RESEARCH
ARTICLE
Somatosensory Temporal Discrimination in Essential Tremor and Isolated Head and Voice Tremors Antonella Conte, MD, PhD,1,2† Gina Ferrazzano, MD,1† Nicoletta Manzo, MD,1 Giorgio Leodori, MD,1 Giovanni Fabbrini, MD,1,2 Alfonso Fasano, MD,3 Michele Tinazzi, MD,4 and Alfredo Berardelli, MD1,2* 1
Department of Neurology and Psychiatry, “Sapienza” University of Rome, Rome, Italy 2 IRCCS Neuromed, Pozzilli (IS), Italy 3 Movement Disorders Center, TWH, UHN, Division of Neurology, Toronto Western Hospital and University of Toronto, Toronto, Ontario, Canada 4 Department of Neurological and Movement Sciences, University of Verona, Verona, Italy
ABSTRACT:
The aim of this study was to investigate the somatosensory temporal discrimination threshold in patients with essential tremor (sporadic and familial) and to evaluate whether somatosensory temporal discrimination threshold values differ depending on the body parts involved by tremor. We also investigated the somatosensory temporal discrimination in patients with isolated voice tremor. We enrolled 61 patients with tremor: 48 patients with essential tremor (31 patients with upper limb tremor alone, nine patients with head tremor alone, and eight patients with upper limb plus head tremor; 22 patients with familial vs. 26 sporadic essential tremor), 13 patients with isolated voice tremor, and 45 healthy subjects. Somatosensory temporal discrimination threshold values were normal in patients with familial essential tremor, whereas they were higher in patients with sporadic essential tremor. When we classified patients according to tremor distribution, somatosensory temporal discrimination threshold values
According to the Consensus Statement of Movement Disorder on Tremor, essential tremor (ET) is defined as a bilateral, largely symmetric postural or kinetic tremor involving the hands and forearms that is visible
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*Correspondence to: Prof. Alfredo Berardelli, Department of Neurology 30, and Psychiatry, “Sapienza” University of Rome, Viale dell’Universita 00185 Rome, Italy, E-mail: [email protected] Funding agencies: None.
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. †
These authors equally contributed to the manuscript.
Received: 25 September 2014; Revised: 9 January 2015; Accepted: 15 January 2015 Published online 4 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26163
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were normal in patients with upper limb tremor and abnormal only in patients with isolated head tremor. Temporal discrimination threshold values were also abnormal in patients with isolated voice tremor. Somatosensory temporal discrimination processing is normal in patients with familial as well as in patients with sporadic essential tremor involving the upper limbs. By contrast, somatosensory temporal discrimination is altered in patients with isolated head tremor and voice tremor. This study with somatosensory temporal discrimination suggests that isolated head and voice tremors might possibly be considered as separate clinical C entities from essential tremor. V 2015 International Parkinson and Movement Disorder Society
K e y W o r d s : essential tremor; isolated tremor; somatosensory temporal discrimination
and persistent; additional or isolated tremor of the head may occur in the absence of abnormal posture. Tremor in body parts other than the upper limbs and head may be present.1 Essential tremor may occur sporadically (sporadic ET) or be inherited as an autosomal dominant trait (familial ET).1-6 A postural tremor similar to that present in ET also may be present in patients affected by dystonia.7,8 Tremor in dystonia is classified as dystonic tremor (tremor in the same body part as that affected by dystonia), tremor associated with dystonia (tremor that occurs in a body part not affected by dystonia), and dystonia geneassociated tremor (tremor present in patients with a dystonic pedigree). Clinical features do not always allow tremor caused by ET to be differentiated from tremor present in patients with dystonia, particularly when dystonia is not evident. Whether tremor present
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TABLE 1. Clinical and demographic features of patients enrolled in the study
UL tremor UL and head tremor Head tremor Voice tremor
Patients
Sex (M/F)
Age (years)
Familiarity (yes/no)
Tremor duration (years)
TRS tot
TRS UL
31 8 9 13
20/11 0/8 3/6 13/0
63.7 6 15 73 6 5.6 62.1 6 16.3 64.6 6 13.8
19/12 3/5 0/9 2/11
17.3 6 14.6 6.1 6 3.9 20.4 6 15.6 4.3 6 3.8
15.14 6 8.2 18.5 6 10.5 9.5 6 7.3 6.2 6 2.3
6.3 6 3.3 7.3 6 4.4 0 0
Data are expressed as mean 6 SD. TRS tot, Tremor Rating Scale total score; TRS UL, Tremor Rating Scale upper limb subscore; UL, upper limbs
in isolated regions of the body, including the head and voice, can be considered part of the clinical spectrum of ET or is part of the clinical spectrum of dystonia is also unclear.9 Some studies that have investigated a triphasic electromyographic pattern accompanying ballistic wrist flexion movements, reciprocal inhibition, and accelerometric measurements have sought neurophysiological hallmarks that would allow ET to be differentiated from tremor present in dystonia.10,11 A promising technique that may be used to differentiate ET from dystonia is the somatosensory temporal discrimination threshold (STDT). The STDT is defined as the minimum interstimulus interval at which participants recognize a pair of tactile stimuli as temporally separate.12 Patients with dystonia, including those with dystonic tremor, have consistent abnormalities characterized by an increased STDT.13-19 By contrast, a recent study conducted on a limited sample of ET patients found that the STDT in such patients is normal.20 The ability to differentiate ET from tremor in dystonia has important clinical and therapeutic implications (eg, for isolated tremor) and would be useful in the planning of genetic studies.6 The aim of this paper was first to confirm that the STDT is normal in ET by investigating a large number of patients and extending the observation to patients with familial and sporadic ET. The question of whether the STDT is normal in both familial and sporadic ET was not previously addressed.20 Finally, to evaluate whether STDT values depend on body parts involved by tremor, we tested the STDT in ET patients with a varying tremor distribution as well as in patients with isolated voice tremor, a still debated condition, as if it were a clinical entity separate from ET.1
Methods Study Participants and Clinical Assessment We enrolled a total of 61 patients: 48 with classical ET, diagnosed according to published criteria (22 with familiar ET and 26 with sporadic ET),1 and 13 with isolated voice tremor. Patients were recruited from the movement disorder outpatient clinic of the Department of Neurology, Sapienza University of Rome.
