Essential tremor plus – a syndrome with greater cerebellar involvement?

Summary

Introduction: Essential tremor (ET) is characterized by isolated action tremor of the upper limbs, with or without tremor of the head, voice, or lower limbs. The newly defined ET plus (ET+) syndrome is characterized by the presence of additional mild neurological symptoms that are not indicative of other disease. Aim: This study investigated the incidence of ET+ in our patients to better understand the pathophysiological basis of both entities, with a special focus on cerebellar involvement. Methods: In a cohort of 51 patients with ET (27 women, mean age 67.5 ± 13.1 years), we verified anamnestic data and neurological findings. Tremor severity and the degree of disability in activities of daily living were assessed using The Essential Tremor Rating Assessment Scale (TETRAS), while symptoms of cerebellar involvement used the Scale for the Assessment and Rating of Ataxia (SARA). Results: ET+ was identified in 22 patients (mostly due to resting hand tremor), while 29 patients had “pure” ET. The two groups did not differ in age of onset or symptom duration. Patients with ET+ had a higher incidence of head tremor compared to those with ET (81 vs. 43%; P < 0.05) and higher scores on both the TETRAS and SARA scales (all P < 0.01). Conclusion: ET+ patients exhibited more severe overall tremor disability, a higher incidence of head tremor, and more pronounced signs of ataxia compared to patients with “pure” ET. Cerebellar involvement appears to play a significant role in additional manifestations of disability that characterize ET+ syndrome.

Keywords:

essential tremor – Cerebellum – head tremor – essential tremor plus – resting hand tremor

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

Essential tremor (ET) is the most common cause of tremor and the most common disorder with involuntary movements in adults. The etiopathogenesis of ET remains unclear, although some studies have suggested cerebellar dysfunction and speculated on its possible neurodegenerative involvement in ET [1-3]. The diagnosis of ET is a clinical one, based on classical diagnostic criteria, based on the finding of bilateral, predominantly symmetrical postural or kinetic tremor of the hands and forearms, or head tremor, without the finding of other abnormal neurological signs [4]. However, classic ET studies have also found patients with ancillary findings such as mild impairments in memory, posture, or stability during tandem gait [5-9]. There was no consensus on which of these additional symptoms are still acceptable within the definition of ET. Therefore, the 2018 consensus update on tremor classification defines ET as an isolated upper limb (HL) bilateral action tremor syndrome of at least 3 years duration [10]. Tremor can also occur in other locations (head, voice, lower limbs) but not in isolation -⁠ the underlying condition is an action tremor of the HK. No other neurological symptoms such as dystonia, ataxia or parkinsonism may be present. Therefore, according to this new classification consensus, a new syndromological unit, essential tremor plus (ET+), has been extracted from ET. These are cases of patients who, in addition to action tremor, have other mild symptoms that are not sufficient on their own to diagnose another syndrome or disease (resting tremor of the HK, impairment of tandem gait, suggestive dystonic posture of the HK or another part of the body, signs of mild cognitive deficit, etc.) [10]. However, shortly after its inception, the concept of ET+ became the subject of controversy regarding its validity and utility [11-13]. According to one study, individuals classified as ET+ even prevail among patients with ET [11].

The aim of this study was to determine the prevalence of ET+ in our cohort of patients and to evaluate the differences in anamnestic data and clinical findings between patients with ET and ET+ with special attention to cerebellar involvement.

 

Methodology and subjects

Subjects

Patients were recruited at the Centre for Extrapyramidal Diseases, Department of Neurology, 1st Faculty of Medicine, Charles University in Prague from May 2020 to September 2022. Patients with comorbidities affecting neck movement, phonation, HK movements (including findings of hypokinesia or rigidity), stability or gait were not included in the study. In the case of treatment of head tremor by administration of botulinum toxin to the neck muscles, the minimum interval after the previous dose was set at 12 weeks. Each patient was asked to discontinue medication used for tremor for at least 24 h before the examination. The study was approved by the institutional ethics committee and all patients were duly informed and signed informed consent.

