In this blog post, we use these relevant SEO keywords to frame our discussion: essential tremor, Parkinson’s disease, tremor-dominant, nonmotor symptoms, hyposmia, PD, ET, differential diagnosis, action tremor, resting tremor, disease onset, family history, NMSS, urinary symptoms, clinical features, scale assessment, retrospective study, logistic regression, TETRAS, UPDRS.
ABSTRACT
Background
Distinguishing between essential tremor (ET) and tremor-dominant Parkinson’s disease (PD-TD) can be challenging due to overlapping motor symptoms. This study aims to investigate the differences in nonmotor symptoms (NMS) between ET and PD-TD patients to provide additional evidence for differentiating these two conditions.
Methods
This retrospective study included 1656 participants, comprising 558 PD-TD patients, 584 ET patients, and 514 controls. ET patients were assessed using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS), while PD-TD patients were evaluated based on the Unified Parkinson’s Disease Rating Scale (UPDRS). All participants were assessed for NMS using the Nonmotor Symptoms Scale (NMSS).
Results
The composite NMSS score for the PD-TD group was significantly higher than that for the ET group and the control group (23.44 ± 20.20 vs. 12.60 ± 14.89 vs. 9.37 ± 12.44, p < 0.001). Compared to ET patients, PD-TD patients had an increased risk of all NMS, especially in hyposmia (OR = 7.70, 95% CI: 5.11–11.62). The NMSS score, urinary symptoms, and hyposmia may play a role in differentiating ET from PD-TD. The area under the curve (AUC) is 0.766 (95% CI: 0.739–0.793), with a sensitivity of 80.8% and specificity of 58.6%. When family history is included in the analysis, the AUC increases to 0.819 (95% CI: 0.795–0.843), with sensitivity improving to 82.4% and specificity to 68.2%.
Conclusions
The study reveals significant differences in NMS between ET and PD-TD. Compared to patients with ET, those with PD-TD exhibit more frequent and severe NMS. NMS and family history are helpful in differentiating between ET and PD-TD.
Keywords: essential tremor, hyposmia, nonmotor symptom, tremor-dominant Parkinson’s disease
This study highlights significantly higher nonmotor symptoms (NMS) in tremor-dominant Parkinson’s disease (PD-TD) compared to essential tremor (ET), particularly hyposmia (OR = 7.70, 95% CI: 5.11–11.62). NMSS scores, urinary symptoms, and hyposmia may help distinguish PD-TD from ET. The area under the curve (AUC) is 0.766 (95% CI: 0.739–0.793), with 80.8% sensitivity and 58.6% specificity. Including family history improves the AUC to 0.819 (95% CI: 0.795–0.843), with sensitivity at 82.4% and specificity at 68.2%.
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1. INTRODUCTION
Essential tremor (ET) and Parkinson’s disease (PD) are common movement disorders whose prevalence increases with age, affecting approximately 4.6% and 1.8% of the population over 65 years old, respectively. ET is primarily characterized by action tremor of the upper limbs, while resting tremor is more common in PD patients. However, clinical observations have identified a degree of symptom overlap between ET and PD. For example, a large percentage of PD patients experience action tremor, and a noteworthy proportion of ET patients may present with resting tremor. Some patients with ET may also exhibit “soft neurological signs” such as questionable dystonic posturing, and there is a potential for ET to progress into PD. These factors complicate the accurate diagnosis of these two diseases. The tremor-dominant PD (PD-TD), characterized predominantly by tremor, further blurs the clinical distinction between PD and ET, with up to 37%–50% of tremor cases being misdiagnosed at initial presentation.
Several studies have explored different approaches to distinguish between ET and PD. In addition to the evaluation of clinical symptoms, various experimental techniques have been applied, such as neurophysiology, neuroimaging, and fluid biomarker assessments. These methods show potential in aiding differential diagnosis, particularly in the early or prodromal stages of the diseases. Furthermore, olfactory testing has also been investigated as a valuable supplementary tool for differentiating ET from PD. The differentiation between ET and PD primarily relies on the evaluation of clinical symptoms, particularly the differences in motor symptoms. In fact, aside from motor symptoms, patients with ET and PD experience various nonmotor symptoms (NMS), such as mild cognitive impairment, depression, anxiety, and sleep disorders, which often appear in the early stages of the disease. Identifying these distinct NMS may aid in differentiating ET from PD-TD. Research indicates that ET and PD-TD may exhibit distinct NMS profiles, yet due to the limited number of studies and small sample sizes of included patients, the precise differences in NMS between them remain contentious. Given this background, this study is dedicated to exploring the differences in NMS between ET and PD-TD, aiming to provide additional criteria for distinguishing between the two.
