Essential tremor plus affects disease prognosis: A longitudinal study

To the Editor: Essential tremor (ET) is a common movement disorder with significant clinical heterogeneity.[1] Following the proposal of “ET-plus”, the cross-sectional investigation of ET has increased. However, the characteristics of pure ET vs. ET-plus remain unclear. Herein, we present a longitudinal follow-up study of pure ET and ET-plus patients that aimed to clarify disease progression and outcome, to determine the annual incidence rates of pure ET to ET-plus, and ET to Parkinson’s disease (ET-PD), and to investigate the clinical biomarkers influencing disease outcomes. ET patients, diagnosed according to the 2018 International Movement Disorder Society Tremor Group ET diagnostic criteria[2] from May 1, 2021, to April 30, 2022 in Xiangya Hospital, Central South University, were reviewed. The study was registered at ClinicalTrials.gov (No. NCT04198246) and was approved by the Medical Ethics Committee of Xiangya Hospital, Central South University (No. 202105090). Informed consent was obtained from all patients, who were followed up from November 1, 2022, to October 31, 2023. Neurologists performed follow-up evaluations through face-to-face interviews such as hospital visits, community clinic consultations, and home surveys. The diagnosis of ET-PD necessitates satisfying the following three criteria: (1) the diagnosis of PD must adhere to the clinical diagnostic criteria outlined by the International Parkinson and Movement Disorder Society in 2015, and the diagnosis of PD should occur at least five years after the onset of the disease. (2) At the initial diagnosis of ET, there should be no presence of any signs of PD (e.g., bradykinesia, rigidity muscles). (3) During the initial diagnosis of ET, the absence of any red flags for possible emerging PD (e.g., isolated postural tremor without kinetic tremor, unilateral kinetic tremor) is required. Demographic and clinical data were collected from the PD and Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC; http://pd-mdcnc.com) at baseline and follow-up. The Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-I was used to evaluate the impact of tremors on daily living, while TETRAS-II evaluated tremor distributions and severity. Global cognitive function was assessed using Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Dystonic posturing, the severity of non-motor symptoms, and ataxia severity were evaluated using the Unified Dystonia Rating Scale (UDRS), Non-Motor Symptoms Scale (NMSS), and the Scale for the Assessment and Rating of Ataxia, respectively. Tandem gait was assessed by observing participants performing 10 consecutive tandem steps along a straight line while keeping their arms at their sides. The rapid eye movement sleep behavior disorder questionnaire Hong Kong (RBDQ-HK) was used to evaluate rapid-eye-movement sleep behavior disorder (RBD). A total score ≥18 or a score ≥13 on the second part of the RBDQ-HK indicated probable RBD (pRBD). Continuous variables are presented as means ± standard deviation, while categorical variables are presented as percentages and frequencies. The non-parametric Mann–Whitney U test was used to compare the distribution of continuous variables between different groups. Binary variables were compared using the chi-squared test. In longitudinal analyses, Wilcoxon matched-pairs signed-rank test was used to assess within-group differences in continuous variables. Linear logistic regression analysis was used to investigate the predictive factors affecting the annual progress rate of scores on various scales. Cox regression analysis models were used to explore the prognostic factors for ET. A binary logistic regression model was used to investigate factors associated with adherence to antitremor medications. Statistical significance was set at P <0.05. Statistical analyses were performed using IBM SPSS version 25.0 (IBM Corp. , Armonk, USA) . A total of 541 ET patients, including 267 (49.4%) pure ET patients and 274 (50.6%) ET-plus patients, were recruited, of whom 22 were lost to follow-up due to refusal or incorrect contact information (dropout rate: 4.1%), and 7 patients passed away. In all, 51 ET patients completed only telephone follow-up due to a lack of cooperation for face-to-face visits. Thus, 461 successfully completed face-to-face follow-up [Figure 1], among whom 218 (47.3%) and 243 (52.7%) were initially diagnosed with pure ET and ET-plus, with average follow-up intervals of 23.29 ± 5.98 and 21.83 ± 5.47 months, respectively.Figure 1: Follow-up flowchart for 541 ET patients. ET: Essential tremor; PD: Parkinson’s disease; TAD: Tremors associated with dystonia.ET-plus patients exhibited significantly higher average annual rates of deterioration in NMSS (1.02 ± 6.02 points/year vs. 0.72 ± 2.42 points/year, Z = 3.541, P <0.001), MMSE (0.23 ± 0.82 points/year vs. 0.16 ± 0.66 points/year, Z = 2.782, P = 0.005), and MoCA (0.33 ± 0.89 points/year vs. 0.29 ± 0.63 points/year, Z = 3.331, P = 0.001) scores compared to pure ET patients. ET-plus patients further exhibited a non-significant trend toward more severe annual deterioration in TETRAS-I (0.67 ± 2.66 points/year vs. 0.57 ± 1.65 points/year, Z = 1.588, P = 0.112) and TETRAS-II (0.49 ± 1.81 points/year vs. 0.47 ± 1.47 points/year, Z = 0.929, P = 0.353) scores. A strong negative association was found between the baseline and annual increase in TETRAS-I scores (β = –0.023, 95% confidence interval [CI] = –0.044 to −0.002, P = 0.035). After adjusting for other demographic and clinical variables (including sex, age at onset, and disease duration), as well as neurological soft signs (mild cognitive impairment, rest tremor, and questionable dystonic posturing), impaired