We also enrolled 45 healthy (M/F: 23/22) age-matched (mean 6 standard deviation: 61 6 14 years) subjects. Written informed consent was obtained from all of the patients and healthy subjects. The experimental procedure was approved by the institutional review board at Sapienza University of Rome and conducted in accordance with the Declaration of Helsinki. Information regarding the demographic characteristics, family history and disease course were collected during a face-to-face interview (Supplemental Data Table 1). During the face-to-face interview, data on first-degree relatives were considered for family history of dystonia or tremor. All of the patients with tremor were clinically evaluated by means of the Tremor Rating Scale.21 The ET patients were divided into three groups on the basis of the tremor distribution: 31 patients with upper limb tremor alone, nine patients with head tremor alone (without dystonic posture), and eight patients with upper limb plus head tremor. Exclusion criteria were other abnormal neurological signs; concurrent or recent exposure to drugs potentially causing tremor; presence of known causes of enhanced physiological tremor; clinical evidence of functional origin of tremor; head trauma in the 3 months preceding the onset of tremor. Because the temporal sensory processing data yielded by STDT testing are only reliable if cognitive functions are normal, patients with Mini-Mental State Examination score less than 26 were excluded. Patients who had altered STDT values were also tested for possible neuropathy by means of conventional nerve conduction studies. To exclude a pattern of laryngeal dystonia, all patients with voice tremor underwent a laryngoscopy.22
STD Procedure The STD was investigated by delivering paired stimuli starting with an interstimulus interval of 0 ms (simultaneous pair), and progressively increasing the interstimulus interval in 10-ms steps, according to the experimental procedures used in previous studies.12,15,20,23 Paired tactile stimuli consisted of squarewave electrical pulses delivered with a constant current stimulator (Digitimer DS7AH) through surface skin electrodes with the anode located 0.5 cm distally to the cathode applied to the volar surface of the
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index finger of the left and right hands, neck, and face. The stimulation intensity was defined for each subject by delivering a series of stimuli at an increasing intensity from 2 mA in 0.5-mA steps; the intensity used for the STD was the minimal intensity perceived by the subject in 10 of 10 consecutive stimuli. The first of three consecutive interstimulus intervals at which participants recognized the stimuli as temporally separate was considered the STDT. To keep the subjects’ attention level constant during the test and to minimize possible perseverative responses, we included “catch” trials consisting of a single stimulus delivered randomly,12 and we delivered paired stimuli with intervals of 3 and 5 s. Each session comprised four separate blocks. The STDT was defined as the average of four STDT values and entered in the data analysis.
and in the three body parts (hand, neck, face) did not detect any significant differences between right and left side and in the three different body parts (factor side: F(1,104) 5 0.29; P 5 0.59; factor side and group interaction: F(1,104) 5 0,37; P 5 0.54; side and body parts interaction: F(2,208) 5 2,58; P = 0.08; factors side, body parts, and group interaction: F(2,208) 5 0.62; P 5 0.53) but a significant group factor (F(1,91) 5 13.0; P 5 0.0004). Patients had higher STDT values than healthy subjects. Because the STDT values were similar on the right and left body sides in patients and healthy subjects, we used the STDT values on the right side to compare STDT values for subsequent statistical analysis.
Statistical Analysis
Between-group repeated measures ANOVA revealed a significant group factor (F(3,89) 5 12.86, P = 0.0005), although no significant group 3 body part interaction (F(6,178) 5 2.84; P 5 0.07). When we compared patients with familial and sporadic ET with healthy subjects, between-group ANOVA showed a significant group factor (three groups: familial ET, sporadic ET, and healthy subjects) (F(2,90) 5 18.96; P < 0.000001), although no significant body part and group interaction (F(4,180) 5 1.78; P 5 0.13). Post-hoc analysis showed that STDT values differed between patients with sporadic ET and healthy subjects, although not between patients with familial ET and healthy subjects (healthy subjects vs. patients with sporadic ET: P < 0.0001; healthy subjects vs. patients with familial ET: P 5 0.99). Therefore, STDT values were similar in patients with familial ET and in healthy subjects, whereas they were higher in patients with sporadic ET than in healthy subjects (Fig. 1). Independent sample t test to compare age at onset in patients with familial versus sporadic ET showed no significant differences (P 5 0.2).