 

Anamnestic data and clinical examination

Each patient was screened using a structured questionnaire focusing on family history of tremor, symptoms of the disease and their development, comorbidities, and the effects of alcohol and tremor medications. The clinical examination by a neurologist (PH) consisted of an assessment of tremor severity using The Essential Tremor Rating Assessment Scale (TETRAS) [14] including the Activities of Daily Living (ADL) and Performance Subscale (PS) incl. Head tremor subscale (TETRAS PS, item 1) and Action tremor subscale (TETRAS PS, item 4) consisting of the sum of the right and left HK tremor subscores (postural HK tremor in forearm and wing position and kinetic HK tremor). Resting HK tremor was assessed using the Movement Disorder Society -⁠ Unified Parkinson's Disease Rating Scale (MDS-UPDRS), items 3.17 and 3.18 [15]. Head position was assessed by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and none of the patients included in the study had scores exceeding one point on any of the items for rotation, laterocollis, antero -⁠ or retrocollis, and lateral or sagittal displacement in the TWSTRS I.A subscale [16]. Signs of cerebellar involvement or symptoms of ataxia were tested using the Scale for the Assessment and Rating of Ataxia (SARA) [17].

 

Division into subgroups

For the purpose of this study, patients were divided into two subgroups, ET and ET+, whose diagnosis was made according to the current criteria [10]. The criterion for inclusion in the ET+ group was the presence of resting HK tremor according to the MDS-UPDRS, items 3.17 and 3.18 [15]. Patients with a total resting tremor score from both HKs greater than 2 were classified as ET+. Patients with mild head deviations at rest, with a non-zero score on any of the items of the TWSTRS I.A subscale, were further classified as ET+ [16].

 

Statistical analysis

The chi-square test was used for descriptive analysis and to determine the significance of head tremor prevalence, family history and the effect of alcohol.

In the statistical analysis, the TETRAS ADL, TETRAS PS, PS item 4, PS without PS item 1, and SARA scales were compared. Values greater than 1.5 interquartile range (IQR) were designated as outliers and were not considered in testing. Normality of data was tested using the Shapiro-Wilk test. Because the data were not normally distributed, results are presented as medians and interquartile ranges. The Mann-Whitney test was used for comparisons between groups. The significance level of p = 0.05 was adjusted to p = 0.01 by Bonferroni correction for multiple comparisons.

Furthermore, the correlation between the TETRAS ADL and SARA scales was calculated using Spearman's Rho. The calculations were performed using STATISTICA 12.0 software (StatSoft, Prague, Czech Republic).

 

Results

A total of 51 patients with a previous diagnosis of ET were included in the study (27 women and 24 men, mean age 67.5 ± 13.1 years). According to the current diagnostic criteria [10], 29 (57%) patients were included in the "pure" ET subgroup (12 women and 17 men, mean age 66.4 ± 12.6 years), and 22 (43%) patients were included in the ET+ subgroup (15 women and 7 men, mean age 69.0 ± 13.7 years). Of these, 18 (82%) were found to have resting HK tremor in addition to action tremor (three patients in combination with mild head deviation), three had mild head deviation in addition to HK tremor, and one patient had a known cognitive deficit. Resting tremor occurred symmetrically in both HKs in 11/18 (61%) patients and was unilateral or asymmetric in 7/18 (39%) patients. None of the patients were found to have bradykinesia or rigidity.

Patients with ET and ET+ did not differ in age of onset of tremor or duration of difficulty, in frequency of family history of tremor, or in the reported effect of alcohol on tremor (table 1). HK tremor was reported as the first symptom by 29/30 (97%) ET patients and 18/21 (86%) ET+ patients (p = 0.152). Head tremor was reported as the first symptom by 1/30 (3%) ET patients and 3/21 (14%) ET+ patients.

