Essential tremor (ET) is a tremor syndrome, classically characterized by bilateral, upper limb, postural or action tremor, which may include tremor in other locations (1). There has been variability in terms of the diagnostic criteria used by clinicians and whether it must be diagnosed in isolation, without other neurologic signs, or may encompass accompanying clinical features. In relation to this, it has been proposed that ET may have multiple underlying etiologies, leading to the multiple observed phenotypes (2). In 2018, a new classification for tremor syndromes was introduced which addressed the phenotypic heterogeneity of ET and other tremor syndromes (3). In this classification, patients with tremor consistent with ET, but with additional neurologic signs of uncertain significance such as impaired tandem gait or dystonia, are classified now as essential tremor-plus (ET-plus).

When severe, ET may lead to social isolation and disability, increasing vulnerability to anxiety and depression (4–6). Currently, no curative treatments exist for ET, but several medications may be used to improve symptoms, including primidone, propranolol, and topiramate (1, 7). Yet, 25–50% of patients do not respond to medications, and many experience significant side effects (1). There also exist several invasive treatments, including lesioning or stimulating the ventralis intermedius nucleus (VIM) of the thalamus, effectively reducing upper extremity tremor (8, 9). In particular, deep brain stimulation (DBS) has been the preferred treatment for patients with refractory ET for the past 2 decades (10). However, there are some risks associated with DBS, which must be considered when determining whether a patient may benefit from it, including paresthesias, headache, gait disorder, dysarthria, stroke, and death (7).

DBS provides both symptomatic and functional benefits to patients with ET very early in the postoperative period (11). An improvement in tremor severity by 40% has been observed, which persists with long-term follow-up (12). Studies of long-term outcomes from VIM DBS for ET have reported progressive reduction in efficacy in 16–73% of patients, with mean follow-up ranging from 1–5 years (13–16). Given the new classification for tremor, it is unknown whether there is a difference in treatment response in patients with ET and ET-plus. Because of the potential variability in underlying etiology in ET-plus, it raises the concern that ET-plus patients may have worse long-term outcomes.

The primary objective of this study was to identify whether patients with ET-plus have worse long-term tremor outcomes after VIM DBS than patients with ET. We hypothesized that patients with ET-plus would have worse tremor outcomes than the pure ET patient group. Additionally, we aimed to explore demographic or clinical factors in patients with both ET and ET-plus that could predict loss of benefit with VIM DBS over time.

We conducted a retrospective chart and video review of all patients who underwent VIM DBS for ET and ET-plus at the Foothills Medical Center in Calgary, Alberta, between 2001 and 2018. ET was defined based on the tremor classification as “isolated tremor syndrome of bilateral upper limb action tremor, at least 3 years' duration, with or without tremor in other locations (e.g. head, voice or lower limbs), and the absence of other neurological signs, such as dystonia, ataxia or parkinsonism” (3). ET-plus was defined as “tremor with the characteristics of ET and additional neurological signs of uncertain significance such as impaired tandem gait, questionable dystonic posturing, memory impairment, or other mild neurological signs of unknown significance that do not suffice to make an additional syndrome classification or diagnosis” (3). Inclusion criteria were: (1) clinical diagnosis of ET or ET-plus at the time of DBS implantation, agreed upon by two movement disorder neurologists and one functional/stereotactic neurosurgeon; (2) DBS insertion in the VIM nucleus of the thalamus; (3) at least one-year follow-up duration; (4) age ≥ 18-years-old. Exclusion criteria included missing tremor severity data at baseline or postoperative clinical assessment, and surgical complications resulting in failed implantation or removal of device.