We first used a between-group analysis of variance (ANOVA) analysis to evaluate any differences in STDT values between the left and right sides as well as in the three body parts tested in all of the patients (ie, those with ET and those with isolated voice tremor) and in healthy subjects. To assess the diagnostic accuracy (sensitivity and specificity) of STDT testing in differentiating patients from healthy subjects, we used the receiver operating characteristic curve analysis. We calculated the “cutoff value” corresponding to the highest diagnostic accuracy (minimal falsenegative and false-positive results). The “cutoff value” was the point on the receiver operating characteristic curve that maximizes correct classifications of pathological conditions and minimizes errors. In a further repeated-measures ANOVA, we divided the whole sample of patients with ET according to their form (familial or sporadic) and tremor distribution (upper limbs, head, upper limbs plus head). Bonferroni’s test was used for post-hoc analysis. Holm’s test for multiple comparisons was applied. Data were tested for non-sphericity. Greenhouse-Geisser’s correction was applied when needed. Unpaired t test was used to compare age at onset between patients with familial ET versus patients with sporadic ET. We used Pearson’s product correlation coefficient to investigate any correlations between the STDT values and demographic and clinical features (tremor duration, tremor rating scale score, age of the patients).
STDT Values in Patients With ET and Healthy Subjects
Results Comparison of STDT Values in All Patients and Healthy Subjects on the Two Body Sides and in the Three Body Parts Tested Between-group repeated-measures ANOVA used to evaluate whether STDT values in patients and healthy subjects differed on the two body sides (left or right)
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FIG. 1. Somatosensory temporal discrimination threshold (STDT) in patients with familial and sporadic essential tremor and in healthy subjects. Y axis: STDT expressed in milliseconds. Column represents mean value; bar represents standard error.
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tremor and isolated voice tremor and healthy subjects showed that a cutoff value of 93.33 ms yielded 88.9% sensitivity and 77.8% specificity in discriminating patients with head tremor alone from healthy subjects, whereas a cutoff value of 95 ms yielded 61.5% sensitivity and 80% specificity in discriminating patients with isolated voice tremor from healthy subjects.
Discussion FIG. 2. Somatosensory temporal discrimination threshold (STDT) in patients with essential tremor stratified according to the body part involved by tremor (UL, upper limbs; UL1head, upper limbs plus head, isolated head tremor), in patients with isolated voice tremor and in healthy subjects (HS). Y axis: STDT expressed in milliseconds. Column represents mean value, bar represents standard error.
When we compared patients with ET divided according to tremor distribution with healthy subjects, between-group ANOVA revealed a significant group factor (four groups: patients with upper limb tremor alone; patients with head tremor alone; patients with upper limb plus head tremor; and healthy subjects) (F(3,89) 5 11.14; P 5 0.000002), though no significant body part and group interaction (F(6,178) = 1.93; P 5 0.07). Post-hoc analysis showed that STDT values were normal in patients with upper limb tremor alone (P 5 0.21) and in those with upper limb plus head tremor (P 5 0.87), whereas they were significantly higher than normal in patients with head tremor alone (P < 0.0008) (Fig. 2).
STDT Values in Patients With ET, Patients With Isolated Voice Tremor, and Healthy Subjects When we compared patients with isolated voice tremor with those with ET and healthy subjects, between-group ANOVA revealed a significant group factor (F(4,101) 5 11.78; P < 0.00006), although no significant body part and group interaction (F(8,202) 5 1.77; P 5 0.09). Post-hoc analysis showed that STDT values differed between patients with isolated head and voice tremor and healthy subjects (healthy subjects vs. patients with upper limb tremor alone: P 5 0.40; healthy subjects vs. patients with head tremor alone: P 5 0.000006; healthy subjects vs. patients with voice tremor alone: P 5 0.00002; healthy subjects vs. patients with upper limb plus head tremor: P 5 0.99). Therefore, STDT values were similar in patients with upper limb tremor alone and upper limb plus head tremor and in healthy subjects, whereas they were higher in patients with head tremor alone or voice tremor alone than in healthy subjects (Figure 2). The receiver operating characteristic curve analysis for the STDT values in patients with isolated head
When we compared familial and sporadic ET, we found that STDT values were similar in patients with familial ET and healthy subjects, whereas they were higher in patients with sporadic ET than in healthy subjects. When we classified patients with ET according to tremor distribution (upper limb alone, head alone, and upper limb plus head tremor), STDT values were normal in subjects with upper limb tremor, whereas they were significantly higher in patients with isolated head tremor. Finally, patients with isolated voice tremor also displayed higher STDT values than healthy subjects. We took numerous precautions to ensure that our data were reliable. All of the patients with tremor were clinically evaluated by neurologists who are experts in movement disorders and were classified according to diagnostic criteria.1 Moreover, all of the patients with voice tremor underwent a laryngoscopy to exclude a pattern of laryngeal dystonia.22 Patients were also investigated for any abnormal neurological signs (particularly dystonic posture), concurrent or recent exposure to tremorigenic drugs, and causes of enhanced physiological tremor to avoid confounding effects in the STDT assessment. We also excluded patients who had a familiarity for dystonia, to rule out the possibility that any STDT alteration might be attributable to a dystonic trait (dystonia geneassociated tremor).1,14,17,18,23,24 Any patients or healthy subjects who had a clinically diagnosed peripheral sensory neuropathy were not included in the study either. We also excluded peripheral nerve abnormalities in patients with altered STDT values by means of conventional nerve conduction studies. Subjects with a Mini-Mental State Examination score lower than 26 were excluded to avoid a confounding effect caused by cognitive impairment. Moreover, we tested the STDT in three different body parts (face, neck, and hand) to rule out the possibility that the presence of tremor in the upper limbs might affect the STDT measurement. The results of this study confirm our previous observation20 showing that STD processing is normal in patients with ET as defined by the Consensus agreement on the diagnosis of ET.1 We now show that patients with familial ET also have a normal STDT.
