ABSTRACT
Background
Assessing disease severity can be performed using either clinician‐rated scales (CRS) or patient‐rated outcome (PRO) tools. These two measures frequently demonstrate poor correlations.
Objectives
To determine if the correlation between a CRS and PRO for motor features of cervical dystonia (CD) improves by accounting for non‐motor features.
Methods
Subjects with CD (N = 209) were evaluated using a CRS (Toronto Western Spasmodic Torticollis Rating Scale, TWSTRS) and a PRO (Cervical Dystonia Impact Profile, CDIP‐58).
Results
Linear regression revealed a weak correlation between the two measures, even when considering only the motor subscales of each. The strength of this relationship improved with a regression model that included non‐motor symptoms of pain, depression, and disability.
Conclusions
These results argue that the results of motor assessments in a PRO for CD cannot be fully appreciated without simultaneous assessment of non‐motor co‐morbidities. This conclusion might apply to other disorders, especially those with frequent non‐motor co‐morbidities.
Keywords: dystonia, cervical dystonia, torticollis, depression, anxiety, patient‐reported outcome measure, rating scale
Measures that reliably assess severity of a clinical condition are essential for monitoring responses to therapy in the clinic, determining efficacy in clinical trials, and as correlative measures for scientific studies. Traditionally, most measures for severity focused on clinician‐rated scales (CRSs). These CRSs are based on a medical understanding of the illness, and they can be scientifically validated. These measures also have some drawbacks. They are typically limited to observations made during a short visit to the clinic and do not reflect what happens at home or under other circumstances, they may not always measure what is important to individuals affected with an illness, and they are subject to clinician and patient bias. 1
In recent years, pharmaceutical regulatory agencies such as the US Food and Drug Administration and the European Medicines Authority have emphasized an alternative strategy to assess the severity of a condition. 2 , 3 This strategy focuses instead on the patient perspective, using patient‐centered or patient‐reported outcome measures (PROs). Such measures help to discern symptoms not apparent to the clinician during a brief clinic visit, and to understand the impact of the condition on the affected individual. 4 These measures also have limitations. For example, results are based on the subjects’ interpretation of their symptoms and they sometimes confound the condition being assessed with unrelated problems. 5
CRSs and PROs are complimentary, with different advantages and disadvantages. 6 Ideally, data obtained from both methods would yield similar results. However, results from CRSs and PROs frequently do not correspond. 7 , 8 In the current study, we explored the hypothesis that non‐motor factors may be responsible for the poor correspondence between an illness‐specific CRS and PRO for individuals with cervical dystonia (CD). CD is a neurological disorder characterized by excessive involuntary contractions of muscles of the neck, leading to abnormal head postures, jerky or tremulous head movements, and neck pain. 9 CD is often associated with poor quality of life, because affected individuals have difficulty with many activities of daily living such as reading, looking at a television or computer screen, or driving a car. 10 CD also is associated with a high frequency of psychiatric co‐morbidities. 11 , 12 , 13
Methods
We took advantage of a large dataset available from the Dystonia Coalition, an international multicenter research initiative that aims to advance clinical and translational research for all types of dystonia (www.dystoniacoalition.org). 14 In a study aimed at assessing rating scales for CD, 11 sites recruited 209 affected individuals. 15 Subjects were assessed using a CRS specifically validated for CD, the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), motor severity subscale. 16 Each subject also completed a validated PRO, the Cervical Dystonia Impact Profile (CDIP‐58). 17 The nature and severity of depression and anxiety were simultaneously assessed by self‐rating with the Beck Depression Inventory (BDI‐II) 18 and the Liebowitz Social Anxiety Scale (LSAS). 19
Results
Descriptive statistics for the 209 subjects with CD are shown in Table 1. In keeping with other studies of this disorder, the majority were female (73.7%) and white (94.3%). 20 Mean age was 59.7 (σ = 10.1, range = 29–83), with average duration of illness of 15.3 years (σ = 11.4, range = 0–60). The overall severity of illness varied widely, as judged by the broad ranges of scores for the TWSTRS and CDIP‐58 (Table 1). Psychiatric features as measured by the BDI‐II and LSAS also varied widely (Table 1). In keeping with prior studies, 11 , 12 , 13 a large percentage of individuals in this cohort reached the cutoff scores for suggesting the presence of clinically significant depressive (59 cases or 28.2% of the total using a cutoff score of 14) or social anxiety symptoms (97 cases or 46.4% using a cutoff score of 30).
