs of cerebellar dysfunction (ETc) was compared to 25 healthy controls. In addition, 12 ET patients with thalamic DBS participated in the study. Balance control was assessed during gait and stance including tandem gait performed on a treadmill as well as static and dynamic posturography. Motor speech control was analyzed through syllable repetition tasks. Signs of balance impairment were found in early stages and advanced stages of ET. During locomotion, ET patients exhibited an increased number of missteps and shortened stride length with tandem gait. ETc patients and, to a lesser extent, ETpt patients had increased postural instability in dynamic posturography conditions that are sensitive to vestibular or vestibulocerebellar dysfunction. ETc but not ETpt patients exhibited significantly increased syllable durations. DBS had no discernable effect on speech performance or balance control. We conclude that the deficits in balance as well as the subclinical signs of dysarthria in a subset of patients confirm and extend previous findings that ET is associated with an impairment of the cerebellum.     

Thalamic Deep Brain Stimulation May Improve Restless Legs Syndrome in Patients With Essential Tremor

ObjectivesTo determine change in restless legs syndrome (RLS) symptoms in essential tremor (ET) patients undergoing bilateral thalamic ventral intermedius (VIM) deep brain stimulation (DBS) surgery.Materials and MethodsWe retrospectively reviewed our database of ET patients with RLS who had undergone VIM DBS for tremor from 2012 to 2020. We reviewed the patients with available International Restless Leg Syndrome Study Group RLS scale scores before and after DBS. Percentage of responders, defined as proportion of patients experiencing three or more point improvement of RLS scores post-DBS, was calculated. We performed two-tailed t-test of pre-DBS and post-DBS RLS scores.ResultsWe identified 13 patients with ET and RLS who had undergone bilateral VIM DBS, of whom nine (69%) were responders post-DBS. Five of 13 patients (38%) had complete resolution of RLS post-DBS. For all patients, mean pre-DBS RLS score was 15.8 ± 7.9 which improved by 46% post-DBS to a mean of 8.5 ± 8.8 (p = 0.007). Four patients rated their RLS scale one night with the stimulator OFF and another night with the stimulator ON. The mean RLS score with stimulator ON was 15.5 ± 7.6 which improved by 53% to a mean of 6.25 ± 7.8 (p = 0.008), with two having complete resolution of RLS with stimulator ON. Of the nine responders, six preferred to keep their stimulator ON at night due to relief of RLS and better subjective quality of sleep.ConclusionsWe report for the first time improvement of RLS in patients with ET after bilateral thalamic DBS. Although many ET patients with nonrechargeable DBS systems switch off their stimulator at night to conserve battery life, those with RLS may potentially benefit from keeping their stimulator ON at night to relieve their RLS.     

Perverted Head-Shaking and Positional Downbeat Nystagmus in Essential Tremor

Even though the pathophysiology is not completely understood, cerebellar dysfunction has been invoked in essential tremor (ET). We evaluated cerebellar dysfunction in ET with the presence of perverted head-shaking (pHSN) and positional downbeat nystagmus (pDBN) which are known to reflect cerebellar dysfunction. First, we reviewed the videooculography (VOG) of 185 patients with ET from March 2007 to April 2010. Seventeen of 28 patients with pHSN and pDBN were followed up for at least a 1.8-year interval from baseline to determine the clinical course. And then, we recruited 52 consecutive patients with ET and compared their ocular motor findings with 51 normal controls using VOG. Among the 185 patients with ET, 28 (15.1 %) showed pHSN (n?=?23, 12.4 %) or pDBN (n?=?8, 4.3 %). Seventeen of them who were followed up did not develop Parkinsonism or other neurologic deficits during the observation period. The subsequent case-control study showed a higher prevalence of pHSN or pDBN (11/52, 21.2 %, pHSN in nine and pDBN in five) in patients with ET than in the normal controls (2/51, 3.9 %, pHSN only, P?=?0.015). The tremor rating scale or involved body sites did not differ between the patients with and without pHSN/pDBN. pHSN and pDBN were more common in patients with ET than in the normal controls. This result supports that cerebellar dysfunction is associated with ET.     

An Open-Label, Single-Dose, Crossover Study of the Pharmacokinetics and Metabolism of Two Oral Formulations of 1-Octanol in Patients with Essential Tremor

Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer-chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor-suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1–64 mg/kg; n?=?4), and (part B) a fixed dose (64 mg/kg; n?=?10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg.Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was assessed using spirography, whereas safety was assessed with electrocardiograms, vital signs, adverse effects surveys, and an intoxication assessment. Plasma concentrations of 1-octanol were detectable at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement. These findings provide preliminary evidence for a new class of compound that may be effective in the treatment of ET.     

