Introduction

Orthostatic Tremor (OT) is a movement disorder characterized by a sensation of unsteadiness and high frequency leg tremors present only upon standing. Both the sensation of unsteadiness and the tremors disappear or improve substantially by sitting, walking or leaning [1]. The 1998 Movement Disorder Society Consensus Statement on Tremors noted that in OT clinical findings were limited to barely visible or only palpable fine amplitude leg tremors, with diagnosis requiring surface EMG (sEMG) showing a 13–18 Hz pattern [2]. These criteria were also confirmed within the 2018 Consensus Statement of the Classification of Tremors, were Primary OT was described as an isolated tremor syndrome devoid of other clinical findings [3]. Therefore, as an isolated tremor disorder, associated movement phenomenology (including ataxia) is not expected within OT. Primary Orthostatic Tremor Plus occurs when patients with a baseline neurological condition (e.g. Parkinson Disease or Dementia) present with an associated Orthostatic Tremor [3].

The pathophysiology of OT is not well understood. However, many factors seem to point to cerebellar involvement, starting with findings in functional imaging and the fact that some ataxic illnesses are associated with secondary OT [4]. Interestingly, the medications typically used to treat OT can affect cerebellar function which might add information on the location of the oscillator. One study used positron emission tomography (PET) to show increased cerebellar blood flow bilaterally in OT subjects at rest. Moreover, bilateral cerebellar and contralateral lentiform and thalamic activation was present during postural upper limb tremor in OT patients, which was similar to previous findings in PET studies of patients with essential tremor and writing tremors [5, 6]. A recent diffusion tensor imaging MRI study found white matter changes to be preferentially located in the cerebellum and in key components of the frontal-thalamic-cerebellar circuit [7] and MR spectroscopy showed a concordant NAA decrease in cerebellar white matter [8], while resting state MRI revealed a decrease of activity in cerebellar and somatosensory networks [9]. Damage to the cerebellum or its pathways has also been described in several cases of OT secondary to cerebellar cortical degeneration, pontine infarction [10, 11, 12], SCA2 [12], and SCA3 [13], all with associated limb ataxia.

Historically, OT has been mostly described as a pure tremor syndrome. In fact, there has been a paucity of prospectively collected data from large patient series specifically aimed at identifying accompanying signs and symptoms in primary OT patients. This might be in part due to the rarity of the condition. However, assessing patients in a systematic, controlled fashion has led to the discovery of other commonly associated signs and symptoms in OT, including cognitive dysfunction and anxiety-spectrum disorders [14, 15]. In terms of presence of ataxia in OT, there is discrepancy in cohort descriptions ranging from a majority of patients with cerebellar symptoms in the only prospective study showing ataxia in 14 out of 18 examined subjects of a screened cohort of 37 patients [16], while retrospective analyses did not find ataxia at all in 68 OT patients [17] or exceptional cases of ataxia with 1 out of 5 patients designated as OT plus out of a cohort of 45 OT patients [18] and 2 patients out of 184 OT cases [19]. The lack of systematic and prospective data collection might be the culprit for mounting controversy [20, 21, 22].

Given the growing evidence of cerebellar involvement in OT, we hypothesized that ataxia may be more prevalent in this patient population than previously suggested by retrospective studies. This study attempts to answer the question of the prevalence of ataxic signs in patients with OT by the prospective, systematic performance of comprehensive ataxia testing in a relatively large cohort of OT participants.

Methods

Results

Test results

There were statistically significant differences between OT patients and controls on the BARS. Using the most stringent criteria (BARS score equal or more than 1), twenty-four (87.5%) OT subjects had an abnormal score vs. 11 (52.4%) controls (Table 3). In 33 patients versus 21 controls BARS total score had a mean of 5.42 ± 3.40 versus 1.14 ± 1.42 (p < 0.001) and a median of 6 versus 1, respectively (Figure 1). When the scores were broken down, appendicular and truncal ataxia were found to be common in the OT subjects compared to controls. We did not find a significant difference in ocular or speech ataxia among our subjects (see Table 3). However, dysarthria and knee-tibia-test scores were elevated exclusively in the OT cohort, not in controls. We also found significant differences on the DLC and DS assessments which is consistent with what was found on the BARS (Table 3). There was no correlation between total BARS score and disease duration (data not shown).