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Because familiarity in patients with a possible diagnosis of ET (ie, without clinical features of dystonia) is an additional clinical feature for the diagnosis of ET, this finding further strengthens the conclusion that STDT is normal in patients with ET. Unlike patients with familial ET, patients with sporadic ET have abnormal STDT values. Because the STDT is abnormal in patients with sporadic ET, though not in patients with familial ET, we may conclude that STDT abnormalities in sporadic ET are not attributable to the tremor per se interfering with sensory discrimination (ie, afferent volley generated by tremor). Because tremor duration is similar in familial and sporadic ET, and may even last longer than 10 years, we believe that the abnormal STDT values in patients with sporadic ET are unlikely to develop into Parkinson’s disease in the future.25-27 Because familial ET and sporadic ET we studied also had similar age at onset of tremor, the hypothesis that our patients with sporadic ET are affected by senile tremor is unlikely.28 Although the group of sporadic ET patients as a whole had an abnormal STDT, when they were stratified according to tremor distribution, we found that patients with upper limb tremor had a normal STDT, whereas patients with isolated head tremor had an abnormal STDT. The involvement of the upper limbs was thus associated with normal STDT values in both sporadic and familial ET. Because the number of patients with familial and sporadic ET in the different subgroups stratified according to tremor distribution was unbalanced, the present study does not allow drawing definite conclusions on whether familiarity also plays a role within the different topographic subgroups of tremor. This specific issue might be addressed in future studies. We also found that patients with isolated voice tremor, like those with isolated head tremor, had abnormal STDT values, whereas patients with upper limb tremor and healthy subjects did not. Previous studies have shown that the STDT is abnormal in basal ganglia disorders, including Parkinson’s disease and dystonia.13-20,25-27 On the basis of our clinical examination, none of our patients had tremor that could be classified as parkinsonian tremor. Because all of our patients with isolated voice tremor were female and sex may influence STDT values,18 the group of isolated voice tremor patients in our study might have had higher STDT values because of a “gender” effect. However, because the patients we enrolled with upper limb and head tremor were all female and had normal STDT values, we exclude this hypothesis. Some of the patients we clinically classified as being ET patients may not actually have ET. The STDT is commonly abnormal in dystonia, even in unaffected body parts of patients with focal dystonia.15 Although we took several precautions to exclude cases with
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manifest dystonic postures, possibly isolated forms of tremor are actually dystonic in origin. Because the clinical criteria for dystonic tremor have not yet been definitively established, this disorder may be a potential source of misdiagnosis. Tremor is commonly recognized as a manifestation of dystonia,1,7,8 with the estimated overlap between the prevalence of dystonia and that of ET ranging widely from 1% to 10%.29,30 The observation that patients with isolated head and voice tremor have abnormal STDT values, whereas patients with upper limb tremor do not, suggests that the pathophysiological mechanisms underlying these two types of tremor may be different. Based on our observation with STDT, we suggest that isolated head tremor might be considered, similarly to isolated voice tremor, as a separate clinical entity from ET. Because of the lower prevalence of patients with isolated head and voice tremors, we acknowledge that our study samples of patients with isolated head and voice tremors are modest in size. Multicentric studies with large study samples are needed to definitively make this issue clear.
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Kuhlenb€ aumer G, Hopfner F, Deuschl G. Genetics of essential tremor: meta-analysis and review. Neurology 2014;82:1000-1007.
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Defazio G, Gigante AF, Abbruzzese G, et al. Tremor in primary adult-onset dystonia: prevalence and associated clinical features. J Neurol Neurosurg Psychiatry 2013;84:404-408.
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Erro R, Rubio-Agusti I, Saifee TA, et al. Rest and other types of tremor in adult-onset primary dystonia. J Neurol Neurosurg Psychiatry 2014;85:965-968.
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Conte A, Rocchi L, Nardella A, et al. Theta-burst stimulationinduced plasticity over primary somatosensory cortex changes somatosensory temporal discrimination in healthy humans. PLoS One 2012;7:e32979.
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Fiorio M, Gambarin M, Valente EM, et al. Defective temporal processing of sensory stimuli in DYT1 mutation carriers: a new endophenotype of dystonia? Brain 2007;130:134-142.
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Bradley D, Whelan R, Walsh R, et al. Temporal discrimination threshold: VBM evidence for an endophenotype in adult onset primary torsion dystonia. Brain 2009;132:2327-2335.
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Scontrini A, Conte A, Defazio G, et al. Somatosensory temporal discrimination in patients with primary focal dystonia. J Neurol Neurosurg Psychiatry 2009;80:1315-1319.
