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Abstract

Background

The existence of an association between migraine and essential tremor has long been controversial. The prevalence of migraine in essential tremor patients was surveyed to explore the association between the two diseases.

Methods

A case–control clinical study was conducted to investigate the prevalence of migraine in 150 consecutive essential tremor patients and in 150 matched controls without tremor. Detailed information about essential tremor and migraine was obtained using a structured questionnaire at a face-to-face interview. Moreover, a functional variant of the dopamine receptor D3 gene (Ser9Gly, rs6280) was studied in 46 essential tremor patients with and without migraine using direct sequencing analysis.

Results

The prevalence of lifetime migraine in essential tremor patients was significantly higher than that in controls (22.0% vs. 12.7%; p = 0.035; odds ratio = 1.95; 95% confidence interval = 1.05–3.60). No significant difference was found in the migraine features between the essential tremor and control groups and most tremor characteristics were no different in essential tremor patients with and without migraine. A higher male prevalence of essential tremor patients without migraine was observed. Moreover, 44 of 46 (95.7%) essential tremor patients had the dopamine receptor D3 Ser9Gly variant, but no significant difference was found in the frequencies of the variant between essential tremor patients with and without migraine (87.5% vs. 100.0%; p = 0.22).

Conclusion

Our data suggest that essential tremor patients have a higher risk of lifetime migraine than do controls and the dopamine receptor D3 Ser9Gly variant may be lower in essential tremor with migraine than the general essential tremor patients.

Keywords

Essential tremor migraine dopamine receptor D3 gene risk factor

Introduction

Over past decades, there has been controversy about a possible relationship between essential tremor (ET) and migraine (1 –3). One cross-sectional study revealed a bidirectional relationship between the two diseases, finding that 36.5% of ET patients had migraine and 17.2% of migraineurs suffered from ET (1). Another study found that 26.0% of ET patients experienced classic migraine, which was more commonly associated with hereditary ET than with other comorbidities (2). However, these two studies were based on data that did not compare patient characteristics with those of age- and gender-matched controls without tremor. Recently, a case–control study addressed this problem and found no association between ET and migraine when the headache features were compared in 28/110 (25.4%) patients with migraine and ET and 24/110 (21.8%) controls (3).

So, is there a relationship between the two diseases? ET and migraine may share a genetic background. The dopamine D3 receptor (DRD3) gene encodes the DRD3 receptor, expressed in the basal ganglia, cerebral cortex, cerebellum and brainstem nuclei (4,5), which have been implicated in the pathogenesis of ET (6,7) and migraine (8,9). The single nucleotide polymorphism (SNP) ‘rs6280’ in the DRD3 gene, which causes a Ser9Gly amino acid change in the ETM1 locus, was found to be associated with risk and age at onset of ET in a recent study (10). Additionally, dopamine has been thought to participate in the pathogenesis of migraine (11) and an increased density of lymphocytic DRD3 receptor has been reported in migraineurs (12). Furthermore, no other non-synonymous variant was found in the DRD3 coding sequence in ET patients by a genome-wide scan, apart from the SNP rs6280 variant (10). Thus, the DRD3 Ser9Gly variant can be defined as a functional variant of the DRD3 gene. Further analyses may suggest the possibility of a common mutation and a better understanding of the molecular mechanism(s) in the relationship between ET and migraine. However, to our knowledge, there is no reported study on the frequencies of the DRD3 Ser9Gly variant in ET patients with and without migraine.

In this case–control study, we explored the prevalence of migraine in a large sample of consecutive outpatients with ET. A comparative analysis was also designed to find any association between migraine and ET and the proportions of DRD3 Ser9Gly polymorphism in ET patients with and without migraine.

Materials and methods

Standard protocol approvals

The study protocol was approved by the Ethical Committee of the Chinese PLA General Hospital and complied with the Declaration of Helsinki. Informed consents were obtained from all patients and controls before the study.