Table 3

Coordination Exam results.

BRIEF ATAXIA RATING SCALE (n)	Number of patients with BARS item ≥1 (%)	Number of controls with BARS item ≥1 (%)	P Value (2-tailed Student’s t-test)
Gait (33 cases, 21 controls)	23 (69.7)	5 (23.8)	<0.01
Knee tibia test – right (33 cases, 21 controls)	11 (33.3)	0 (0)	0.01
Knee tibia test – left (33 cases, 21 controls)	8 (24.2)	0 (0)	0.03
Finger to nose – right (33 cases, 21 controls)	25 (85.8)	5 (23.8)	<0.01
Finger to nose – left (33 cases, 21 controls)	28 (84.8)	6 (28.6)	<0.01
Dysarthria (33 cases, 21 controls)	3 (9.1)	0 (0)	0.16
Oculomotor (33 cases, 21 controls)	13 (39.4)	6 (28.6)	0.34
Number of Participants with BARS total ≥1 (33 cases, 21 controls)	29 (87.9)	11 (52.4)	<0.01
BARS total Score (33 cases, 21 controls)	Median, Mean, SD	Median, Mean, SD	P Value (Chi Square Test)
	6, 5.42, 3.16	1, 1.14, 1.42	<0.001
DETAILED LIMB COORDINATION TESTING (n)	Number of patients with abnormal test (%)	Number of controls with abnormal test (%)	P Value (Fisher exact test)
Finger to nose (34 cases, 21 controls)	24 (70.6)	8 (38.1)	<0.01
Rapid alternating hand movements (34 cases, 20 controls)	11 (32.4)	2 (10)	0.301
Finger Chase (Finger following finger) (34 cases, 20 controls)	28 (82.4)	8 (40)	<0.01
Sequential hand movements (34 cases, 21 controls)	21 (61.8)	4 (19)	<0.01
Heel knee shin (34 cases, 21 controls)	8 (23.5)	0 (0)	0.02
Toe following finger (34 cases, 20 controls)	23 (67.6)	7 (35)	0.01
Hand rhythm tapping (34 cases, 21 controls)	7 (21.2)	2 (9.5)	0.6
DETAILED STANCE AND GAIT TESTING (n)	Number of patients with abnormal test (%)	Number of controls with abnormaltest (%)	P Value(Fisher exact test)
Truncal sway (32 cases, 20 controls)	9 (28.1)	0 (0)	<0.01
Stance base (34 cases, 21 controls)	28 (82.4)	4 (19)	<0.01
Stance with eyes closed feet apart (34 cases, 20 controls)	25 (73.5)	0 (0)	<0.01
Stance with eyes open and feet together (34 cases, 19 controls)	26 (76.5)	2 (10.5)	<0.01
Stance with eyes closed and feet together (34 cases, 19 controls)	31 (91.2)	5 (26.3)	<0.01
Tandem gait (33 cases, 21 controls)	20 (60.6)	3 (14.3)	<0.01
Pull test (more than 3 steps backwards) (33 cases, 21 controls)	23 (69.7)	6 (28.6)	<0.01

Figure 1 

Distribution of BARS total scores (A) and BARS finger-to-nose-test scores (B) among OT patients versus controls.

Discussion

Based on this prospective study, the presence of ataxia in OT seems more common than previously reported [18, 19]. Previous negative studies were either retrospective [18, 19], or did not include systematic ataxia exams [25]. Our data is in agreement with previous findings of mild oculomotor ataxia found in prospective studies with distinct neuro-ophthalmologic methodology [16, 26], while retrospective studies did find ataxia only in exceptional cases: no ataxia in 68 OT patients [17], 1 patient designated as OT plus with ET and ataxia among a cohort of 45 cases (5 OT plus) [18], 2 patients in a cohort of 184 patients [19]. The discrepancy could be in part due to disease duration, which was longer in the prospective study (14.1 years) and closer to our cohort’s (18 years), whereas the disease duration in retrospective studies was below 10 years [18, 19]. One retrospective study however included follow up visits after a median of 6 years, which resulted in a disease duration of 14 years [17], but focused on progression of OT symptoms.