Data from the preoperative baseline and at each postoperative follow-up were extracted from the charts. Baseline clinical characteristics collected included: gender, handedness, age of onset of ET, age at surgery, family history (tremor, Parkinson Disease [PD], developmental delay), tremor characteristics (body distribution, activation conditions, symmetry, improvement with alcohol), previous treatments including maximum dose (propranolol, primidone, topiramate, clonazepam, gabapentin), additional neurological signs of uncertain significance (dystonia, rigidity, bradykinesia, myoclonus, mild cognitive impairment identified during presurgical neurocognitive assessment, impaired tandem gait) and etiology (acquired, genetically defined, idiopathic familial or idiopathic sporadic). Impaired tandem gait was defined as greater than one out-of-line misstep on a 10-step tandem gait (17). Bradykinesia was evaluated using finger tapping, hand movements, pronation-supination movements, toe tapping and leg agility, with abnormality defined as any of the following: regular rhythm is broken by interruptions or hesitations of movement, slowing of movements, amplitude decrement. Occasionally, when patients have severe action tremor, tremor interferes with the ability to adequately rest the arms for assessment of rest tremor. In these cases, patients were not classified as clearly having rest tremor. Tremor characteristics to appropriately classify patients as having ET or ET-plus were extracted independently from pre-operative videos by two movement disorders specialists (VB and DM), blinded to patient characteristics, with supplementation from paper charts for aspects of the examination not filmed (e.g. mild cognitive impairment). As emphasized by the consensus statement on the classification of tremor, the interpretation of these soft neurological signs is subjective (3), but consensus was achieved by both movement disorders specialists for the interpretation of soft signs and classification given as part of the present study. Postoperative videos and chart notes from follow-up visits were used to detect new-onset additional neurological findings such as the development of dystonia, gait disturbances or parkinsonian manifestations after surgery. Using the baseline chart and video data, the tremor was classified to Axis 1 tremor syndromes as ET or ET-plus, as described by the Task Force on Tremor of the International Parkinson and Movement Disorder Society (3). Structural imaging was reviewed when available for evidence of small vessel disease, stroke, basal ganglia abnormalities, and other intracranial abnormalities.

Surgery was performed by one surgeon (ZK) and utilized magnetic resonance-guided stereotaxy based on coordinates of the anterior and posterior commissure and the Schaltenbrand and Wahren brain atlas (18). Intraoperative microelectrode recordings and micro-stimulation were used to optimize anatomical targeting and correct placement confirmed with postoperative magnetic resonance imaging. Electrodes were implanted and externalized for several days to allow for postoperative testing for tremor effects and side-effects prior to a second surgical procedure in which the pulse generator was implanted. All patients were implanted with Medtronic devices.

Patients were seen in follow-up 6 months postoperatively and then on an annual basis. Tremor severity data using the Fahn-Tolosa-Marin Tremor Rating Scale (FTM) (19) was recorded prospectively in a database by movement disorder nurse clinicians (KH and PL) at each follow-up appointment. Stimulation parameter data (contact configuration, voltage, pulse width, frequency) were extracted from the records from the first and most recent programming session.

Tremor outcomes were assessed using the FTM (19). FTM is divided into three parts: (A) quantifies the tremor at rest, with posture and with action in 9 body parts; (B) rates action tremor of the upper extremities (FTM-B); and (C) assesses functional disability, with higher scores indicating worse disability (19). As primary outcome, changes in FTM-B scores for the treated limb were compared between ET and ET-plus at 1 year, 2 years, 3–5 years and 6-10 years follow-up. FTM-B was selected due to its specificity for action tremor of the upper limb, given the aim of DBS for ET is typically to reduce upper limb tremor (19). For patients with bilateral staged treatments we considered only the first treated side and included only the data obtained before the second implant, as has been done in previous studies (20). Additionally, we explored associations between worse FTM-B outcomes and demographic/clinical variables at each follow-up visit, searching for potentials predictors of response.

The study was approved by the Conjoint Health Research Ethics Board, University of Calgary (REB18-2052, approved January 21, 2019).

Charts were reviewed for 35 patients undergoing VIM DBS implantation. A total of 9 patients were excluded due to: surgical complication affecting outcome (n = 2), and missing FTM-B data from baseline or post-surgical visits (n = 7). In total, 26 patients were included in the final analysis.

The main goal of this single-center retrospective study was to identify whether patients with ET-plus experience less improvement in tremor after VIM DBS compared to patients with ET. Our patients with ET-plus did not have worse short- or long-term motor outcomes compared to patients with ET after receiving VIM DBS. Additionally, our patients with ET-plus did not have worse quality of life measures at each follow-up interval compared to patients with ET. This is a reassuring finding, providing evidence for the ongoing use of VIM DBS in ET-plus patients, despite the presence of additional neurological signs. This finding supports recently published research showing that VIM DBS is an effective treatment for ET-plus, with a similar degree of tremor suppression as seen in ET (22).