2. METHODS
2.1. Patients and Study Design
This retrospective study, conducted from May 2020 to May 2023, involved the continuous evaluation of participants recruited through outpatient and inpatient departments across 19 clinical centers in China. The study excluded patients diagnosed with secondary Parkinsonism, acquired or physiological tremors, dystonia, and other types of tremor disorders. The control group was composed of healthy volunteers, ensuring through evaluation that they did not have any significant neurological diseases, nor did they or their family members have a history of ET, PD, or other tremor conditions. All participants underwent comprehensive neurological examinations and assessments.
The clinical demographic data collected included gender, age, age at onset (AAO) of disease, disease duration, medical history, family history (ET probands have blood relatives with ET, and PD probands have blood relatives with PD), and both motor and nonmotor symptoms, which were obtained from the China Parkinson’s Disease and Movement Disorder Multi-Center Database and Collaborative Network (PD-MDCNC). This study received approval from the Medical Ethics Committee of Xiangya Hospital, Central South University, and was conducted in strict accordance with the ethical principles of the Declaration of Helsinki. Informed consent was obtained from all participants.
2.2. ET Criteria
The diagnostic process for individuals with ET is guided by the criteria put forth by the International Parkinson and Movement Disorder Society (MDS). In evaluating tremor severity, the assessment employs the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS). This scale is bifurcated into two segments: TETRAS Part I, which quantifies the tremor’s impact on the functionality of daily living, and TETRAS Part II, which delineates the tremor by type (inclusive of postural and kinetic tremors), its spatial distribution (spanning head, facial regions, vocal cords, limbs, and trunk), and its intensity. The grading on the TETRAS scale is directly proportional to the severity of tremor manifestations, with higher scores indicating greater severity.
2.3. PD Criteria
The diagnosis of PD patients adhered to the MDS Clinical Diagnostic Criteria, utilizing the Unified Parkinson’s Disease Rating Scale (UPDRS) and its associated subscores, as well as the Hoehn and Yahr Scale (H&Y) for staging the disease. The tremor score (calculated as the sum of items 20 and 21 from Part III of the UPDRS divided by 4) and the akinetic/rigid score (the sum of items 22–27 and item 31 from Part III of the UPDRS divided by 15) ratio was computed. When this ratio is greater than or equal to 1, patients are classified as having the PD-TD. The study included PD-TD patients with Hoehn and Yahr Scale ≤ 2.5.
2.4. Scale Assessment
Within the framework of this investigation, a meticulous process of medical history documentation and neurological evaluations was carried out for all subjects, with the Nonmotor Symptoms Scale (NMSS) serving as the primary tool for quantifying NMS. The NMSS, encompassing a diverse set of 30 questions, spans nine pivotal domains: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucination, memory/attention, gastrointestinal tract, urinary, sexual, and miscellaneous symptoms. The frequency of each NMS was then calculated based on the proportion of patients who scored ≥ 1 on each item or domain of the NMSS. The Mini-Mental State Examination (MMSE) was utilized to assess cognitive function.
2.5. Statistical Analysis
This study’s statistical analyses were meticulously executed using SPSS software, version 26.0. Prior to the analytical phase, an elaborate process was undertaken to code, cleanse, and verify the integrity of the dataset. For the presentation of data, continuous variables were expressed as mean ± standard deviation, and categorical variables were delineated in percentages. The analytical strategy incorporated the use of chi-square tests for categorical variables and Mann–Whitney U tests for continuous variables to facilitate comparative analysis between groups. Further comparative evaluations among the ET, PD-TD, and the control cohorts on continuous variables were conducted employing generalized linear models (GLM), with adjustments for pertinent confounders such as age, gender, body mass index (BMI), and AAO. Using both univariate and multivariate logistic regression analyses, we identified risk factors for NMS in ET and PD-TD to construct a clinical diagnostic prediction model. The diagnostic performance of the model was quantified using the area under the receiver operating characteristic (ROC) curve (AUC). Statistical significance was determined at a threshold of p < 0.05.