Clinical studies

In total, 150 unrelated Han Chinese patients diagnosed with definite ET (74 males, 76 females, mean age 54.2 ± 15.9 years) were recruited consecutively from the Department of Neurology, Chinese PLA General Hospital, from 1 March 2011 to 1 July 2013. All patients were diagnosed based on the Washington Heights-Inwood Genetic Study ET criteria (13), which was developed at movement disorder clinics. Tremor was rated on an ordinal scale ranging from 0 to +3 (0 = no visible tremor; +1 = barely perceptible tremor or intermittent tremor; +2 = obvious tremor, amplitude <2 cm; +3 = violent, jerky tremor, amplitude >2 cm). The detailed inclusion criteria were the following: (i) on examination, a + 2 postural tremor in at least one arm (head tremor may also be present but was insufficient for a diagnosis); (ii) on examination, there must be a + 2 kinetic tremor during at least four tasks or a + 2 kinetic tremor on one task and a + 3 kinetic tremor on a second task. Tasks included pouring water between two cups, finger-to-nose movements, drinking water from a cup and drawing spirals. Exclusion criteria included: (i) tremor induced by alcohol withdrawal, hyperthyroidism, Parkinson's disease, psychogenic disorders, anti-dopaminergic drug intake or lithium therapy; (ii) other diseases that affected the patient's quality of sleep, including chronic obstructive pulmonary disease, coronary heart disease and chronic pain disorders other than migraine; (iii) tremor resulting from other known causes.

Additionally, 150 control subjects (74 males, 76 females, mean age 53.8 ± 15.5 years) were consecutively recruited from students, hospital staff and non-consanguineous relatives of inpatients who were available conveniently in our hospital. Inclusion criteria for the controls were: (i) without ET; (ii) match with ET patients by gender, age (±2 years) and ethnicity. Exclusion criteria were the same as for the ET group.

All ET patients and control subjects underwent a face-to-face interview and a complete physical and neurological examination by the same two neurologists, who were trained to diagnose ET at movement disorder clinics. In the interview, all participants were asked to fill out a structured questionnaire, including detailed information on ET (age at tremor onset, duration and onset site of tremor, whether it spread to other body parts, family history of tremor and any therapy for tremor). Migraine was diagnosed according to the International Classification of Headache Disorders 3rd edition (beta version; ‘ICHD-3-beta’) diagnostic criteria (14). A detailed history of migraine including lifetime/current, age at onset, duration of the headache, presence of aura, accompanying symptoms, frequency per month and location and severity of pain using a visual analogue scale (VAS) was also obtained in the interview. The duration interval of tremor or headache was calculated from the onset of tremor or migraine to the time of assessment. Subsequently, migraineurs were assessed by the same two independent headache specialists blinded for ET diagnosis. Only patients who were diagnosed by both specialists were eligible for migraine study enrolment. These patients were also asked to describe any change in the features of migraine after onset of ET or the beginning of therapy for tremor. Migraine improvement was defined as a reduction of 35–75% in the frequency of attacks or a decrease in the severity of pain or a shortened duration of the attack.

Genetic studies

The DRD3 gene (Ser9Gly, rs6280) was evaluated in 46 ET patients (20 males, 26 females, mean age 50.5 ± 15.3 years), a subset of the 150 ET patients above, randomly recruited from Department of Neurology, Chinese PLA General Hospital, between 1 July 2012, and 1 July 2013. The patients were separated into two groups: with and without migraine. A single-blind grouping method was used to compare the frequencies of the Ser9Gly variant in the two groups. The diagnostic criteria for ET and migraine were as described above. After patients signed a written informed consent, genomic DNA was extracted from peripheral blood plasma using a standard phenol-chloroform extraction method (15). Polymerase chain reaction (PCR) amplification of the target region of the DRD3 gene was performed using a Veriti thermal cycler system (ABI) and 3 µL of DNA and 1.2 µL primers in a 30-µL reaction volume for 35 cycles at 95℃ for 40 s, 58℃ for 1 min, 72℃ for 1 min and a final extension step at 72℃ for 5 min. PCR primers used were forward: 5′-TGTAAAACGACGGCCAGTTAACTAAGCAACCAAGC-3′ and reverse: 5′-GGATGAGGGACAGGATGG-3′. PCR products were sequenced directionally using an ABI 3730XL automated sequencer (Applied Biosystems). Alignments and analyses were carried out using the DNAStar software (DNAStar, Inc.). The outcomes of the variant at the protein level were predicted according to cDNA sequences deposited in the National Center for Biotechnology Information RefSeq (the RefSeq accession number of the DRD3 gene is NG_008842.1). DNA samples from 50 healthy unrelated individuals recruited from the physical examination centre in the outpatient department of our hospital were used as normal controls and were screened by sequencing.