TABLE 1.
Descriptive Statistics for Participants
| Measure | Mean | SD | Min | Max |
|---|---|---|---|---|
| Mean Age (Years) | 59.7 | 10.1 | 29 | 83 |
| Mean Dx Duration (Years) | 15.3 | 11.4 | 0 | 60 |
| Sex, Female | 154 (73.7%) | |||
| Race | ||||
| White | 197 (94.3%) | |||
| Black | 7 (3.3%) | |||
| Other | 5 (2.4%) | |||
| CDIP‐58 | ||||
| Total score | 131.0 | 50.9 | 58 | 277 |
| Neck subscore | 19.71 | 6.5 | 0 | 30 |
| Pain subscore | 15.05 | 6.28 | 0 | 25 |
| Disability subscore | 36.48 | 18.04 | 0 | 89 |
| TWSTRS | ||||
| TWSTRS total | 33.56 | 13.22 | 5 | 61.75 |
| TWSTRS motor | 16.40 | 5.46 | 3 | 29 |
| TWSTRS pain | 7.91 | 5.55 | 0 | 18.75 |
| TWSTRS disability | 9.18 | 5.72 | 0 | 24 |
| BDI‐II | 10.3 | 9.6 | 0 | 44 |
| LSAS | 36.9 | 29.6 | 0 | 126 |
Abbreviations: TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale; BDI‐II, Beck Depression Inventory; LSAS, Liebowitz Social Anxiety Scale; CDIP‐58, Cervical Dystonia Impact Profile (Neck‐movement Subscale), showing raw and untransformed scores.
A series of bivariate correlations revealed significant associations among multiple variables (Table 2). In particular, there was a significant relationship between the TWSTRS motor score and the CDIP‐58 (r = 0.32, P < 0.01). This correlation only moderately improved when the TWSTRS motor score was correlated only with the neck movement subscale of the CDIP‐58 (r = .40, P < 0.01), indicating only partial correlations even when the PRO focused exclusively on neck symptoms.
TABLE 2.
Associations between PROs, CRSs, and Psychiatric Symptoms Measures
| Scale | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | LSAS | 1.00 | |||||||||
| 2 | BDI‐II | 0.62** | 1.00 | ||||||||
| 3 | CDIP‐58 total | 0.57** | 0.72** | 1.00 | |||||||
| 4 | CDIP motor | 0.31** | 0.45** | 0.75** | 1.00 | ||||||
| 5 | CDIP pain | 0.23** | 0.46** | 0.70** | 0.84** | 1.00 | |||||
| 6 | CDIP disability | 0.48** | 0.59** | 0.85** | 0.60** | 0.58** | 1.00 | ||||
| 7 | TWSTRS total | 0.33** | 0.44** | 0.70** | 0.68** | 0.66** | 0.65** | 1.00 | |||
| 8 | TWSTRS motor | 0.18* | 0.17* | 0.32** | 0.40** | 0.33** | 0.33** | 0.73** | 1.00 | ||
| 9 | TWSTRS pain | 0.20** | 0.38** | 0.61** | 0.61** | 0.69** | 0.55** | 0.80** | 0.34** | 1.00 | |
| 10 | TWSTRS disability | 0.39** | 0.48** | 0.71** | 0.60** | 0.54** | 0.66** | 0.83** | 0.40** | 0.56** | 1.00 |
P < 0.01.
P < 0.05.
Abbreviations: TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale – Severity; BDI‐II, Beck Depression Inventory; LSAS, Liebowitz Social Anxiety Scale; CDIP‐58, Cervical Dystonia Impact Profile (Neck‐movement subscale).