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Tinazzi M, Fiorio M, Fiaschi A, Rothwell JC, Bhatia KP. Sensory functions in dystonia: insights from behavioral studies. Mov Disord 2009;24:1427-1436.
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Bradley D, Whelan R, Kimmich O, et al. Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype. J Neurol 2012;259:77-82.
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Conte A, Khan N, Defazio G, Rothwell JC, Berardelli A. Pathophysiology of somatosensory abnormalities in Parkinson disease. Nat Rev Neurol 2013;9:687-697.
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Kimmich O, Molloy A, Whelan R, et al. Temporal discrimination, a cervical dystonia endophenotype: penetrance and functional correlates. Mov Disord 2014;29:804-811.
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Conte A, Modugno N, Lena F, et al. Subthalamic nucleus stimulation and somatosensory temporal discrimination in Parkinson’s disease. Brain 2010;133:2656-2663.
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Tinazzi M, Fasano A, Di Matteo A, et al. Temporal discrimination in patients with dystonia and tremor and patients with essential tremor. Neurology 2013;80:76-84.
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Supporting Data Additional Supporting Information may be found in the online version of this article at the publisher’s web-site.
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ARTICLE
Somatosensory Temporal Discrimination in Essential Tremor and Isolated Head and Voice Tremors Antonella Conte, MD, PhD,1,2† Gina Ferrazzano, MD,1† Nicoletta Manzo, MD,1 Giorgio Leodori, MD,1 Giovanni Fabbrini, MD,1,2 Alfonso Fasano, MD,3 Michele Tinazzi, MD,4 and Alfredo Berardelli, MD1,2* 1
Department of Neurology and Psychiatry, “Sapienza” University of Rome, Rome, Italy 2 IRCCS Neuromed, Pozzilli (IS), Italy 3 Movement Disorders Center, TWH, UHN, Division of Neurology, Toronto Western Hospital and University of Toronto, Toronto, Ontario, Canada 4 Department of Neurological and Movement Sciences, University of Verona, Verona, Italy
ABSTRACT:
The aim of this study was to investigate the somatosensory temporal discrimination threshold in patients with essential tremor (sporadic and familial) and to evaluate whether somatosensory temporal discrimination threshold values differ depending on the body parts involved by tremor. We also investigated the somatosensory temporal discrimination in patients with isolated voice tremor. We enrolled 61 patients with tremor: 48 patients with essential tremor (31 patients with upper limb tremor alone, nine patients with head tremor alone, and eight patients with upper limb plus head tremor; 22 patients with familial vs. 26 sporadic essential tremor), 13 patients with isolated voice tremor, and 45 healthy subjects. Somatosensory temporal discrimination threshold values were normal in patients with familial essential tremor, whereas they were higher in patients with sporadic essential tremor. When we classified patients according to tremor distribution, somatosensory temporal discrimination threshold values
According to the Consensus Statement of Movement Disorder on Tremor, essential tremor (ET) is defined as a bilateral, largely symmetric postural or kinetic tremor involving the hands and forearms that is visible
------------------------------------------------------------
*Correspondence to: Prof. Alfredo Berardelli, Department of Neurology 30, and Psychiatry, “Sapienza” University of Rome, Viale dell’Universita 00185 Rome, Italy, E-mail: [email protected] Funding agencies: None.
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. †
These authors equally contributed to the manuscript.
Received: 25 September 2014; Revised: 9 January 2015; Accepted: 15 January 2015 Published online 4 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26163
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were normal in patients with upper limb tremor and abnormal only in patients with isolated head tremor. Temporal discrimination threshold values were also abnormal in patients with isolated voice tremor. Somatosensory temporal discrimination processing is normal in patients with familial as well as in patients with sporadic essential tremor involving the upper limbs. By contrast, somatosensory temporal discrimination is altered in patients with isolated head tremor and voice tremor. This study with somatosensory temporal discrimination suggests that isolated head and voice tremors might possibly be considered as separate clinical C entities from essential tremor. V 2015 International Parkinson and Movement Disorder Society
K e y W o r d s : essential tremor; isolated tremor; somatosensory temporal discrimination
and persistent; additional or isolated tremor of the head may occur in the absence of abnormal posture. Tremor in body parts other than the upper limbs and head may be present.1 Essential tremor may occur sporadically (sporadic ET) or be inherited as an autosomal dominant trait (familial ET).1-6 A postural tremor similar to that present in ET also may be present in patients affected by dystonia.7,8 Tremor in dystonia is classified as dystonic tremor (tremor in the same body part as that affected by dystonia), tremor associated with dystonia (tremor that occurs in a body part not affected by dystonia), and dystonia geneassociated tremor (tremor present in patients with a dystonic pedigree). Clinical features do not always allow tremor caused by ET to be differentiated from tremor present in patients with dystonia, particularly when dystonia is not evident. Whether tremor present
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TABLE 1. Clinical and demographic features of patients enrolled in the study
UL tremor UL and head tremor Head tremor Voice tremor
Patients
Sex (M/F)
Age (years)
Familiarity (yes/no)
Tremor duration (years)
TRS tot
TRS UL
31 8 9 13
20/11 0/8 3/6 13/0
63.7 6 15 73 6 5.6 62.1 6 16.3 64.6 6 13.8
19/12 3/5 0/9 2/11
17.3 6 14.6 6.1 6 3.9 20.4 6 15.6 4.3 6 3.8
15.14 6 8.2 18.5 6 10.5 9.5 6 7.3 6.2 6 2.3
6.3 6 3.3 7.3 6 4.4 0 0