The evidence for the use of VIM DBS for ET-plus is particularly important in light of recent studies showing clinically relevant dystonia emerging after thalamic neurosurgical procedures (23, 24). In our series, none of the patients developed new symptoms compatible with dystonia, parkinsonism or gait disturbances after the VIM DBS surgery. Thus, in ET-plus with subtle dystonia, our study suggests that VIM DBS should continue to be offered to patients with medically refractory tremor. Currently, there is no published research comparing unilateral thalamotomy in the treatment of essential tremor-plus vs. essential tremor, leaving it as an important area for further evaluation. Given the published cases of clinically relevant dystonia emerging after thalamotomy for treatment of tremor in patients with pre-existing dystonia, caution should be exercised when considering thalamotomy for the treatment of ET-plus, with DBS likely being a safer option (24).

Additionally, we aimed to explore potential predictors of tremor response to VIM DBS over time for patients with ET and ET-plus. Higher baseline FTM-B score was correlated with larger changes in the same limb tremor scores at Year 1 and Year 2 follow-up, as has been shown in previous studies (20). Over time, this difference may become less significant as all patients experience some worsening of tremor (25). Although not statistically significant in the present study, a trend is seen of worsening of tremor severity at the 6–10 years post-operative follow-up interval in both ET and ET-plus groups (Figure 1). Previous studies of long-term outcomes from VIM DBS for ET have described up to 35% experiencing waning of benefit, while other have described up to 70% experiencing loss of benefit (13–16). It appears that this loss of benefit is not mediated by diagnosis of ET vs. ET-plus, but may instead be related to disease progression, misdiagnosis, or tolerance to stimulation (12). Further research must be undertaken to better evaluate for predictors of long-term treatment effect.

The presence of voice tremor at baseline was found to be associated with worse contralateral hand tremor outcomes at Years 3–5 follow-up when patients underwent VIM DBS for treatment of upper limb tremor. Outcomes of voice tremor treatment were not evaluated in this study. This finding may indicate an alternate underlying diagnosis to that of ET or ET-plus, such as segmental dystonia, particularly when the voice tremor is the predominant symptom (3). It should be noted that this does not however indicate that VIM DBS is inappropriate in the treatment of vocal dystonia. A recent small randomized controlled trial has shown left VIM DBS to trend toward improvement in quality of life and voice quality in patients with adductor spasmodic dystonia, a task-specific vocal cord dystonia (26).

There were several demographic, imaging and clinical characteristics, including specific tremor features, evaluated in this study that did not show correlation with post-VIM DBS tremor scores. These included age at surgery, age of onset of tremor, body distribution, and duration of time between the onset of tremor and surgery, as supported by previous research (20). Additionally, alcohol responsiveness did not predict response to DBS, which is in agreement with a previous study (20). A lack of benzodiazepine response has previously been described as a predictor for outcome after DBS, which our study failed to corroborate (20).

This study has a number of limitations. Most importantly, it is retrospective in nature, with small sample size. We did not have access to 3D data regarding electrode location, and thus could not include the location of active contacts in standardized space with statistical analysis comparing ET and ET-plus. In addition, nurse clinicians, when evaluating FTM, were not blinded to patient characteristics or treatment. To overcome limitations from its retrospective nature, we examined the videos blinded to time point, treated limb, and clinical characteristics to extract tremor characteristics and classification. Regardless, this comprehensive study is among the largest studies evaluating VIM DBS specifically for ET and ET-plus using the 2018 classification for tremor, providing evidence for ongoing use of DBS in both ET and ET-plus.

In our small cohort, there are no significant differences in short- and long-term motor treatment response between ET and ET-plus patients treated with VIM DBS. Further prospective research with larger sample sizes are necessary to further understand the predictors of treatment failure in ET and ET-plus, allowing for appropriate patient selection for invasive treatment of tremor. Our findings suggest that patients with ET-plus, resulting in additional neurological signs, should continue to be considered for DBS for treatment of action tremor.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Conjoint Health Research Ethics Board, University of Calgary (REB18-2052, approved January 21, 2019). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

GG: conceptualization, methodology, investigation, data curation, formal analysis, and writing — original draft. DM: methodology, investigation, and writing — review & editing. KH and PL: resources, investigation, and writing — review & editing. ZK: methodology, resources, investigation, writing — review & editing, and funding acquisition. VB: conceptualization, methodology, investigation, formal analysis, writing — review & editing, supervision, and funding acquisition. All authors read and approved the final manuscript.

This work was supported by the Neuromodulation Research & Education Fund, Alberta Health Services and Natural Sciences and Engineering Research Council of Canada (#RGPIN/04126-2017) grant to ZK.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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