3. RESULTS
3.1. Clinical Characteristics of the Study Population
This retrospective investigation encompassed 1656 Chinese adults, including 558 PD-TD patients, 584 ET patients, and 514 individuals in the control group. Gender distribution across the PD-TD and ET cohorts did not reveal statistically significant differences, though a slight male predominance was noted in the PD-TD group. The groups presented distinct average ages: 60.35 ± 9.83 years for PD-TD, 53.80 ± 16.21 years for ET, and 60.93 ± 19.79 years for the control group, underscoring significant age disparities. ET patients demonstrated an earlier AAO compared to PD-TD counterparts (42.17 ± 17.00 vs. 56.53 ± 10.11, p < 0.001), with ET also exhibiting a prolonged disease course (11.63 ± 10.25 years vs. 3.82 ± 3.64 years for PD-TD, p < 0.001). A notable difference was the higher incidence of familial history among ET patients compared to those with PD-TD (48.63% vs. 10.93%, p < 0.001).
Moreover, limb tremor asymmetry was markedly more pronounced in PD-TD patients than in ET patients (71.86% vs. 23.97%, p < 0.001). When examining tremor distribution, ET patients more frequently reported head tremor than their PD-TD counterparts, although facial tremor incidence remained comparable between groups. PD-TD patients, however, experienced a greater prevalence of lower limb tremors. Distinctions in tremor types were evident, with PD-TD largely manifesting as resting tremors, whereas ET was predominantly associated with postural/action tremors, illustrating the nuanced clinical presentations within these cohorts.
3.2. Comparison of NMS Severity Among PD-TD, ET, and Controls
The aggregated analysis underscores a progressive elevation in NMS total scores from the control group through the ET cohort to the PD-TD group (9.37 ± 12.44 vs. 12.60 ± 14.89 vs. 23.44 ± 20.20), with these differences achieving statistical significance. The PD-TD group’s NMS severity markedly surpasses that observed in the ET and control groups, with the ET group similarly exhibiting enhanced severity over the control, albeit to a lesser extent. Excluding the cardiovascular segment, a comparative analysis across all domains of the NMSS revealed significant disparities among the groups.
Subsequent adjusted scoring for NMS identified no notable discrepancies between ET and control groups within the cardiovascular, perceptual problems, urinary symptoms, and sexual function domains. Conversely, substantial variations were apparent in sleep/fatigue, mood/cognition, attention/memory, gastrointestinal symptoms, and other symptoms’ domains. A juxtaposition of PD-TD and control groups disclosed a singular domain without significant variance (cardiovascular), contrary to all other NMS domains, which diverged significantly. Comparing ET to PD-TD groups, cardiovascular, attention/memory, and sexual function domains displayed no significant scoring differences, whereas pronounced discrepancies were evident across the remaining domains. The MMSE scores for patients with ET were higher than those for PD-TD (p < 0.001). However, after adjusting for confounding factors, including age, sex, BMI, and AAO, the difference was not statistically significant.
3.3. Comparison of NMS Frequency Among PD-TD, ET, and Controls
Based on the NMSS, seven common NMS were identified. Among patients with ET, the most frequent NMS included insomnia (41.95%), mood disturbances (34.76%), urinary symptoms (32.88%), and fatigue (30.99%), with hyposmia being less common (9.24%). In contrast, patients with the PD-TD more commonly experienced urinary symptoms (60.75%), fatigue (49.10%), and mood disturbances (47.49%). The most frequent NMS in the control group were urinary symptoms (32.88%) and insomnia (22.76%).
Compared to the control group, the difference in urinary symptoms among ET patients was not significant (OR = 1.00, 95% CI: 0.78–1.29); however, adjusted data indicated a relatively higher risk of urinary symptoms in ET patients (OR = 1.57, 95% CI: 1.18–2.11). ET patients generally had a higher risk of other NMS compared to the control group, especially in terms of mood disturbances (OR = 5.20, 95% CI: 3.65–7.41). PD-TD patients also exhibited a universally higher risk across all NMS compared to the control group, often exceeding threefold, particularly in the area of hyposmia (OR = 13.80, 95% CI: 8.90–21.39).