Statistical analysis

Data were analysed using non-parametric statistical methods, including logistic regression analysis with odds ratios (OR) and 95% confidence intervals (CI). To describe the demographic data and clinical features of ET and migraine, we used percentages, arithmetic mean values and simple SD. Student's t-test or the Mann–Whitney U-test was used to compare quantitative variables. Proportions were compared by chi-squared tests. SPSS software (ver. 13.0 for Windows) was used for statistical analyses. All calculated p-values were two-tailed and statistical significance was set at a p-value <0.05.

Results

In the present study, the prevalence of lifetime migraine in ET patients was significantly higher than that in the control group (22.0% vs. 12.7%; p = 0.035; Table 1). In all, 33 ET patients and 19 controls met the diagnostic criteria for lifetime migraine and not for other headache types, according to the ICHD-3-beta classification. Moreover, no significant difference was found in the features of tremor between 46 genotyped and 150 total ET patients. Compared with the control group, ET patients had an increased risk of lifetime migraine (OR = 1.95; 95% CI = 1.05–3.60).

Table 1.

Characteristics of tremor in essential tremor patients and controls without tremor.

	Essential tremor
Characteristics of tremor	Genotyped (n = 46)	Total (n=150)	P₁ value	Controls (n = 150)	P₂ value
Gender
Male	20 (43.5%)	74 (49.3%)	0.49	74 (49.3%)	1.00
Female	26 (56.5%)	76 (50.7%)		76 (50.7%)
Age (years)	50.5 ± 15.3	54.2 ± 15.9	0.16	53.8 ± 15.5	0.82
Lifetime migraine
With	16 (34.8%)	33 (22.0%)	0.08	19 (12.7%)	0.035
Without	30 (65.2%)	117 (78.0%)		131 (87.3%)
Mean age at onset (years)	41.2 ± 14.7	42.9 ± 15.1	0.52	–	–
Duration of tremor (years)	9.3 ± 9.1	11.4 ± 9.9	0.21	–	–
Onset site of tremor
Left upper limbs	4 (8.7%)	10 (6.7%)	0.64	–	–
Right upper limbs	8 (17.4%)	37 (24.7%)	0.31	–	–
Double upper limbs	17 (37.0%)	55 (36.7%)	0.97	–	–
Head	16 (34.8%)	45 (30%)	0.54	–	–
Other site	1 (2.2%)	3 (2%)	1.00	–	–
Spread to other body parts	19 (41.3%)	61 (40.7%)	0.94	–	–
Family history of tremor	15 (32.6%)	60 (40.0%)	0.37	–	–

P₁: ET patients genotyped vs. total ET patients; P₂: total ET patients vs. controls.

Characteristics of the migraines in ET patients and controls without tremor are presented in Table 2. No significant difference was found in migraine features between the 33 migraineurs in the ET group and the 19 in the control group. These features included gender ratio, age at visit to the clinic, mean age at migraine onset, severity of pain (evaluated by VAS), presence of aura, site of migraine, frequency per month, the prevalence of current migraine and accompanying symptoms. Interestingly, the prevalence of migraine with aura was non-significantly lower in the ET group than in the control group (15.2% vs. 26.3%, p = 0.54). Likewise, the duration of headache seemed longer in ET patients rather than controls; for nausea and vomiting, predominant symptoms were observed in ET patients with migraine. However, the severity of pain was similar in both groups.