Objective examinations showed significantly more frequent head tremor in patients with ET+ compared to ET, which was more severe in ET+ than in ET according to the TETRAS PS 1 subscore (Tables 1, 2). Furthermore, ET+ patients had significantly higher disability scores in the TETRAS ADL and PS subscales as well as in the HK action tremor subscore (TETRAS PS item 4) (table 2, fig. 1). The significant difference in PS scores persisted even after removal of the head tremor subscore (PS item 1). Furthermore, ET+ patients showed significantly higher SARA ataxia scores compared with ET. The most prominent differences were in gait, speech, and HK intention tremor (table 3). The severity of disability according to the TETRAS ADL subscale correlated with the severity of cerebellar disability in SARA (Spearman's Rho 0.72, p < 0.001) when the calculation was applied to the whole set of 51 patients (fig. 2).

 

Discussion

The aim of this study was to examine in detail the cohort of subjects followed up in our ET centre, to exclude patients with symptoms corresponding to the clinical unit ET+ and to compare the findings between patients with ET+ and "pure" ET. The proportion of 43% of patients in our cohort who were classified as ET+ due to the presence of neurological symptoms other than action tremor HK is similar to the 39% of patients with ET in a previous paper [12], whereas another publication reported reclassification to ET+ in up to 83% of patients with an initial diagnosis of ET [11]. Our groups of patients with "pure" ET and ET+ were of comparable age, age of onset and duration of disease progression, with a significantly higher proportion of women in the ET+ group. In both groups, HK tremor was the predominant first symptom of the disease. However, there was a significantly higher incidence of head tremor in ET+ patients compared with ET. Both TETRAS subscores were also higher in the ET+ group, demonstrating more severe impairment in normal daily activities and higher objective severity of tremor.

The main secondary symptom in 82% of our ET+ patients was resting tremor of the HK, which was also the most frequent finding in 88% and 63% of ET+ patients in previous studies [11,12]. According to an earlier study in which patients were classified into a single ET cohort, resting tremor was associated with longer duration and more severe ET symptoms [18]. This is supported by the results of our study, in which ET+ patients had comparable disease duration but a higher level of tremor disability according to the TETRAS PS score, even after removal of the head tremor subscore. The TETRAS PS subscale is otherwise narrowly focused on action tremor, so that resting tremor is not directly reflected in its score, and may possibly affect only the rating on the social impact of tremor item of the TETRAS ADL. However, in cases of ET with asymmetric occurrence of resting tremor, suspicion of seeding Parkinson's disease (PD) may arise, which is indeed more common in patients with ET than would be consistent with a coincidence of the two diseases [19]. Therefore, the condition of at least 3 years of isolated action tremor duration was added to the new ET classification criteria to, among other things, distinguish the simultaneous development of PN [10]. However, none of our patients were found to have rigidity or hypokinesia, so PN did not seem likely at that time and they remained classified as ET+.

Unsurprisingly, the severity of impairment in activities of daily living by tremor as assessed by the TETRAS ADL in our patients correlated with the severity of cerebellar impairment in SARA. According to one of the classic papers, intention tremor, hypermetria, and also head and trunk tremor were already evident in some ET patients, which the authors attributed to cerebellar impairment [9]. The incidence of intention tremor and other signs of cerebellar involvement was significantly related to the duration of the disease [9]. In our patients, we did not demonstrate an association with disease duration, but signs of cerebellar involvement, especially abnormalities of gait, speech, and severity of intention tremor HK, were significantly more severe in ET+ patients. However, a limitation of our study is the relatively small patient population, which did not allow us to analyze the item scores of the TETRAS and SARA scales in detail or to look for associations of the higher representation of women in our ET+ group. Another limitation is that we did not verify by targeted examination possible proprioceptive impairment, which could bias the results of some ataxia tests.

