Longitudinal Follow‐Up of Mood in Cervical Dystonia and Influence on Age at Onset

ABSTRACT

Background

Anxiety and depression are highly prevalent conditions in cervical dystonia and considered intrinsic to the disease mechanism. Psychiatric symptoms do not appear to be influenced by botulinum toxin therapy. Studies focusing on changes in mood disorder during the course of the disease are limited in this chronic, lifelong disorder.

Objective

To assess the longitudinal prevalence of mood disorder, pain, and quality of life in patients with cervical dystonia attending a botulinum toxin clinic.

Methods

Patients involved in phase I of our study were invited to be involved in reassessment using the Beck Depression Inventory, Second Revision; Beck Anxiety Index; Cervical Dystonia Impact Profile–58 (CDIP‐58); and the Toronto Western Spasmodic Torticollis Rating Scale–2 Pain Scale (TWSTRS2‐Pain).

Results

A total of 53 participants took part after a mean study interval duration of 24 months. There were no significant differences between the 2 study time points in the prevalence of anxiety (P = 0.2919) and depressive symptoms (P = 0.5). Self‐reported quality of life by CDIP‐58 (P = 0.96) and pain by TWSTRS2‐Pain (P = 0.9321) were unchanged. Men and women with significant symptoms of mood disorder had an earlier age of onset of cervical dystonia (P = 0.008).

Conclusion

Anxiety and depressive symptoms persist in cervical dystonia, seem to be unrelated to pain severity, and need to be specifically targeted to improve quality of life. The relationship between mood disorder and age of onset suggest that mood disorder may be part of the disease pathophysiology.

Dystonia is a hyperkinetic movement disorder characterized by sustained or repetitive muscle contractions causing abnormal, often repetitive postures that can be associated with tremor and pain. Primary dystonia refers to pure dystonia with no additional neurological signs other than tremor; adult‐onset isolated focal dystonia (AOIFD) is the most common form of primary dystonia and presents as a number of phenotypes including cervical dystonia, focal hand dystonia, blepharospasm, spasmodic dysphonia, and oromandibular dystonia. ¹ AOIFD is rare: its prevalence in Ireland was estimated at 17.8 per 100,000. ²

Cervical dystonia is the most common phenotype of AOIFD worldwide; it is considered an autosomal dominant disorder with a markedly reduced penetrance (10%–15%); ³ only 20% of patients with cervical dystonia have another affected family member. Epigenetic mechanisms, sex, and age at onset may interact to influence phenotype and penetrance. ⁴

Mood Disorder in Cervical Dystonia

Mood disorders, anxiety and depression, are common in cervical dystonia. In 193 patients from our clinic (128 women and 65 men), a history of mood disorder was more common in women (41%) than men (31%); 42% women and 32% men had current mood disorder symptoms. ⁵

It is considered that mood disorders are part of the primary condition and intrinsic to the pathophysiology of AOIFD. ⁶ Recently it was shown that genetic influences on medium spiny neurons in the basal ganglia could lead to both neuropsychiatric symptoms and dystonic syndromes. ⁷ Another influence may be pain and abnormal posturing secondary to the disorder, which can be ameliorated with botulinum toxin therapy. ⁸

We have shown that mood disorders are the main predictors of quality of life (QoL). ⁹ For neurologists, in the setting of a dystonia clinic, it is important to address these influences on QoL to improve outcomes. This study was designed to follow‐up our previous assessment of anxiety and depression in our cohort of patients with cervical dystonia. ⁴ The aim was to determine the longitudinal fluctuations in mood symptoms in patients with cervical dystonia undergoing botulinum toxin treatment.

Participants and Methods

Study Participants

All patients with adult‐onset idiopathic cervical dystonia attending a botulinum toxin clinic at St Vincent's University Hospital who had participated in a previous study of mood disorder ⁵ were invited to take part in the study. More than 60% of those clinically diagnosed with cervical dystonia in the Republic of Ireland are treated in this hospital. ² We excluded patients with other forms of dystonia, including generalized dystonia, segmental dystonia, and other forms of focal dystonia as well as those with other neurological conditions and comorbidities that would prevent the completion of questionnaires used in this study.