Table 2.

Characteristics of migraine in essential tremor and control groups.

Characteristics of migraine	Essential tremor (n = 33)	Control (n = 19)	p-value
Age (years)	54.6 ± 14.0	50.2 ± 13.8	0.28
Gender
Male	8 (24.2%)	5 (26.3%)	1.00
Female	25 (75.8%)	14 (73.7%)
Current migraine	14 (42.4%)	11 (57.9%)	0.28
Mean age at onset (years)	33.8 ± 12.0	35.8 ± 15.7	0.52
Duration of headache (years)	20.7 ± 11.8	15.4 ± 14.2	0.052
Severity of pain (VAS)
Mild (0–3)	0	0	0.89
Moderate (4–6)	18 (54.5%)	10 (52.6%)
Severe (7–10)	15 (45.5%)	9 (47.4%)
Migraine with aura	5 (15.2%)	5 (26.3%)	0.54
Migraine without aura	28 (84.8%)	14 (73.7%)
Site of pain
Unilateral	29 (87.9%)	15 (78.9%)	0.64
Bilateral	4 (12.1%)	4 (21.1%)
Accompanying symptoms
Nausea	26 (78.8%)	11 (57.9%)	0.11
Vomiting	24 (72.7%)	8 (42.1%)	0.29
Photophobia	16 (48.5%)	10 (52.6%)	0.77
Phonophobia	25 (75.8%)	16 (84.2%)	0.71
Frequency per month
Low (<1/month)	13 (39.4%)	5 (26.3%)	0.34
Medium (1–3/month)	17 (51.5%)	10 (52.6%)	0.94
High (>3/month)	3 (9.1%)	4 (21.1%)	0.43

Tremor features in the ET patients with and without migraine are presented in Table 3. The 150 patients with ET were separated into two groups: with and without migraine. The ET patients without migraine group contained significantly more male patients than did the group with migraine (56.4% vs. 24.2%; p < 0.001). Other characteristics of tremor were similar in the two groups, including age at visit, age at tremor onset, duration of tremor, site of tremor onset and spread of tremor to other body parts. Of the 150 ET patients, 69 (46.0%) were treated and the detailed treatments for tremor were as follows: 51 received treatment with arotinolol (dose: 5–20 mg/day); three with propranolol (dose: 10–30 mg/day); one with topiramate (dose: 50 mg/day); one with clonazepam (dose: 1.5 mg/day); two with metoprolol (dose: 25–50 mg/day); five with benzhexol (dose: 1–4 mg/day); six with surgery. Of 33 ET patients with migraine, two patients received medications acting on ET and migraine (one patient received propranolol at a dose of 20 mg/day and another one was treated with topiramate at a dose of 50 mg/day). The migraine of both patients was unaltered after drug treatment for ET.

Table 3.

Characteristics of tremor in essential tremor patients with and without migraine.

Characteristics of tremor	Essential tremor with migraine (n = 33)	Essential tremor without migraine (n = 117)	p-value
Age (years)	54.6 ± 14.0	54.2 ± 16.6	0.90
Gender
Male	8 (24.2%)	66 (56.4%)	<0.001
Female	25 (75.8%)	51 (43.6%)
Mean age at onset (years)	44.9 ± 15.2	42.4 ± 15.4	0.42
Duration of tremor (years)	9.7 ± 9.4	11.8 ± 10.0	0.24
Onset site of tremor
Left upper limbs	2 (6.1%)	8 (6.8%)	1.00
Right upper limbs	9 (27.3%)	24 (20.5%)	0.41
Double upper limbs	10 (30.3%)	48 (41.0%)	0.26
Head	12 (36.4%)	34 (29.1%)	0.42
Other site	0 (0%)	3 (2.6%)	0.82
Spread to other body parts	17 (51.5%)	45 (38.5%)	0.18
Family history of tremor	17 (39.4%)	48 (41.0%)	0.87
Treatments for tremor
Arotinolol	9 (27.3%)	42 (35.9%)	0.36
Propranolol	1 (3.0%)	2 (1.7%)	1.00
Topiramate	1 (3.0%)	0 (0%)	0.50
Clonazepam	0 (0%)	1 (0.9%)	1.00
Metoprolol	0 (0%)	2 (1.7%)	1.00
Benzhexol	0 (0%)	5 (4.3%)	0.51
Surgery	0 (0%)	6 (5.1%)	0.41
Untreated	22 (66.7%)	59 (50.4%)	0.10

