Objective To investigate the frequency and the main clinical features of tremor in primary adult-onset dystonia (PAOD).
Methods This cross-sectional study was conducted on 429 patients with PAOD from eight Italian movement disorder centres.
Results Of the 429 dystonic patients, 72 (16.7%) had tremor. Although sex and age at dystonia onset were similar in dystonic patients who had tremor and those who did not, patients who had tremor were affected more often by focal cervical dystonia and less often by focal blepharospasm. Dystonia had a greater tendency to spread in patients with tremor. According to the Movement Disorder Society Consensus Statement, tremor was classified as dystonic tremor (DT) in 43 patients and tremor associated with dystonia (TAWD) in 23 patients. Six patients had both types of tremor. Taking into account potential confounding by age at onset and body distribution of the corresponding dystonia type, all the clinical features in patients with DT and in those with TAWD were comparable except the tendency of dystonia to spread, which was greater in patients with DT.
Conclusions Tremor is a relatively common feature occurring in about 17% of patients with primary late-onset dystonia. The association between tremor and dystonia spread suggests that this form of tremor may be a dystonic manifestation. Similarities in phenotypic features of DT and TAWD predominated over differences, suggesting that the two forms of tremor may be manifestations of the same disease. Differences in gender and body distribution of tremor between patients with dystonia and tremor and those of patients with essential tremor also suggest that tremor in dystonia and essential tremor are different entities.
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Tremor, defined as a rhythmic, involuntary, oscillatory movement in a body part, is common in patients with dystonia.1 Its clinical features in dystonic patients may be clinically indistinguishable from those in patients with essential tremor (ET).2 On the basis of clinical and topographic criteria, the Consensus Statement of the Movement Disorder Society on Tremor classified tremor affecting a dystonic body part as dystonic tremor (DT), and tremor affecting a non-dystonic body part as tremor associated with dystonia (TAWD).1 Although there is now a consensus that accepts the association between tremor and dystonia, we still lack reliable estimates regarding the frequency and body distribution of tremor in patients with primary adult-onset dystonia (PAOD). Moreover, we do not yet know whether the presence of tremor alters the PAOD phenotype, including gender distribution, age at onset and tendency of dystonia to spread, whether DT and TAWD are distinct clinical entities, or whether tremor in adult-onset dystonia is a clinical manifestation of dystonia or an ET subtype associated with dystonia. We addressed these issues by investigating a large multicentre sample of patients with PAOD. Using a standardised interview and clinical examination, we compared data for patients with PAOD with and without tremor and data for patients with DT and TAWD.
Patients and methods
Patients with dystonia participating in this cross-sectional assessment were selected over 18 months from among consecutive outpatients attending the movement disorders clinics of eight Italian University neurological departments. Inclusion criteria were a diagnosis of blepharospasm (BSP), oromandibular dystonia (OMD), cervical dystonia (CD), laryngeal dystonia (LD), upper limb dystonia (ULD) and lower limb dystonia (LLD) as focal dystonia or as part of a segmental/multifocal dystonia.3 Only patients with disease duration >1 year were included. Exclusion criteria were: other neurological abnormalities except tremor; features suggesting dopa-responsive, paroxysmal, myoclonic or psychogenic dystonia; exposure to dopamine blockers or other drugs known to induce dystonia or tremor; other causes of secondary dystonia or tremor.3
The presence and distribution of tremor was assessed by senior neurologists with longstanding experience in movement disorders. Tremor was diagnosed according to the Consensus Statement of the Movement Disorder Society, which classified tremor affecting a dystonic body part as DT, and tremor affecting a non-dystonic body part as TAWD.1 Appropriate manoeuvres known to elicit rest, postural and kinetic tremor of the head, upper limbs and lower limbs were performed while patients were walking, standing, lying down and sitting on a chair. Patients also underwent tests for spiral drawing and handwriting. The neurological examination was standardised across centres via a training session in which the neurologists from the participating centres assessed videotaped examinations of dystonic patients with and without tremor. Raters (one for each centre) independently assessed the videorecordings of 20 dystonic patients (12 with and eight without tremor), not included in the study sample. Interobserver reliability was calculated by kappa statistics and assessed according to the Landis classification.4 Our raters yielded substantial agreement (κ=0.83, p<0.00001) for the presence of tremor in dystonic patients. All the patients whose dystonia was being treated with botulinum toxin had received their last injection at least 3 months before the clinical assessment day. Demographic and clinical data were obtained by means of a standardised interview designed to record age, gender, age at dystonia and tremor onset, history of dystonia spread, and time for dystonia to spread. Tremor affecting different body parts was classified as head/face, neck, larynx, upper limb and lower limb tremor. The date of tremor onset (approximated to 1 year) was obtained from the patient's report or our own observation. Informed consent was obtained from all the subjects according to the Declaration of Helsinki; institutional review boards (IRBs) approved the study (IRB approval No 14178, University of Bari, Italy).