The findings of our study are consistent with previous work demonstrating impairment of cerebellar function in patients with ET [9,20] and with work that has shown ataxia of standing and walking in ET dependent on tremor severity [8,21-24]. In addition, in several studies that took into account the presence of head tremor, a relevant subgroup of ET patients showed worse balance and a tendency to fall [23,24]. Furthermore, patients with ET have been shown to have impaired motor and sensory timing at the cerebellar level [25], as evidenced by the impairment in somatosensory temporal discrimination reported in our previous study [26]. The pathogenetic contribution of cerebellar circuitry impairment, particularly cerebellar oscillatory loops and brainstem, to action tremor in ET and to resting tremor in patients with PN is also supported by imaging studies [27]. Thus, even the preponderance of patients with resting tremor in ET+ cohorts supports the role of cerebellar impairment in the pathogenesis of ET.

The question remains whether and how the new classification consensus contributes to clinical diagnosis and to the stratification of tremor patient populations for research purposes [10,13]. A recently published analysis of the large Italian TITAN cohort showed, in a group of patients meeting criteria for pure ET, that taking into account additional clinical details (e.g. age of onset of tremor, familial occurrence, etc.) can increase the benefit of such detailed ("deep phenotypic") analysis in validating pathogenetic hypotheses and determining therapeutic strategies [28]. A problem with the ET+ concept is the variability in the description and interpretation of mild accessory neurological symptoms, which substantially reduces their diagnostic sensitivity and specificity. An example of the ambiguity of the current classification of tremor is the question of the classification of patients with mild head deviation who, although not having fully expressed cervical dystonia, share a number of similarities with this clinical entity. In patients classified as ET+ in the TITAN cohort, probabilistic interpretation of mild accessory symptoms has shown that, for example, the finding of questionable bradykinesia implies up to an 85% probability of not being ET, the finding of resting tremor implies a 64% probability of a diagnosis other than ET, and mild accessory dystonia implies a 46% probability of a diagnosis other than ET [29]. Thus, the ET+ concept in its current form cannot be useful in refining the diagnosis of ET. Additional neurological symptoms of unclear significance, which are not sufficient in themselves to make a diagnosis, may further develop as part of a progressive disease proceeding temporarily under the picture of the ET+ syndrome (e.g. spinocerebellar ataxia or tremor-dominant PN), but may also be manifestations of another disease with a misdiagnosis of ET [13]. Nevertheless, there is currently no evidence that a clear diagnosis of pure ET or ET+ has any pragmatic implications in terms of treatment and prognosis. Thus, for clinical diagnostic purposes, it is advisable to stick primarily to the main criterion of the new consensus, which is an action tremor of HN lasting at least 3 years. The presence of other neurological signs should lead to a detailed analysis of the phenotype of the disability, which may contribute in the search for its etiology [30].

In summary, this work showed that ET+ patients have more severe tremor disability, a higher incidence of head tremor, and more severe cerebellar impairment than patients with "pure" ET. Consistent with previous studies, our results show that cerebellar involvement contributes significantly to both the development of the action tremor of the HK (and possibly head tremor) representing "pure" ET in the current classification, and to the additional neurological symptoms such as resting tremor, ataxia, dystonia, etc., characterizing the ET+ syndrome.

The concept of ET+ can therefore be seen as a challenge to a new nosological perception of ET as a heterogeneous multifactorial syndrome consisting of action tremor and other neurological symptoms, with a prominent pathogenetic role of cerebellar involvement. A detailed analysis of the disease course and phenotype of the disability may contribute to the recognition of subtypes of the disease and to a more precise determination of their specific underlying causes and therapeutic options.

 

Ethical aspects

The work was carried out in accordance with the Helsinki Declaration of 1975 and its revisions in 2004 and 2008. The study was approved by the Ethics Committee of the General University Hospital in Prague (approval date 17 May 2015, approval number 31/18 Grant AZV VES 2019 VFN). All patients signed informed consent.