Furthermore, no significant difference was found in the frequencies of the DRD3 Ser9Gly polymorphism in ET patients with and without migraine (87.5% vs. 100%; p = 0.22). Of 46 ET patients, 44 (95.7%) had the variant. All the ET patients without migraine (30/30) and 14/16 ET patients with migraine had the Ser9Gly variant. Two sets of chromatograms for the DRD3 Ser9Gly variant, homozygotes (G25A) and heterozygotes (G25G/A), are shown in Figure 1 (a) and (b) respectively. The DRD3 gene (rs6280) variant was located at 3q13.3, as indicated by arrows in the chromatograms (Figure 1).

Figure 1.

Two sets of chromatograms of the DRD3 Ser9Gly variant in the essential tremor patients.

Discussion

The main result of this case–control study was that ET was a significant risk factor for lifetime migraine in our large sample, with an OR of 1.95 (95% CI = 1.05–3.60). This finding is consistent with a previous study (1) showing the prevalence of migraine to be significantly higher in ET patients than in control subjects (36% vs. 18%; p = 0.005; OR = 2.7). Moreover, beta-adrenergic blocking drugs and anti-epileptic drugs have been reported to ameliorate clinical symptoms in both conditions (16 –19). Recently, basal ganglia, cerebral cortex, brainstem and cerebellum have also been reported to be involved in migraine (8,9) and ET (6,7). Based on this evidence, an association between ET and migraine is suggested and ET may be a risk factor for migraine.

Our results differ from a recent case–control study (3) that found no significant difference in the frequency of migraine between ET and control groups (25.4% vs. 21.8%, p = 0.53). That study had a smaller sample size than our study (110 vs. 150), which could cause a smaller or no difference in the prevalence of migraine between the ET and control groups. Moreover, the estimated prevalence of migraine varies between countries and world regions, as described in our previous survey (20). The case–control study just mentioned was conducted in Italy, which might result in different results from our study. Additionally, the prevalence of lifetime migraine in the present control group (12.7%) was higher than that in our previous population-based survey (9.3%) in mainland China (20), which may be attributable to an older age in the current population than in the previous investigation (53.8 ± 15.5 vs. 43.6 ± 12.8). It is known to us that an older age would produce a higher prevalence of lifetime migraine. Nevertheless, the difference in the prevalence of lifetime migraine between the ET sufferers and controls without tremor was still significant (22.0% vs. 12.7%, p = 0.035).

Interestingly, most of the migraine features were similar between the ET and control groups in the present study. This is consistent with the study by Barbanti et al. (3). A non-significant lower prevalence of lifetime migraine with aura was observed in the ET group (15.2%) than in the control group (26.3%), which may suggest a lower prevalence of aura in migraineurs with ET than in the general population. However, further studies are necessary on this. For nausea and vomiting, predominant symptoms in ET patients with migraine might be induced by the implication of the brainstem network in both conditions; a non-significantly longer duration of headache in ET patients than controls might be attributed to an older age in ET than control groups. Nevertheless, similar features in both groups are not explainable with the severity of pain. Moreover, no significant difference was found in most tremor characteristics between ET patients with and without migraine. A higher prevalence of male ET patients without migraine was observed, consistent with a previous study suggesting that ET patients had significantly more males than controls (1). Additionally, it was difficult to calculate the frequency of tremor onset sites involving the left and right hands because 38.7% of ET patients (58/150) could not recall which hand was involved first. Although previous studies suggest left hand dominance in both ET (21) and migraine (22), in the 1980s, several studies argued against any association between migraine and left handedness (23 –25). More studies are needed to clarify this.