We, therefore, constructed a predictive multiple linear regression model to test the impact of non‐motor symptoms (anxiety, depression, pain, and disability) on the relationship between TWSTRS and CDIP motor subscales. We first evaluated the strength of the relationship between the TWSTRS motor severity subscale and CDIP‐58 neck movement severity score through which a significant relationship emerged (r 2(209) = 0.17, P < 0.001). This result implies that only 17% of the variability in the patient reported neck movement was accounted for by the clinician's ratings. In the second step, we added the non‐motor features to the relationship between the TWSTRS and the CDIP, which resulted in a stronger predictive model (r 2(209) = 0.51, P < P.001) that accounted for approximately three times the variability of CDIP scores than in the first step. In this model, the prediction of CDIP scores was significantly impacted (Table 3) by the TWSTR motor (β(209) = 0.21, P < 0.001), TWSTRS pain (β(209) = 0.49, P < 0.001), TWSTRS disability (β(209) = 0.34, P < 0.001), and depression scores (β(209) = 0.12, P = 0.03).
TABLE 3.
Comparisons between CDIP and other scales
| Clinical variables | CDIP‐58 | |||
|---|---|---|---|---|
| r 2 | β | 95% CI | P‐value | |
| Stepwise multivariate model 1 | .17 | |||
| TWSTRS motor | 0.56 | 0.38, 0.73 | <.001 | |
| Stepwise multivariate model 2 | .51 | |||
| TWSTRS motor | 0.21 | 0.06, 0.36 | <.001 | |
| TWSTRS pain | 0.49 | 0.32, 0.66 | <.001 | |
| TWSTRS disability | 0.34 | 0.17, 0.52 | <.001 | |
| BDI‐II | 0.12 | 0.01, 0.22 | 0.03 | |
| LSAS | 0.003 | −0.03, 0.04 | .84 | |
Abbreviations: TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale—Severity; BDI‐II, Beck Depression Inventory; LSAS, Liebowitz Social Anxiety Scale; CDIP‐58, Cervical Dystonia Impact Profile (Neck‐movement subscale).
Discussion
We explored the impact of common non‐motor features on the correlation between a CRS and a PRO for the motor features of CD, the most common adult‐onset subtype of dystonia. The correlation between the CRS and PRO was weak, even when both presumably focused on the same physical problems relating to the neck. Accounting for non‐motor co‐morbidities improved the correlation between these measures. Even after accounting for these co‐morbidities, the correlation between the CRS and PRO was imperfect, arguing other factors may also play a role. These results argue for caution when using PROs as an outcome measure for therapeutic trials aimed at alleviating motor symptoms, because PROs may reflect non‐motor symptoms that confound assessment of motor symptoms.
Understanding what aspect of an illness influences a PRO measurement is important, because treatments for different aspects of an illness differ. In CD, treatment of the motor aspects with botulinum toxins requires a different approach than treating the pain or psychiatric aspects. Pain and psychiatric problems may be an inherent problem in CD or a reaction to the illness. Treating only the motor symptoms may not impact the non‐motor symptoms or the patient's perception of their illness. 21 , 22 Separate treatment directed to the non‐motor features may also be required. To detect non‐motor features, the current study relied on the CDIP‐58, BDI‐II and LSAS. However, these tools may be burdensome because of their length and redundancies, so development of a simpler screening tool for non‐motor features may be useful for the future.
These results argue that those from a PRO in CD cannot be fully appreciated without simultaneous assessment of non‐motor co‐morbidities, presumably because these co‐morbidities have a significant impact on patients’ perceptions of severity. Therefore, to gain the best overall assessment of the impact of CD, we must ask both the patient and the doctor, assessing both motor and non‐motor features. This conclusion might apply to many other medical conditions, especially those with frequent non‐motor co‐morbidities.
Author Roles
The authors contributed to this manuscript in one or more of the following ways: (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. Specific author contributions:
A.C.C.: 1B, 1C, 2B, 3A
L.M.S.: 1B, 2A, 2C, 3B
W.M.: 3B
C.C.: 3B
J.P.: 2C, 3B
C.G.G.: 2C, 3B
J.J.: 3B
L.M.: 1B, 3B
S.F.: 1B, 3B
H.A.J.: 1A, 1B, 2A, 2C, 3A, 3B
Disclosures
Ethical Compliance Statement: This study was approved by the IRBs of all sites participating in the Dystonia Coalition. All participants gave written consent for participation following the principles of the Declaration of Helsinki. The Emory University IRB also approved all procedures involving human 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: This work was supported in part by grants to the Dystonia Coalition from the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke and TR001456 from National Center for Advancing Translational Sciences).