Data were expressed as mean±SD unless otherwise indicated and analysed with the Stata V.11.0 package. Differences between groups were analysed by Mann–Whitney U test and χ2 test, as appropriate. The relationship between spread of dystonia and tremor was estimated by Cox proportional hazard regression models, adjusted for referral centre, sex, number of school years and disease duration. The end point for the Cox model was the age at which dystonia spread began. Patients who never experienced dystonia spread were included in the survival functions for the length of observation, but their data beyond that time were censored. HR, two-sided 95% CI, and p values were calculated. Patients with missing data were excluded from analysis. For all the statistical methods, p<0.05 indicated significance and p=0.05–0.1 indicated non-significant trend.
During the study period, 429 patients with PAOD satisfied the eligibility criteria, and all participated in the study. The demographic and clinical features of the study population are shown in table 1.
The examination disclosed postural or postural/kinetic tremor in 72/429 (16.7%; 95% CI 12.3% to 21.2%) patients (54 women and 18 men), while none of the patients had rest tremor. Mean age at tremor onset was 57.2±17.4 years. Tremor affected a single body site in 57 patients (neck in 42, upper limb in 14 and larynx in one), two body sites in 14 patients (neck and upper limb in 11, neck and larynx in three), and three body sites in one patient (chin, neck and upper limb). Tremor involved the neck more commonly than the upper limbs, larynx and chin (57 vs 26, four and one cases), upper limb tremor was unilateral in 8/26 patients, and tremor never affected the lower limbs. Tremor developed at the onset of dystonia or thereafter in 82% of patients, 1–3 years before dystonia onset in 12.5%, and 10 or more years before dystonia onset in 5.5%. The analysis comparing patients who had tremor with those who did not yielded a similar sex distribution and age at dystonia onset, whereas body distribution of dystonia differed in the two groups (table 1). In patients with focal dystonia, CD was more common in the tremor group, BSP was more common in patients without tremor, while the other focal dystonias were similarly common in the two groups (table 1). Patients in whom dystonia spread to one or more distant body sites (segmental/multifocal dystonia) were significantly more common in the tremor group than in the group without tremor (table 1); the tremor group also had a slightly longer dystonia duration (14.2±7.9 vs 11.5±9.7 years, p=0.04). Cox analysis confirmed a greater rate of dystonia spread in the tremor group, even after adjustment for disease duration, sex, education and referral centre (adjusted HR 1.6; 95% CI 1.1 to 2.5; p=0.02). Limiting the analysis to the patients in whom dystonia spread to two or more distant body sites (42/129) also yielded a greater frequency of dystonia spread in the tremor group (table 1), and this finding was confirmed by Cox analysis (adjusted HR 1.8; 95% CI 1.1 to 3.2; p=0.04).
Among the 72 dystonic patients with tremor, 43 (60%) had DT alone, 23 (32%) had TAWD alone, and six (8%) had tremor of both types (table 2). Regardless of whether they were classified as DT or TAWD, postural tremor and postural/kinetic tremor were each diagnosed in half of the cases. The three groups were similar for sex but differed for distribution of tremor in the neck, larynx and upper limb (table 2). Within-group comparisons revealed that DT alone was about four times more common in the neck than in the upper limbs (38/43 vs 10/43, p<0.0001). In contrast, the frequency of TAWD alone was similar in the neck and in the upper limbs (13/23 vs 12/23, p=0.5). The analysis also disclosed that CD was more common in the DT group and in the DT+TAWD group, whereas the other forms of dystonia were similarly distributed in the three groups (table 2). Within-group comparison revealed that DT alone was about 3–4 times more common in CD than in ULD (41/43 vs 13/43, p<0.0001); in contrast, in the TAWD group, cranial dystonia predominated over neck, larynx and ULD (14/23 vs 6/23 vs 3/23 vs 2/23, p<0.0001). Finally, despite a similar disease duration (15.1±7.8 vs 12.6±7.8 vs 13.5±9.5 years, p=0.5), dystonia spread to one or more body sites more commonly and more widely in patients with DT alone than in those with TAWD alone or DT+TAWD (table 2).