This study was approved by St Vincent's Healthcare Group, Ethics and Medical Research Committee (reference: RS21‐037). Written informed consent was obtained from all participants of the study.

Our phase I study was carried out at the same institution and was designed to assess the prevalence of mood symptoms (primarily burden of anxiety and depressive symptoms) in our cervical dystonia service and to review the differences between patients with significant mood symptoms and those without. This study follows the same assessment protocol.

Study Instruments

1. Dystonia pain self‐report was assessed using the Toronto Western Spasmodic Torticollis Ratings Scale–2 Pain Scale (TWSTRS2‐Pain) ¹⁰ ;

2. The Cervical Dystonia Impact Profile–58 (CDIP‐58) is a commonly used, multidimensional, disease‐specific, patient self‐report of health‐related QoL (HrQoL). ¹¹ The 8 subdomains measure head‐ and neck‐related symptoms, pain, walking, upper limb, sleep, annoyance, mood, and psychosocial functioning to provide a comprehensive, holistic assessment. ¹¹ The CDIP‐58 is a validated and reliable rating scale for cervical dystonia in both clinical and nonclinical settings and has been used extensively ¹² ; and

3. Beck's Anxiety Inventory (BAI) and Beck's Depression Inventory, Second Edition (BDI‐II) were employed to assess current anxiety and depression levels. Both questionnaires are 21‐item self‐reporting assessment tools. They are each rated on 4‐point scales from 0 to 3, with a minimum total score of 0 (minimal anxiety/depression) and a maximum total score of 63 (maximum anxiety/depression). We used scores >13 as cutoff points to indicate patients with significant symptoms of anxiety/depression. ¹³ , ¹⁴ Although not intended to replace the gold standard (a structured psychiatric led clinical review), the BDI and BAI have proven reliable and effective measures with strong discriminant properties ¹⁵ , ¹⁶ and have been employed in studies on other movement disorders. ¹⁷ , ¹⁸

Methods

Following the signed, fully informed consent, all patient‐reported assessments (CDIP‐58, BAI, BDI‐II, and TWSTRS2‐Pain scores) were completed 2 weeks before the next botulinum toxin clinic visit, approximately 12 weeks after the previous injection, to mitigate the risk of treatment impacting results. Questionnaires and consent forms were sent to participants by post with a follow‐up phone call and instructions to return them to investigators at the upcoming dystonia clinic review.

Statistical Methods

Normality was tested using Shapiro–Wilks and Kolmogorov–Smirnov tests. We evaluated changes in the BAI and BDI‐II results between the 2 time points. IBM (Armonk, NY) SPSS version 27 was used for the analysis. Some data were approximately normally distributed, and independent‐samples t tests (2 tailed) was used to compare the means of independent groups. A Mann–Whitney U test was used to compare nonparametric data. Homogeneity of variances was tested for using Levene's test. A P value of <0.05 was considered significant.

Results

Demographics

A total of 53 patients, 18 men (33.9%) and 35 women (66.1%), with cervical dystonia agreed to participate in this longitudinal study (representing 27% of participants from our phase I study). All patients had isolated, idiopathic adult‐onset cervical dystonia. Patients had a mean age of 61.4 years (±12.4). Mean age of onset of cervical dystonia of 40.4 years (±11.5); mean duration of cervical dystonia was 21 years. All patients had been treated with botulinum toxin and attended the clinic every 3 months. The mean time between the 2 longitudinal assessments was 24 months (range, 22–30 months).

Mean values and standard deviation (SD) for the BAI, BDI‐II, CDIP‐58, and TWSTRS2‐Pain are shown in Fig. 1.

FIG. 1.