Data are expressed as mean 6 SD. TRS tot, Tremor Rating Scale total score; TRS UL, Tremor Rating Scale upper limb subscore; UL, upper limbs
in isolated regions of the body, including the head and voice, can be considered part of the clinical spectrum of ET or is part of the clinical spectrum of dystonia is also unclear.9 Some studies that have investigated a triphasic electromyographic pattern accompanying ballistic wrist flexion movements, reciprocal inhibition, and accelerometric measurements have sought neurophysiological hallmarks that would allow ET to be differentiated from tremor present in dystonia.10,11 A promising technique that may be used to differentiate ET from dystonia is the somatosensory temporal discrimination threshold (STDT). The STDT is defined as the minimum interstimulus interval at which participants recognize a pair of tactile stimuli as temporally separate.12 Patients with dystonia, including those with dystonic tremor, have consistent abnormalities characterized by an increased STDT.13-19 By contrast, a recent study conducted on a limited sample of ET patients found that the STDT in such patients is normal.20 The ability to differentiate ET from tremor in dystonia has important clinical and therapeutic implications (eg, for isolated tremor) and would be useful in the planning of genetic studies.6 The aim of this paper was first to confirm that the STDT is normal in ET by investigating a large number of patients and extending the observation to patients with familial and sporadic ET. The question of whether the STDT is normal in both familial and sporadic ET was not previously addressed.20 Finally, to evaluate whether STDT values depend on body parts involved by tremor, we tested the STDT in ET patients with a varying tremor distribution as well as in patients with isolated voice tremor, a still debated condition, as if it were a clinical entity separate from ET.1
Methods Study Participants and Clinical Assessment We enrolled a total of 61 patients: 48 with classical ET, diagnosed according to published criteria (22 with familiar ET and 26 with sporadic ET),1 and 13 with isolated voice tremor. Patients were recruited from the movement disorder outpatient clinic of the Department of Neurology, Sapienza University of Rome.
We also enrolled 45 healthy (M/F: 23/22) age-matched (mean 6 standard deviation: 61 6 14 years) subjects. Written informed consent was obtained from all of the patients and healthy subjects. The experimental procedure was approved by the institutional review board at Sapienza University of Rome and conducted in accordance with the Declaration of Helsinki. Information regarding the demographic characteristics, family history and disease course were collected during a face-to-face interview (Supplemental Data Table 1). During the face-to-face interview, data on first-degree relatives were considered for family history of dystonia or tremor. All of the patients with tremor were clinically evaluated by means of the Tremor Rating Scale.21 The ET patients were divided into three groups on the basis of the tremor distribution: 31 patients with upper limb tremor alone, nine patients with head tremor alone (without dystonic posture), and eight patients with upper limb plus head tremor. Exclusion criteria were other abnormal neurological signs; concurrent or recent exposure to drugs potentially causing tremor; presence of known causes of enhanced physiological tremor; clinical evidence of functional origin of tremor; head trauma in the 3 months preceding the onset of tremor. Because the temporal sensory processing data yielded by STDT testing are only reliable if cognitive functions are normal, patients with Mini-Mental State Examination score less than 26 were excluded. Patients who had altered STDT values were also tested for possible neuropathy by means of conventional nerve conduction studies. To exclude a pattern of laryngeal dystonia, all patients with voice tremor underwent a laryngoscopy.22
STD Procedure The STD was investigated by delivering paired stimuli starting with an interstimulus interval of 0 ms (simultaneous pair), and progressively increasing the interstimulus interval in 10-ms steps, according to the experimental procedures used in previous studies.12,15,20,23 Paired tactile stimuli consisted of squarewave electrical pulses delivered with a constant current stimulator (Digitimer DS7AH) through surface skin electrodes with the anode located 0.5 cm distally to the cathode applied to the volar surface of the
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index finger of the left and right hands, neck, and face. The stimulation intensity was defined for each subject by delivering a series of stimuli at an increasing intensity from 2 mA in 0.5-mA steps; the intensity used for the STD was the minimal intensity perceived by the subject in 10 of 10 consecutive stimuli. The first of three consecutive interstimulus intervals at which participants recognized the stimuli as temporally separate was considered the STDT. To keep the subjects’ attention level constant during the test and to minimize possible perseverative responses, we included “catch” trials consisting of a single stimulus delivered randomly,12 and we delivered paired stimuli with intervals of 3 and 5 s. Each session comprised four separate blocks. The STDT was defined as the average of four STDT values and entered in the data analysis.
and in the three body parts (hand, neck, face) did not detect any significant differences between right and left side and in the three different body parts (factor side: F(1,104) 5 0.29; P 5 0.59; factor side and group interaction: F(1,104) 5 0,37; P 5 0.54; side and body parts interaction: F(2,208) 5 2,58; P = 0.08; factors side, body parts, and group interaction: F(2,208) 5 0.62; P 5 0.53) but a significant group factor (F(1,91) 5 13.0; P 5 0.0004). Patients had higher STDT values than healthy subjects. Because the STDT values were similar on the right and left body sides in patients and healthy subjects, we used the STDT values on the right side to compare STDT values for subsequent statistical analysis.