Tremor and Quality of Life in Patients With Advanced Essential Tremor Before and After Replacing Their Standard Deep Brain Stimulation With a Directional System

ObjectivesPatients with essential tremor treated with thalamic deep brain stimulation may experience increased tremor with the progression of their disease. Initially, this can be counteracted with increased stimulation. Eventually, this may cause unwanted side-effects as the circumferential stimulation from a standard ring contact spreads into adjacent regions. Directional leads may offer a solution to this clinical problem. We aimed to compare the ability of a standard and a directional system to reduce tremor without side-effects and to improve the quality of life for patients with advanced essential tremor.Materials and MethodsSix advanced essential tremor patients with bilateral thalamic deep brain stimulation had their standard system replaced with a directional system. Tremor rating scale scores were prospectively evaluated before and after the replacement surgery. Secondary analyses of quality of life related to tremor, voice, and general health were assessed.ResultsThere was a significantly greater reduction in tremor without side-effects (p = 0.017) when using the directional system. There were improvements in tremor (p = 0.031) and voice (p = 0.037) related quality of life but not in general health for patients using optimized stimulation settings with the directional system compared to the standard system.ConclusionsIn this cohort of advanced essential tremor patients who no longer had ideal tremor reduction with a standard system, replacing their deep brain stimulation with a directional system significantly improved their tremor and quality of life. Up-front implantation of directional deep brain stimulation leads may provide better tremor control in those patients who progress at a later time point.     

Cerebellar Pathology in Early Onset and Late Onset Essential Tremor

Early onset and late onset essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes remains to be determined. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes and associated axonal changes, heterotopic PCs, and hairy basket ratings) in 30 ET cases with age of tremor onset <50 years, 30 ET cases with age of tremor onset ≥50 years, and 30 controls (total n = 90). We also used two alternative age of onset cut-points (<40 vs. ≥40 years, and <60 vs. ≥60 years) to define early onset vs. late onset ET. We found that ET cases with tremor onset <50 years and tremor onset ≥50 years had similar PC counts (8.78 ± 1.70 vs. 8.86 ± 1.24, p = 0.839), PC axonal torpedo counts (17.87 ± 18.27 [median =13.00] vs. 12.90 ± 10.60 [median =9.0], p = 0.486) and associated axonal pathology (all p values >0.05), heterotopic PC counts (9.90 ± 11.55 [median =6.00] vs. 5.40 ± 5.10 [median =3.50], p = 0.092), and hairy basket ratings (1.95 ± 0.62 [median =2.00] vs. 2.05 ± 0.92 [median =2.00], p = 0.314). When using the age of onset cut-points of 40 or 60 years, results were similar. Early onset and late onset ET cases share similar cerebellar postmortem features. These data do not support the notion that these age-of-onset related forms of ET represent distinct clinical-pathological entities.     

Obsessive compulsive personality disorder in Progressive Supranuclear Palsy,Multiple System Atrophy and Essential Tremor

Introductionaim of the study was to evaluate the presence of the Obsessive Compulsive Personality Disorder (OCPeD) in Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Essential Tremor (ET) and in a group of healthy subjects.Methodspatients affected by MSA, PSP and ET diagnosed according to currently accepted diagnostic criteria and a group of healthy controls were enrolled in the study. Patients with cognitive impairment were excluded from the study. The Structured Clinical Interview for Personality Disorders-II (SCID-II) has been performed to evaluate the presence of personality disorders (PeDs). The diagnosis of OCPeD was confirmed by a psychiatric interview.Resultsfifteen MSA patients (8 men and 7 women; aged 62.9 ± 7.6 years), 14 PSP patients (8 men and 6 women; aged 69.8 ± 4.4 years), 16 ET patients (10 men and 6 women; aged 70.4 ± 6.4 years) and 20 healthy subjects (10 men and 10 women; aged 65.5 ± 6.0 years) were enrolled. OCPeD was recorded in 5 (35.7%) PSP patients, 2 (13.3%) MSA patients, 2 (12.5%) ET patient and 2 (10%) controls.Conclusiona low frequency of OCPeD, close to those recorded in healthy subjects, was recorded in both MSA and ET patients. Conversely an higher frequency of OCPeD, similar to PD was found among PSP patients, supporting the possibility of an impairment of common basal ganglia network possibly involving the orbito-frontal circuits.