The 53 patients with cervical dystonia were assessed at 2 time points (phase I [P1] and phase II [P2]), 2 years apart, in relation to Beck's Anxiety Inventory (BAI), Beck's Depression Inventory (BDI), Cervical Dystonia Impact Profile–58 (CDIP58), and the Toronto Western Spasmodic Torticollis Rating Scale–2 Pain scale (TWSTRS). This figure demonstrates the overall stability of reported measures during the 2‐year period. The vertical bars indicate mean (± standard deviation) values at the plot showing the P1 and P2 results of all measures used.

Current Symptoms

Anxiety/Depression

Using the previously described cutoff scores for BAI and BDI‐II, 5/18 men (28%) and 19/35 women (54%) met the criteria for significant symptoms of anxiety and/or depression. There were no differences between men and women on mean BAI scores (P = 0.101; Mann–Whitney U = 228). The BDI‐II, however, did show a statistically significant sex difference (P = 0.01; Mann–Whitney U = 183), with more women than men reporting scores >13.

Mood Disorder and Age of Onset

Previously, we showed that women with a history of mood disorders at any point had an earlier age of onset. ⁵ Of the 53 patients in this assessment, we noted a statistically significant difference in the mean age of onset in patients (men and women) with current significant mood symptoms (t ₅₁ = 2.78, P = 0.008).

Dystonia‐Related QoL

The mean (±SD) total CDIP‐58 score was 33 (±23) for our 53 patients at follow‐up. The mean total CDIP‐58 score for women was 36 (±20.6); for men it was 23 (±22). There was a significant difference between men and women in the CDIP‐58 results (P = 0.002, Mann–Whitney U = 147).

Mean scores across the 8 subdomains measured on the CDIP‐58 and interaction with presence of mood symptoms (significant anxiety or depression or both) are shown in Table 1. Patients with scores >13, as expected, had reduced QoL with a mean CDIP‐58 of 47, significantly higher than patients with lower scores. In all subdomains, worse (higher) mean scores were found in participants with significant symptoms of mood disorders.

TABLE 1.

Mean CDIP‐58 total and subdomain scores of the 53 patients with cervical dystonia in the phase II (current) follow‐up study, mean scores of those 24 patients with and 29 patients without current mood disorder, and P values for group differences

CDIP‐58 Subdomains and Total	Overall Mean	Presence of Mood Disorder	Absence of Mood Disorder	P
Head and Neck	54	62	48	0.053
Pain and Discomfort	47	60	37	<0.003
Upper Limb	29	45	16	<0.0001
Walking	28	44	15	<0.0001
Sleep	29	42	18	<0.003
Annoyance	30	48	14	<0.0001
Psychosocial Functioning	38	40	18	<0.001
Mood	21	39	7	<0.0001
Total	33	47	20	<0.0001

Mood disorder considerably affects all aspects of quality of life assessed by the CDIP‐58.

Abbreviation: CDIP‐58, Cervical Dystonia Impact Profile–58.

Dystonia Pain

The mean TWSTRS2‐Pain score for our whole cohort was 13 (±10). Men had a mean of 7, and women had a mean of 16—a significant difference (P < 0.001, Mann–Whitney U = 139). There was also significant difference between patients with and without mood disorders in the TWSTRS2‐Pain scores (P = 0.003; Mann–Whitney U = 184).

Longitudinal Changes Between Phases I and II

Only 11 patients did not have significant symptoms of mood disorders at either time point. Of the patients with current scores of BAI/BDI >13 (n = 24), 4 did not meet the criteria for significant anxiety or depressive symptoms at our initial study and had developed these in the past 2 years. A total of 5 patients with either BAI/BDI scores >13 in our phase I study did not meet that threshold at the current time point.

The mean difference at each time point for all measurement tools is shown in Table 2.

TABLE 2.