Statistical Analysis
Between-group repeated measures ANOVA revealed a significant group factor (F(3,89) 5 12.86, P = 0.0005), although no significant group 3 body part interaction (F(6,178) 5 2.84; P 5 0.07). When we compared patients with familial and sporadic ET with healthy subjects, between-group ANOVA showed a significant group factor (three groups: familial ET, sporadic ET, and healthy subjects) (F(2,90) 5 18.96; P < 0.000001), although no significant body part and group interaction (F(4,180) 5 1.78; P 5 0.13). Post-hoc analysis showed that STDT values differed between patients with sporadic ET and healthy subjects, although not between patients with familial ET and healthy subjects (healthy subjects vs. patients with sporadic ET: P < 0.0001; healthy subjects vs. patients with familial ET: P 5 0.99). Therefore, STDT values were similar in patients with familial ET and in healthy subjects, whereas they were higher in patients with sporadic ET than in healthy subjects (Fig. 1). Independent sample t test to compare age at onset in patients with familial versus sporadic ET showed no significant differences (P 5 0.2).
We first used a between-group analysis of variance (ANOVA) analysis to evaluate any differences in STDT values between the left and right sides as well as in the three body parts tested in all of the patients (ie, those with ET and those with isolated voice tremor) and in healthy subjects. To assess the diagnostic accuracy (sensitivity and specificity) of STDT testing in differentiating patients from healthy subjects, we used the receiver operating characteristic curve analysis. We calculated the “cutoff value” corresponding to the highest diagnostic accuracy (minimal falsenegative and false-positive results). The “cutoff value” was the point on the receiver operating characteristic curve that maximizes correct classifications of pathological conditions and minimizes errors. In a further repeated-measures ANOVA, we divided the whole sample of patients with ET according to their form (familial or sporadic) and tremor distribution (upper limbs, head, upper limbs plus head). Bonferroni’s test was used for post-hoc analysis. Holm’s test for multiple comparisons was applied. Data were tested for non-sphericity. Greenhouse-Geisser’s correction was applied when needed. Unpaired t test was used to compare age at onset between patients with familial ET versus patients with sporadic ET. We used Pearson’s product correlation coefficient to investigate any correlations between the STDT values and demographic and clinical features (tremor duration, tremor rating scale score, age of the patients).
STDT Values in Patients With ET and Healthy Subjects
Results Comparison of STDT Values in All Patients and Healthy Subjects on the Two Body Sides and in the Three Body Parts Tested Between-group repeated-measures ANOVA used to evaluate whether STDT values in patients and healthy subjects differed on the two body sides (left or right)
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FIG. 1. Somatosensory temporal discrimination threshold (STDT) in patients with familial and sporadic essential tremor and in healthy subjects. Y axis: STDT expressed in milliseconds. Column represents mean value; bar represents standard error.
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tremor and isolated voice tremor and healthy subjects showed that a cutoff value of 93.33 ms yielded 88.9% sensitivity and 77.8% specificity in discriminating patients with head tremor alone from healthy subjects, whereas a cutoff value of 95 ms yielded 61.5% sensitivity and 80% specificity in discriminating patients with isolated voice tremor from healthy subjects.
Discussion FIG. 2. Somatosensory temporal discrimination threshold (STDT) in patients with essential tremor stratified according to the body part involved by tremor (UL, upper limbs; UL1head, upper limbs plus head, isolated head tremor), in patients with isolated voice tremor and in healthy subjects (HS). Y axis: STDT expressed in milliseconds. Column represents mean value, bar represents standard error.
When we compared patients with ET divided according to tremor distribution with healthy subjects, between-group ANOVA revealed a significant group factor (four groups: patients with upper limb tremor alone; patients with head tremor alone; patients with upper limb plus head tremor; and healthy subjects) (F(3,89) 5 11.14; P 5 0.000002), though no significant body part and group interaction (F(6,178) = 1.93; P 5 0.07). Post-hoc analysis showed that STDT values were normal in patients with upper limb tremor alone (P 5 0.21) and in those with upper limb plus head tremor (P 5 0.87), whereas they were significantly higher than normal in patients with head tremor alone (P < 0.0008) (Fig. 2).