Further statistical tests comparing DT and TAWD and excluding the six patients with both tremor types who could not accurately report age at onset for each type of tremor revealed that DT appeared earlier than TAWD (age of tremor onset, 54±16.2 vs 61.6±19.6 years, p=0.03) and that age at dystonia onset tended to be lower in the DT group (51±14.8 vs 57±14.7 years, p=0.06). Tremor developed at the onset of dystonia or thereafter in 88% of the patients with DT and in 77% of those with TAWD (p=0.3).
The 10 patients with TAWD (either alone or associated with DT) who manifested segmental dystonia included a subgroup of seven patients in whom dystonia began with BSP (mean age at onset, 61±8 years) and spread later (after 8.7±8.2 years) to the oromandibular region alone (n=6) or to both the oromandibular and cervical regions (n=1). In six of these seven patients, tremor in the neck (four cases) or in the upper limbs (two cases) appeared 4.8±6.7 years after OMD/CD; in the last patient, tremor in the neck developed at age 20 and preceded dystonia (BSP) by 30 years. A second subgroup included three patients who presented with CD alone later followed by OMD. In one of these patients, laryngeal tremor developed 1 year after OMD, whereas the other two patients were unable to report precisely when TAWD began in the upper limb because they only had mild tremor that did not interfere with activities of daily living.
In this large multicentre clinical series of patients with PAOD, a detailed clinical examination disclosed tremor in 16.7% of the cases, whereas in previous studies the frequency of tremor in PAOD ranged from 7% to >70%.5–14 This wide variability between studies probably reflects methodological factors, including small patient samples,5–7 ,13 ,14 focus on one type of focal dystonia alone,5 ,6 ,8–10 12–14 medical chart review rather than clinical examination to identify tremor,8 ,14 and choice of diagnostic criteria.5–14 Unlike other studies, we examined a large, representative sample of Italian patients with PAOD. Our trained investigators used homogeneous diagnostic criteria and reached substantial interobserver agreement in recognising tremor. We therefore think that our study provides valid data that accurately estimate the frequency of tremor in patients with PAOD.
When we compared dystonic patients who had tremor with those who did not, we found a similar sex distribution and age at dystonia onset, whereas dystonia in dystonic patients with tremor tended to spread more often and more widely to other body regions. The greater frequency of CD and the lower frequency of BSP in patients who had tremor is probably due to the fact that about two-thirds of the patients with tremor had tremor involving the dystonic body part, a tremor type that in our sample was more commonly associated with CD and never associated with BSP. The association between tremor and dystonia spread as well as the observation that tremor in most patients started at the onset of dystonia or thereafter raise the possibility that tremor with onset during the course of dystonia is a dystonic manifestation. Our finding that tremor sometimes developed before dystonia leaves a possible link between the two conditions open. Given that dystonia onset may be difficult to identify, tremor reported to precede dystonia may merely reflect a recall bias.
When we compared DT and TAWD, either alone or in combination, we found similar gender distribution and timing of tremor onset to dystonia appearance. In contrast, age at tremor onset and body distribution of tremor differed significantly in the DT and TAWD groups: DT presented earlier and predominated in the neck, whereas TAWD manifested at an older age and was similarly common in the neck and upper limbs. A distinctive finding in the TAWD group was that the older age at tremor onset corresponded to an older age at dystonia onset and a greater frequency of cranial dystonia—that is, the adult-onset dystonia with a later onset. Finally, in the DT group, the ratio of DT affecting the neck to DT affecting the upper limbs matched the ratio of CD to ULD (about 4 : 1). The aforementioned findings suggest that the differences in age at tremor onset, in body distribution of tremor and, possibly, in age at dystonia onset between DT and TAWD patients might reflect differences in age at onset and body distribution for the corresponding dystonia type. Given that extracranial dystonia has a low tendency to spread,15 the greater tendency of dystonia to spread in patients with DT probably depends on factors other than the association of DT with extracranial dystonia. Our finding is nonetheless consistent with a previous study that showed that DT predicted dystonia spread to other body regions in patients with CD.14
Our study may have certain limitations. First, it is not a population-based study. Nevertheless, recruiting consecutive patients in a multicentre setting yielded a large case series that resembles the demographic and clinical features of the Italian PAOD population.16 Second, since we collected data for age at onset retrospectively, some information may have been inaccurate. We consider this unlikely given that we have previously shown that patients achieve high test–retest reliability in reporting age at dystonia onset.16 Although some tremor events documented herein manifested themselves before patient referral to the recruiting centre, some patients were followed-up for several years, and tremor events were recorded during the clinical follow-up. Third, tremor and dystonia were diagnosed on clinical grounds and were therefore exposed to bias. To overcome this flaw, we clinically examined a large sample of patients and assessed all the body sites potentially affected by dystonia and tremor (including unusual sites, such as the lower limbs).16 We also achieved substantial reliability in diagnosing tremor. Similarly, previous studies by our group show that our observers reach substantial agreement in diagnosing dystonia at different body sites.16 Finally, the lack of an association between tremor and focal dystonia, including OMD, LD, ULD and LLD, may have been caused by lack of statistical power due to the low number of patients studied.