Comparisons of measures of mood disorder, quality of life, and pain in the 53 patients with cervical dystonia at 2 time intervals approximately 2 years apart with analysis of 2‐tailed, independent‐sample t tests

Test	Time I	Time II	MD	P Value
BAI	10.3 (9.3)	12.2 (13.4)	1.75	0.2919
TWSTRS2‐Pain	13.3 (8.4)	13.2 (9.6)	−0.09	0.9321
BDI‐II	10.8 (8.7)	11.7 (11.3)	0.87	0.5
CDIP‐58	32.2	33	−0.13	0.96

Values given are means (standard deviations) and mean differences (MDs) between the 2 groups.

Abbreviations: BAI, Beck's Anxiety Inventory; BDI‐II, Beck Depression Inventory, Second Revision; CDIP‐58, Cervical Dystonia Impact Profile–58; Toronto Western Spasmodic Torticollis Rating Scale–2 Pain Scale (TWSTRS2‐Pain).

Discussion

Cervical dystonia is a chronic lifelong disorder with remission being rare and typically transient. ¹⁹ Recognition of mood symptoms in cervical dystonia can be traced back as far Jean Charcot (late 1800s) and his student Edouard Brissaud; the latter coined the term “torticollis mental.” Some of the evidence used to support the psychogenic origin theory of this disorder was the association with psychiatric symptoms and stress as well as the peculiar geste antagoniste. ²⁰

When our initial phase I study began, the literature contained extensive data on prevalence and types of psychiatric features. A handful of studies have assessed changes in mood symptoms, ²¹ , ²² with some focusing on the immediate impact of botulinum toxin therapy. ⁸ , ²³ Our large cohort of patients with adult onset idiopathic cervical dystonia, invariably treated with botulinum toxin, did not show any major differences in mood symptoms across the 2 time points over 2 years. More than half of the women, and nearly one third of the men, in this study suffered from significant symptoms of anxiety, depression, or both.

The relationship between mood disorder and age at onset was demonstrated by us before but only in women. ⁵ Here we noted a significant difference in age at onset for both men and women not described in other dystonia literature. This is an interesting finding as it lends further evidence that mood disorders may represent an intrinsic part of the AOIFD mechanism and are not secondary to motor symptoms. Researchers should consider exploring dystonia genetics in the context of mood disorders.

The evidence of a high continuing prevalence of mood disorders in this population indicates that mood disorders continue to play a significant role in affecting HrQoL despite patients reporting good or excellent results with botulinum toxin over many years. ²⁴ The influence of mood symptoms on HrQoL was demonstrated by the marked difference in mean CDIP‐58 scores between participants with either anxiety or depression or both and those participants without significant mood symptoms.

The Head and Neck subdomain was the only portion of the CDIP‐58 to not show statistically significant group differences. Along with Pain and Discomfort, the questions in these 2 sections are most specific for cervical dystonia motor symptoms. ²⁵ It would seem, from this cohort, that mood symptoms do not influence these specific motor symptoms (or vice versa). However, our own phase I study, with a much larger cohort of 193 patients, showed that mood symptoms did influence CDIP‐58 Head and Neck subdomain scores.

It has been long accepted that dystonia is more than just a motor disorder; however, mechanisms of disease remain unknown. We have previously suggested that a network involving the superior colliculus, amygdala, and pulvinar mediates the motor and nonmotor features of this elusive disorder. ²⁶ Furthermore, this study highlights the importance of regular mood assessments in botulinum toxin clinics. The BAI and BDI‐II are well validated, easily applied, and in our studies took patients only minutes to complete. We would recommend that they be routinely implemented into dystonia clinics for a holistic assessment of patients with cervical dystonia. Targeting these symptoms with, for example, selective serotonin receptor antagonists, may help to improve overall QoL.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

AM: 1A, 1C

SR: 1B, 1C, 2B, 3A

IN: 2B, 3A

SOR: 1A, 3B

MH: 1A, 1B, 3A, 3B

Disclosures

Ethical Compliance Statement: This study was approved by the St Vincent's University Hospital Medical Research and Ethics Committee (Reference: RS21‐037). Informed consent was obtained from all study participants. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.