 

Financial support

This study was supported by the Grant Agency of Charles University, grant no. 580218, the project of the General University Hospital in Prague, Ministry of Health of the Czech Republic-RVO-VFN64165 and the research program of Charles University: Cooperatio Neuroscience.

 

Table 1. Anamnestic data.

	ET	ET+	p
Age of onset of difficulties	36,3 ± 22,8	37,1 ± 20,7	0,456
Duration of difficulty	30,5 ± 19,7	31,5 ± 19,1	0,428
Sex	11/30 (37%) women	15/21 (71 %) women	0,015
Family history	17/30 (57 %)	16/21 (76 %)	0,151
Effect of alcohol	18/25 (72 %)	10/17 (59 %)	0,374
Head tremor	13/30 (43 %)	17/21 (81 %)	0,020

p is the result of the t test for age of onset and duration of difficulty, otherwise it is the result of the Chi-squared test.

ET, patients with essential tremor; ET+, patients with essential tremor plus

 

 

Table 2. Clinical data.

	ET	ET+	p
TETRAS ADL	14.0 (IQR 12.3)	25 (IQR 16)	0,004
TETRAS PS	10,0 (IQR 6,0)	17,8 (IQR 8,3)	< 0,001
PS item 1	0.0 (IQR 1.0)	1.0 (IQR 1.0)	0,009
PS item 4	7,5 (IQR 4,8)	11.3 (IQR 4.0)	< 0,001
PS without item PS 1	9.5 (IQR 5.1)	16.3 (IQR 8.3)	< 0,001
SARA	1.5 (IQR 2.9)	5.0 (IQR 4.0)	< 0,001

p is the result of the Mann-Whitney test. The significance level p was corrected to p = 0.01

ADL, Activities from Daily Living; ET, essential tremor patients; ET+, essential tremor plus patients; IQR, interquartile range; PS, Performance Subscale; PS item 1, head tremor; PS item 4, upper limb action tremor summary score; TETRAS, The Essential Tremor Rating Assessment Scale; SARA: Scale for the Assessment and Rating of Ataxia

 

 

Table 3: SARA scale item ratings.

	ET	ET+	p
SARA 1 -⁠ walking	0 (IQR 1)	1 (IQR 2)	0,006
SARA 2 -⁠ standing	0 (IQR 1)	1 (IQR 1)	0,016
SARA 3 -⁠ sit	0 (IQR 0)	0 (IQR 0)	0,779
SARA 4 -⁠ speech	0 (IQR 0)	1 (IQR 1)	0,006
SARA 5 (dx.) -⁠ taxe on HK	0 (IQR 0)	0 (IQR 0)	0,779
SARA 5 (sin.) -⁠ taxe on HK	0 (IQR 0)	0 (IQR 0)	0,928
SARA 6 (dx.) -⁠ intention tremor	1 (IQR 1)	2 (IQR 1)	< 0,001
SARA 6 (sin.) -⁠ intentional tremor	1 (IQR 0.8)	2 (IQR 1)	< 0,001
SARA 7 (dx.) -⁠ diadochokinesis	0 (IQR 0)	0 (IQR 0)	0,509
SARA 7 (sin.) -⁠ diadochokinesis	0 (IQR 0)	0 (IQR 1)	0,313
SARA 8 (dx.) -⁠ taxe on DK	0 (IQR 0)	0 (IQR 0)	0,992
SARA 8 (sin.) -⁠ taxe per DK	0 (IQR 0)	0 (IQR 0)	0,992

p is the result of the Mann-Whitney test. The significance level of p was corrected to p = 0.01.

DK, lower limb; dx. -⁠ right; ET -⁠ essential tremor patients; ET+ -⁠ essential tremor plus patients; HK -⁠ upper limb; IQR -⁠ interquartile range; SARA -⁠ Scale for the Assessment and Rating of Ataxia; sin. -⁠ left