Some authors have suggested that tremor occurring in dystonia and ET are related.1 ,5 ,17 Two phenotypic differences, however, emerged when we compared the clinical and demographic features of our patients with dystonia who had tremor with those of patients with ET previously reported.1 ,18–20 First, women predominated in the dystonic patients with tremor (54 women vs 18 men, ratio 3 : 1), whereas the majority of studies on ET either do not show a gender difference or show a higher prevalence among men than women (median female: male ratio, 0.66 : 1). Second, in our sample, tremor more commonly affected the neck than the upper limbs and voice (57/72 vs 26/72 vs 4/72 cases), whereas it is known that tremor in ET patients affects the upper limbs more commonly (95–97% of patients), and the voice (20–62%) and neck (30–48%) less commonly.1 ,18–21 These phenotypic differences raise the possibility that tremor manifesting itself during the course of dystonia and ET are different entities. Supporting this view, neurophysiological observations indicated different electromyographic patterns in the upper limb in patients with arm tremor and dystonia in the neck and in patients with ET without dystonia.22
The data from this study accurately estimate the prevalence, body distribution and characteristics of tremor presenting during the course of dystonia. Tremor is a relatively common feature of primary late-onset dystonia, affecting about 17% of these patients. The greater tendency of patients with dystonia and tremor to dystonia spread suggests that tremor that manifests itself during dystonia is closely linked to dystonia. This hypothesis is also supported by the time of appearance of TAWD in the neck or in the upper limbs of our patients with segmental cranial dystonia. In these patients, neck or upper limb tremor followed or preceded cranial dystonia but never manifested itself between BSP and OMD, supporting the somatotopic rules for dystonia spread.19 Our findings also raise the possibility that DT and TAWD are manifestations of the same disease. Finally, differences in gender and body distribution of tremor between patients with PAOD and those of ET make unlikely the suggested relationship between tremor in dystonia and tremor of patients affected by ET.
Contributors GD: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, statistical analysis, study supervision, and obtaining funding. AFG: drafting/revising the manuscript and acquisition of data. GA: drafting/revising the manuscript, study concept or design, and analysis or interpretation of data. ARB: drafting/revising the manuscript and acquisition of data. ME: analysis or interpretation of data and acquisition of data. CC: drafting/revising the manuscript and analysis or interpretation of data. GF: drafting/revising the manuscript and analysis or interpretation of data. PG: drafting/revising the manuscript, study concept or design, and analysis or interpretation of data. RL: drafting/revising the manuscript and analysis or interpretation of data. LM: drafting/revising the manuscript, contribution of vital reagents/tools/patients, and acquisition of data. FM: drafting/revising the manuscript and acquisition of data. AG: drafting/revising the manuscript and acquisition of data. LS: drafting/revising the manuscript, study concept or design, and analysis or interpretation of data. MT: drafting/revising the manuscript and analysis or interpretation of data. PL: drafting/revising the manuscript, study concept or design, and analysis or interpretation of data. AB: drafting/revising the manuscript, study concept or design, and analysis or interpretation of data. The corresponding author has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was funded by the Comitato Promotore Telethon, Italy (grant No GGP05165).
Competing interests GD received funds from the Italian Ministry of University for a research project on dystonia. GA received funds from the Italian Ministry for Universities for a research project on dystonia and honoraria for symposia from Novartis, Lundbeck, Glaxo Smith Kline, UCB. He is a member of an advisory board for Boehringer Ingelheim. GF received honoraria for lectures from Boehringer Ingelheim, GSK Pharmaceutical, Novartis Pharmaceuticals, Lundbeck. He is a member of an advisory board for Boehringer Ingelheim. AB received honoraria for lectures from Boehringer Ingelheim, GSK Pharmaceutical, Novartis Pharmaceuticals, Lundbeck. He is a member of an advisory board for Boehringer Ingelheim.
Patient consent Obtained.
Ethics approval IRB approval No 14178, University of Bari, Italy.
Provenance and peer review Not commissioned; externally peer reviewed.