The results from our genetic study clearly indicate that the frequencies of the functional variant (Ser9Gly) are very similar in ET patients with and without migraine (87.5% vs. 100%; p = 0.22). A non-significant lower frequency of the variant was observed in ET with migraine than without migraine, which may suggest a lower frequency of DRD3 Ser9Gly variant in ET with migraine than the general ET patients. However, additional large-scale studies are needed to confirm this important finding and to clarify the possible pathogenesis.

Although an association between ET and migraine was supported in our study, no significant difference was found in the clinical features of migraine or ET when both conditions coexisted. Thus, it seems reasonable to suggest that the same general brain structure(s) may be implicated in the pathophysiological mechanism(s) of ET and migraine, although likely involving different nerve circuits and molecular changes. Recently, the extrapyramidal system has been somewhat involved in the processing and modulation of nociceptive information and/or may be part of the complex behavioural adaptive response that characterizes headache (8), migraine has also been widely investigated in other movement disorders. In comparison to the general population, migraine prevalence has been reported to be higher in Tourette's syndrome (26,27), similar in Sydenham's chorea (28). The lifetime prevalence of migraine in Parkinson's disease has been reported to range from 19.3 to 27.8% in case–control studies, in contrast to a lower frequency of current migraine than healthy controls (29). Restless legs syndrome (RLS) has also been observed to be more common in migraine patients than in control populations (30), although the exact mechanisms and/or contributing factors for the association between migraine and RLS remain unclear. Furthermore, in previous studies, the cerebellum has commonly been implicated in the mechanisms of migraine (31) and ET (7,32) through altered neural circuits or vascular infarcts. The olivo–cerebellar pathways of central nervous circuits have been reported to be involved in the pathogenesis of ET (7,32). Moreover, a recent population-based cross-sectional study suggested that patients with migraine were at increased risk for vascular lesions in the posterior circulation affecting the cerebellum (33), which might yield subtle alterations in the olivo–cerebellar circuit. However, we did not perform any clinical examination using imaging techniques to determine whether such a vascular event had occurred in our group. If ET patients with migraine had such infarcts in their posterior circulation, a potential central component would need to be assessed in future studies.

Strengths and limitations

The present study has several strengths, including the large sample for a case–control design and exploration of the possible correlation of ET and migraine by comparative analysis using the latest ICHD-III (beta version) diagnostic criteria for migraine and examining a functional variant (Ser9Gly) in the DRD3 gene first in ET patients with and without migraine. Nevertheless, several limitations of this study should be considered. First, patients with ET were enrolled at a tertiary referral centre; this was not a population-based study. Second, we cannot rule out possible recall bias for the characteristics of ET and migraine. Some patients could not remember clinical features clearly, such as age at tremor or migraine onset. Third, we did not test other dopamine-receptor (D1, D2, D4 and D5) gene variants in ET patients with and without migraine, which may have shown significant differences. Finally, there was limited access to the blood samples of the patients, only 46 ET patients were genotyped. A large-scale study is necessary on this in the future.

Clinical implications

Our results suggested that ET patients have a higher risk of lifetime migraine than controls.

The dopamine receptor D3 Ser9Gly variant may be lower in ET with migraine than the general ET patients.

Footnotes

Funding

This work was supported by the National Natural Science Foundation of China, Grant Nos. 30970417 and 81171058. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

None declared.

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Higher prevalence of migraine in essential tremor: A case–control study

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Materials and methods

Standard protocol approvals

Clinical studies

Genetic studies

Statistical analysis

Results

Discussion

Strengths and limitations

Clinical implications

Footnotes

Funding

Conflict of interest

References