tandem gait was identified as a strong predictor of an increasing annual TETRAS-II score. The magnitude of annual increase in TETRAS-II scores for patients with impaired tandem gait was 0.505 (β = 0.505, 95% CI = 0.074–0.936, P = 0.022) points greater than those without impaired tandem gait. A strong negative association was found between the baseline and annual increase in TETRAS-II scores (β = −0.054, 95% CI = −0.074 to −0.034, P <0.001). Moreover, for every 1-year increase in age, the annual increase in TETRAS-II scores increased by 0.019 points (β = 0.019, 95% CI = 0.009–0.029, P <0.001). Annual decreases in MoCA scores were correlated with age (β = 0.014, 95% CI = 0.009–0.018, P <0.001), impaired tandem gait (β = 0.224, 95% CI = 0.028 to 0.419, P = 0.025), face tremor (β = −0.248, 95% CI = −0.0417 to −0.079, P = 0.004), voice tremor (β = 0.181, 95% CI = 0.007–0.355, P = 0.042), and baseline MoCA scores (β = 0.079, 95% CI = 0.059–0.099, P <0.001). A total of 468 patients with ET (including 461 patients followed up face-to-face and 7 deceased patients) were included in the disease outcome investigation. With an average follow-up duration of 22.6 months (1.88 years), 8/468 (1.7%) ET patients progressed to PD, yielding an annual conversion rate of 9.1/1000 person-years. Among 222 patients with pure ET, 2 (0.9%) progressed to PD, yielding an annual conversion rate of 4.6/1000 person-years. Among 246 patients with ET-plus, 6 (2.4%) progressed to PD, with a conversion rate of 13.4/1000 person-years, 2.9-fold higher than that of pure ET. One of the 468 (0.2%) ET patients progressed to tremors associated with dystonia (TAD), yielding an annual conversion rate from ET to TAD of 1.1/1000 person-years. Cox regression analysis indicated that the rest tremor (hazard ratio [HR] = 8.752, 95% CI: 2.040–37.544, P = 0.004), pRBD (HR = 9.208, 95% CI: 1.885–44.970, P = 0.006), and baseline NMSS score (HR = 1.030, 95% CI: 1.009–1.052, P = 0.005) were positively correlated with the risk of PD in patients with ET [Supplementary Table 1, https://links.lww.com/CM9/C192]. In the pure ET group, 13 patients (13/222, 5.9%) progressed to ET-plus, with an annual conversion rate from pure ET to ET-plus of 30.2/1000 person-years. Further, 8 out of 13 patients progressed to mild cognitive impairment, 3 (3/222, 1.4%) to questionable dystonic posturing, and 2 (2/222, 0.9%) to impaired tandem gait. Cox regression analysis identified age at onset (HR = 1.061, 95% CI: 1.015–1.110, P = 0.009) as a significant predictor of conversion [Supplementary Table 2, https://links.lww.com/CM9/C192]. Patients with both pure ET and ET-plus experience progressive deterioration of motor and non-motor symptoms, with tremors gradually spreading to various bodily regions. The progression of ET may differ according to clinical subtype. Our results indicated that ET-plus patients may experience a faster rate of disease progression than pure ET patients, with the two conditions associated with variance in trait conditions and progression rates. We further identified several significant predictors of motor symptom progression, including age and impaired tandem gait. The presence of neurological soft signs may be a promising prognostic factor for ET progression. This longitudinal study identified an annual conversion rate from pure ET to ET-plus of 30.2/1000 individuals per year in a Chinese ET cohort. Age at onset was an important predictor of conversion. For every 1-year increase in age at onset, there was a 6.1% increase in the adjusted odds of conversion to ET-plus. This may be attributed to the increased occurrence of degenerative neuropsychiatric disorders with advancing age. The median age at the time of conversion to ET-plus was 71 years, with a median disease duration of 8 years. Our study provides some explanation for previous findings indicating that ET-plus patients were older and had older age at onset,[3] and that older ET patients were more likely to exhibit aging effects and neurological soft signs. This study supports the hypothesis that ET-plus may indicate an advanced disease stage, rather than representing a distinct clinicopathological entity.[4] Regarding non-motor features, poor cognitive function may be a significant predictive factor for ET-plus in patients with pure ET. Herein, the annual conversion rate from ET-plus to PD was 13.4/1000 person-years, which is 2.9-fold higher than in patients with pure ET, indicating that ET-plus may represent a transitional stage between ET and PD. Further, the median duration of progression from ET to PD was 11 years, with a median age of 61.5 years at conversion. In a large pathological study of 231 ET patients, 25.1% exhibited pathological Lewy bodies in their brains, which is higher than the average reported in other studies on control populations (16.4%).[5] Therefore, the presence of pathological Lewy bodies in ET patients may serve as a potential pathological mechanism in the progression of ET to PD. In conclusion, disease progression was faster in ET-plus patients than in pure ET patients, while neurological soft signs can predict disease progression. The annual conversion rate from pure ET to ET-plus was 30.2/1000 persons/year. Age at onset is an important clinical predictor of this conversion. The annual conversion rate from ET to PD is 9.1/1000 persons per year. Rest tremor, pRBD, and more severe non-motor symptoms are significant clinical predictors of conversion from ET to PD. Acknowledgements The authors are grateful to all participants for their generous participation in this study. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. U20A20355, 82171256, and 82202051). Conflicts of interest None.

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