The strengths of our study include its prospective nature, the systematic assessment of ataxia, the use of validated scales, the use of multiple tests, the use of controls, the high level of intra- and inter-rater agreement, and the relatively large cohort for a rare disease. Limitations of our study include the relatively small cohort of patients. Also, a minority of our patients were taking medications for OT, which were not stopped for the sake of this study and could cause or worsen ataxia, particularly in toxic levels. But the use of toxic levels would be unlikely in these stable patients. In fact it has been reported that many OT patients end medical treatments quickly if side effects occur [20]. Importantly, many participants who were found to have signs of ataxia, were not taking any medications. Another important limitation is that by choosing to use spousal controls, the gender distribution was not egalitarian, particularly since more females are affected by OT.

The presence of ataxia or cerebellar dysfunction is germane to the pathophysiological understanding of many movement disorders and especially tremor disorders like essential tremor [27] and OT [28]. Ataxia was consistently mild in our sample, which renders its detection in OT more difficult. This might help explain why ataxia has not been consistently reported in OT. Importantly, ataxia scales have been primarily designed to rate severity of ataxia in known cerebellar disorders rather than as screening tools to extract mild ataxia from complex movement disorder patients. The difficulty of choosing an ataxia test in this setting is illustrated by a recent study where the authors were successfully using eyeblink classical conditioning as marker of cerebellar dysfunction in OT patients, while the clinical ataxia scale (SARA, Scale for the Assessment and Rating of Ataxia) [29] did not reach significance in their cohort of 13 patients compared to controls, most likely due to underpowered sample size [26]. As neurologists, we favor direct measurements of motor disability using clinical scales, which was the emphasis in our study. OT gives us the advantage of occurring only when standing, so that ataxia examinations carried out while sitting or lying down should be less affected by the tremor. However, we acknowledge that OT pathophysiology has not been unraveled yet and rare cases with symptoms in other body positions have been described [18]. A limitation of our study is that direct influence of subclinical tremor on BARS rating cannot be excluded completely. BARS does not contain any standing item as opposed to SARA [29] or ICARS [30], which might conveniently render it best for OT populations. We did not find a correlation of BARS total score and disease duration. However, since the OT-10 Severity Scale was not available when we completed the data collection, we were unable to calculate a correlation of OT and ataxia severity.

There is some agreement to a single central tremor generator in OT, but the location of such a generator remains unclear [28]. The findings of this study are supportive of cerebellar pathway involvement. Increased cerebellar activation seems undisputed in OT patients [6, 31, 32]. Moreover, activated cerebello-thalamic pathways seem to be involved in several tremor disorders such as essential and writing tremors [5]. It is unclear if cerebellar activation comprises an attempt to compensate tremor of a different source that may or may not arrive at attenuating it. Also a primary cerebellar defect could lead to OT oscillations based on recent findings of grey matter atrophy in cerebellar lobule VI with concurrent hypertrophy in the upper vermis and cerebrocortical motor regions in OT [31].

With our finding that ataxia is common in OT we see opportunities for additional studies. We did not evaluate brain images in our OT patients and in light of previous studies, cerebellar subregional volumes would be interesting to study in OT. Reproduction of previous studies of functional imaging [33] on a larger scale to enhance focal and time resolution would also be useful in determining the role of the cerebellum in OT. Also, as more findings are added to the list of motor and non-motor associations in primary OT (now to include ataxia, cognitive and behavioral components), revisions to existing diagnostic criteria might be entertained. Lastly, we believe that as clinicians, these findings could make us consider a more thorough coordination exam in patients with OT, and the avoidance of possible offending drugs.