STDT Values in Patients With ET, Patients With Isolated Voice Tremor, and Healthy Subjects When we compared patients with isolated voice tremor with those with ET and healthy subjects, between-group ANOVA revealed a significant group factor (F(4,101) 5 11.78; P < 0.00006), although no significant body part and group interaction (F(8,202) 5 1.77; P 5 0.09). Post-hoc analysis showed that STDT values differed between patients with isolated head and voice tremor and healthy subjects (healthy subjects vs. patients with upper limb tremor alone: P 5 0.40; healthy subjects vs. patients with head tremor alone: P 5 0.000006; healthy subjects vs. patients with voice tremor alone: P 5 0.00002; healthy subjects vs. patients with upper limb plus head tremor: P 5 0.99). Therefore, STDT values were similar in patients with upper limb tremor alone and upper limb plus head tremor and in healthy subjects, whereas they were higher in patients with head tremor alone or voice tremor alone than in healthy subjects (Figure 2). The receiver operating characteristic curve analysis for the STDT values in patients with isolated head
When we compared familial and sporadic ET, we found that STDT values were similar in patients with familial ET and healthy subjects, whereas they were higher in patients with sporadic ET than in healthy subjects. When we classified patients with ET according to tremor distribution (upper limb alone, head alone, and upper limb plus head tremor), STDT values were normal in subjects with upper limb tremor, whereas they were significantly higher in patients with isolated head tremor. Finally, patients with isolated voice tremor also displayed higher STDT values than healthy subjects. We took numerous precautions to ensure that our data were reliable. All of the patients with tremor were clinically evaluated by neurologists who are experts in movement disorders and were classified according to diagnostic criteria.1 Moreover, all of the patients with voice tremor underwent a laryngoscopy to exclude a pattern of laryngeal dystonia.22 Patients were also investigated for any abnormal neurological signs (particularly dystonic posture), concurrent or recent exposure to tremorigenic drugs, and causes of enhanced physiological tremor to avoid confounding effects in the STDT assessment. We also excluded patients who had a familiarity for dystonia, to rule out the possibility that any STDT alteration might be attributable to a dystonic trait (dystonia geneassociated tremor).1,14,17,18,23,24 Any patients or healthy subjects who had a clinically diagnosed peripheral sensory neuropathy were not included in the study either. We also excluded peripheral nerve abnormalities in patients with altered STDT values by means of conventional nerve conduction studies. Subjects with a Mini-Mental State Examination score lower than 26 were excluded to avoid a confounding effect caused by cognitive impairment. Moreover, we tested the STDT in three different body parts (face, neck, and hand) to rule out the possibility that the presence of tremor in the upper limbs might affect the STDT measurement. The results of this study confirm our previous observation20 showing that STD processing is normal in patients with ET as defined by the Consensus agreement on the diagnosis of ET.1 We now show that patients with familial ET also have a normal STDT.
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Because familiarity in patients with a possible diagnosis of ET (ie, without clinical features of dystonia) is an additional clinical feature for the diagnosis of ET, this finding further strengthens the conclusion that STDT is normal in patients with ET. Unlike patients with familial ET, patients with sporadic ET have abnormal STDT values. Because the STDT is abnormal in patients with sporadic ET, though not in patients with familial ET, we may conclude that STDT abnormalities in sporadic ET are not attributable to the tremor per se interfering with sensory discrimination (ie, afferent volley generated by tremor). Because tremor duration is similar in familial and sporadic ET, and may even last longer than 10 years, we believe that the abnormal STDT values in patients with sporadic ET are unlikely to develop into Parkinson’s disease in the future.25-27 Because familial ET and sporadic ET we studied also had similar age at onset of tremor, the hypothesis that our patients with sporadic ET are affected by senile tremor is unlikely.28 Although the group of sporadic ET patients as a whole had an abnormal STDT, when they were stratified according to tremor distribution, we found that patients with upper limb tremor had a normal STDT, whereas patients with isolated head tremor had an abnormal STDT. The involvement of the upper limbs was thus associated with normal STDT values in both sporadic and familial ET. Because the number of patients with familial and sporadic ET in the different subgroups stratified according to tremor distribution was unbalanced, the present study does not allow drawing definite conclusions on whether familiarity also plays a role within the different topographic subgroups of tremor. This specific issue might be addressed in future studies. We also found that patients with isolated voice tremor, like those with isolated head tremor, had abnormal STDT values, whereas patients with upper limb tremor and healthy subjects did not. Previous studies have shown that the STDT is abnormal in basal ganglia disorders, including Parkinson’s disease and dystonia.13-20,25-27 On the basis of our clinical examination, none of our patients had tremor that could be classified as parkinsonian tremor. Because all of our patients with isolated voice tremor were female and sex may influence STDT values,18 the group of isolated voice tremor patients in our study might have had higher STDT values because of a “gender” effect. However, because the patients we enrolled with upper limb and head tremor were all female and had normal STDT values, we exclude this hypothesis. Some of the patients we clinically classified as being ET patients may not actually have ET. The STDT is commonly abnormal in dystonia, even in unaffected body parts of patients with focal dystonia.15 Although we took several precautions to exclude cases with
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manifest dystonic postures, possibly isolated forms of tremor are actually dystonic in origin. Because the clinical criteria for dystonic tremor have not yet been definitively established, this disorder may be a potential source of misdiagnosis. Tremor is commonly recognized as a manifestation of dystonia,1,7,8 with the estimated overlap between the prevalence of dystonia and that of ET ranging widely from 1% to 10%.29,30 The observation that patients with isolated head and voice tremor have abnormal STDT values, whereas patients with upper limb tremor do not, suggests that the pathophysiological mechanisms underlying these two types of tremor may be different. Based on our observation with STDT, we suggest that isolated head tremor might be considered, similarly to isolated voice tremor, as a separate clinical entity from ET. Because of the lower prevalence of patients with isolated head and voice tremors, we acknowledge that our study samples of patients with isolated head and voice tremors are modest in size. Multicentric studies with large study samples are needed to definitively make this issue clear.
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Supporting Data Additional Supporting Information may be found in the online version of this article at the publisher’s web-site.
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