Financial Disclosures for the Previous 12 Months: Dr. Laura Scorr discloses grants (Addex Pharma S.A., Boston Scientific, Neurocrine, Dystonia Medical Research Foundation, American Parkinson's Disease Association). Dr. William McDonald discloses honoraria (Signant Health and Sage Therapeutics), grants (NIMH and NIA), and other (JB Fuqua Foundation, Skyland Trail, and 3Keys). Dr. Comella discloses honoraria (Acorda Therapeutics, Lundbeck Ltd., Merz Pharmaceuticals, Acadia Pharmaceuticals, Ipsen Pharmaceuticals, Jazz Pharmaceuticals, Adamas Pharmaceutical, Neurocrine Biosciences Inc., Revance Therapeutic, Sunovion., EON Biopharma) and royalties (Cambridge, Wolters Kluwer). Dr. Joel Perlmutter discloses honoraria (ENROLL HD, Huntington Disease Study Group, CHDI, Parkinson Study Group, Beth Israel Hospital, U Illinois in Chicago, Boston University), grants (NIH NS075321, NS103957, NS107281 NS107281‐03S1, NS097437, U54NS116025, U19 NS110456, AG64937, NS097799, NS075527, ES029524, NS109487, R61 AT010753, RO1NS118146, UG3MH126861, NS124738, R01AG065214, NS124789, R34AT001015) and foundation support (Michael J. Fox Foundation), Barnes‐Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson disease research fund), American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, Greater St. Louis Chapter of the APDA, Paula and Rodger Riney Fund, Jo Oertli Fund, Huntington Disease Society of America, Murphy Fund, Fixel Foundation, N. Grant Williams Fund, Pohlman Fund. Dr. Christopher Goetz discloses honoraria (Genetech, Psychogenics Inc, CHDI, International Parkinson and Movement Disorder Society, Elsevier Publishers, Arizona State University), grants (NIH, Department of Defense, Michael J. Fox Foundation), and royalties (Elsevier Publishers, Wolters Kluwer, Oxford University Press). Dr. Joseph Jankovic discloses honoraria (AbbVie Inc; Eon BioPharma; Neurocrine; Revance Therapeutics; Teva Pharmaceutical Industries Ltd.), grants (AbbVie Inc; CHDI Foundation; Dystonia Coalition; Emalex Biosciences, Inc; Medtronic Neuromodulation; Michael J Fox Foundation for Parkinson Research; Parkinson's Foundation; Revance Therapeutics, Inc; Teva Pharmaceutical Industries Ltd.), and royalties (Cambridge; Elsevier; Medlink: Neurology; Lippincott Williams and Wilkins; UpToDate; Wiley‐Blackwell). Dr. Laura Marsh discloses grants (VA MVP‐MIND, VA CSP‐G002, VA CSP‐2015 C‐SAPP Study, VA Million Veteran Program MVP‐MIND). Dr. Stewart Factor discloses honoraria (Acorda, Alterity, Biogen, Lunbeck, Sunovion), royalties (Blackwell Futura, Springer, Demos, UptoDate), grants (Addex Pharma S.A., Biohaven, Boston Scientific, Impax, Medtronic, Neurocrine, Sun Michael J. Fox Foundation, NIH [U10 NS073266]), Parkinson Foundation, Pharmaceuticals Advanced Research Company, Prilenia Therapeutics CHDI Foundation, Sunovion, Vaccinex, Voyager), and other (Signant Health [Bracket Global LLC] and CNS Ratings LLC). Dr. H.A. Jinnah discloses honoraria (Addex, Allergan, BridgeBio/CoA Therapeutics, Cavion/Jazz Therapeutics, Ipsen, Retrophin, Revance, and Takaha/Ene Pharmaceuticals, International Parkinson's Disease and Movement Disorders Society), grants (National Institutes of Health NS116025 and NS065701, Office of Rare Diseases Research at the National Center for Advancing Translational Sciences TR001456, International Parkinson's Disease and Movement Disorders Society, Abvie, Addex, Eon, Jazz, Revance, Sage), and foundation support (The Benign Essential Blepharospasm Foundation, The Dystonia Medical Research Foundation, and Dysphonia International).
Acknowledgments
We thank Dr. Glenn Stebbins from Rush University for offering his statistical expertise on this project.
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