Compared to ET patients, PD-TD patients showed an increased risk in all NMS except for insomnia, with the most significant increase observed in hyposmia, which was 7.7 times higher than in ET patients (OR = 7.70, 95% CI: 5.11–11.62). For other NMS, the risk increase in PD-TD compared to ET ranged from one to two times, indicating that the most significant difference between PD-TD and ET patients lies in hyposmia.
The co-occurrence of multiple NMS indicated that up to 94.44% of PD-TD individuals reported experiencing at least one NMS, compared to 71.23% of ET patients and 54.86% of control group members. PD-TD patients commonly exhibited between one and four concurrent NMS, with three NMS being the most common scenario. By contrast, both the ET group and the control group showed a decreasing trend in the number of concurrent NMS, with a more pronounced reduction in the control group, where 72.76% had no or only one NMS.
3.4. Clinical Prediction Models for ET and PD-TD
Univariate and multivariate logistic regression analyses conducted on the NMS of ET and PD-TD showed that the NMSS total score, urinary symptoms, and hyposmia are independent risk factors for distinguishing ET from PD-TD. Based on ROC analysis, the AUC for the NMSS level difference was 0.706 (95% CI: 0.677–0.736), the AUC for urinary symptoms difference was 0.639 (95% CI: 0.607–0.672), and the AUC for hyposmia difference was 0.654 (95% CI: 0.622–0.686). A higher AUC of 0.766 (95% CI: 0.739–0.793) was achieved when combining NMSS total score, urinary symptoms, and hyposmia, exhibiting a sensitivity of 80.8% and a specificity of 58.6%. Incorporating family history into the model further improved the AUC to 0.819 (95% CI: 0.795–0.843), with a sensitivity of 82.4% and a specificity of 68.2%, thus enhancing the differentiation between ET and PD-TD.
4. DISCUSSION
ET and PD-TD often exhibit overlap in motor symptoms, and the characteristics of NMS in these diseases have not been fully elucidated. Our study expanded the sample size to compare the NMS differences among ET, PD-TD, and a control group. The results indicated that patients with PD-TD exhibited a greater number and severity of NMS compared to those with ET. These diseases show significant differences in NMS, particularly in NMSS scores, urinary symptoms, and hyposmia. Accurately identifying these distinct NMS is crucial for assessing and developing management strategies and diagnostic procedures for ET and PD-TD.
We conducted a retrospective study revealing that PD-TD patients tend to have a later AAO and a shorter disease duration, aligning with previous findings. Additionally, ET is associated with a more prominent positive family history. Differences in motor symptoms between PD-TD and ET patients included more pronounced limb tremor asymmetry in PD-TD, while head tremor was more frequent in ET. Although these distinctions are useful, many patients still exhibit symptom overlap. Our results underscore that distinguishing these two groups based on NMS provides valuable supplementary diagnostic information.
Our logistic regression and ROC analyses showed that the NMSS total score, urinary symptoms, and hyposmia partially reflect the differences between ET and PD-TD, with an AUC of 0.766 (sensitivity 80.8%, specificity 58.6%). Adding family history to the model improved the AUC to 0.819 (sensitivity 82.4%, specificity 68.2%), highlighting the importance of both clinical NMS evaluation and family history in differential diagnosis. Notably, hyposmia demonstrated one of the largest odds ratios, indicating substantial diagnostic utility.
Future work could benefit from a longitudinal approach and more extensive coverage of nonmotor assessments, including anxiety, depression, and REM sleep behavior disorder. In clinical practice, a systematic assessment of NMS, especially urinary symptoms and hyposmia, combined with carefully taken family histories, can significantly reduce misdiagnosis rates and facilitate personalized treatment strategies.
tremor, ET, PD, NMS, diagnosis
AI-generated medical content is not a substitute for professional medical advice or diagnosis; I hope you found this blog post informative and interesting. www.parkiesunite.com by Parkie
Leonardo Prompt for Photo-Realistic Image
Prompt Text:
Ultra-realistic portrait photograph of two individuals: one representing essential tremor (with slight head tremor) and the other representing tremor-dominant Parkinson’s (showing slight resting tremor), high detail, warm clinical lighting, calm facial expressions, subtle medical setting.
Taglines:
- NMS Insights for Clarity
- ET and PD in Focus
- Unmasking Tremor Differentials
negative prompt
Malformed limbs, extra limbs, mutated hands, disfigured face, bad anatomy, malformed hands, Text, lettering, captions, generating images with text overlays