These authors have contributed equally to this work
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Dystonia is a disorder characterized by sustained or intermittent muscle contractions causing abnormal repetitive movements and postures [
Idiopathic BSP has a reported prevalence between 20 and 133 cases per million [
Our understanding of BSP is based mostly on case reports and case series from expert centers. Some of these focused on idiopathic cases, while others included cases with known causes. Some focused strictly on motor features, while others focused on non-motor features. Methods of ascertainment and assessment varied considerably. The purpose of the current study was to provide a comprehensive description of the clinical features of isolated BSP. First, we provide a summary of 10,324 cases reported in 41 separate manuscripts from the literature. Next, we describe the clinical features of BSP from the Dystonia Coalition (DC), an international multicenter project involving all types of dystonia, 884 of whom had BSP. Finally, we provide details on clinical features associated with spread of dystonia beyond the upper face. By providing a detailed description for a large number of subjects with BSP, we aim to improve clinical recognition and facilitate more timely diagnosis and treatment.
The Embase (Elsevier), PubMed (National Library of Medicine), and Web of Science: Core Collection (Clarivate Analytics) databases were searched with various combinations of keywords (blepharospasm, eyelid spasm, orbicularis oculi muscle spasm, eyelid contraction, eyelid twitch, cohort studies, longitudinal studies, follow-up studies, prospective studies, retrospective studies) and controlled vocabulary (i.e., MeSH, EMTREE) terms for BSP and cohort studies. The search included cases described as
PRISMA flow diagram for literature review.
Data from the DC were collected and analyzed for subjects enrolled across 45 international sites from 2011–2020 [
The DC database includes several sub-studies [
The study was approved by the IRBs of all participating clinical sites. All participants gave written consent for participation following the principles of the Declaration of Helsinki. The Emory University IRB and the National Institute of Health IRB also approved all procedures involving human participants.
Because of the different methods and different types of data collected, analyses were completed separately for the literature review and DC cohorts. Results are given as average values ± standard deviations. Descriptive analyses for demographic and clinical characteristics were completed with two sample t-tests for continuous variables and chi-square tests for categorical variables, with
For the DC cohort, we also compared BSP cases with onset of dystonia in the upper face to BSP cases with onset elsewhere. The DC cohort was also used to determine factors associated with spread of BSP beyond the face. Multivariate logistic regression was performed to estimate associations between spread of dystonia from the upper face and specific characteristics. Presence of dystonia elsewhere was determined by GDRS>0 in another body region. Demographic and clinical features of interest in the regression analysis were age at onset, dystonia duration, gender, family history, GDRS and BFM scores for upper face, BDI total score, and LSAS total score. A small amount of missing data was identified, but did not vary by exposure or outcome, and was treated as missing at random. All data analysis was performed with SAS version 9.4.
Among 41 papers considered, 38 reported more females than males, with an overall weighted average of 71% female (
Sex and Age at Onset.
Several studies also addressed potential risk factors for developing BSP including prior eye disease, eye surgery, trauma, stressful event, psychotropic and antiemetic use and white-collar occupation [
Six reports described presenting symptoms of BSP [
Among cases with established diagnoses of BSP, non-motor features were common. A large-scale epidemiological study [
BSP is considered a chronic disorder and patients often report symptoms worsen over time. BSP also spreads to other parts of the body more frequently than dystonia that starts in other body regions [
Among all 884 cases with BSP, the average age was 64 ± 11, the average age at onset was 49 ± 14, and 67% were female. Only 36% of the 884 cases had isolated focal BSP at onset (defined as dystonia limited to the orbicularis oculi and nearby muscles of upper face), and dystonia remained limited to the face in only 18%. The remainder of BSP cases had dystonia onset in other body regions.
Clinical characteristics of blepharospasm in the Dystonia Coalition cohort.
Upper face onset N = 320 | Other site onset N = 564 |
|
|
---|---|---|---|
Age (years) | 64 ± 10 | 63 ± 12 | 0.75 |
Age of Onset (years) | 51 ± 13 | 48 ± 15 | <0.01 |
Duration (years) | 12 ± 14 | 15 ± 15 | <0.01 |
Percent Female | 65% (n = 209) | 68% (n = 382) | 0.46 |
Areas Affected | |||
Lower Face, Jaw, Tongue | 58% (n = 186) | 54% (n = 307) | 0.29 |
Larynx | 13% (n = 43) | 21% (n = 121) | <0.01 |
Neck | 47% (n = 150) | 68% (n = 383) | <0.01 |
Limbs | 16% (n = 36) | 17% (n = 29) | 0.79 |
Trunk | 3% (n = 9) | 8% (n = 42) | <0.01 |
Sensory Trick | 56% (n = 180) | 54% (n = 305) | 0.53 |
BFM Severity | |||
Upper Face | 5 ± 2 | 3 ± 2 | <0.01 |
Total | 10 ± 7 | 11 ± 11 | <0.01 |
GDRS Severity | |||
Upper Face | 5 ± 2 | 3 ± 3 | <0.01 |
Total | 10 ± 7 | 13 ± 12 | <0.01 |
BDI-II Total Score | 9 ± 8 | 9 ± 8 | 0.44 |
LSAS Total Score | 29 ± 28 | 33 ± 29 | 0.20 |
This table includes data for the entire cohort of 884 subjects with blepharospasm in the Dystonia Coalition cohort, divided according to those who had onset in the upper face, or those who had onset elsewhere with spread to the upper face. Abbreviations: BDI-II, Beck depression inventory version 2; BFM, Burke-Fahn-Marsden dystonia rating scale; GDRS, global dystonia rating scale; LSAS, Liebowitz social anxiety scale.
The precise motor features of BSP were evaluated in more detail in a subset of 131 cases participating in a sub-project aimed at assessing these features. Clinician-rated assessments revealed subjects most commonly had mixed features of excessive blinking, periocular spasm, and apraxia of eyelid opening. Of the 131 cases, excessive blinking was reported for 98%, periocular spasm for 93%, and apraxia of eyelid opening for 29% (
Motor and non-motor features of blepharospasm. These plots illustrate
Approximately half of the entire cohort of 884 cases reported a sensory trick lessened the severity of their dystonia. Among the 386 subjects in a sub-study that completed scales assessing psychiatric features, social anxiety was present in 40%, as indicated by LSAS scores greater than 30 points. Depression was present in 24%, as indicated by BDI-II scores greater than 13 points. For the subset of 151 subjects in the BSP scales subproject, patients filled out a questionnaire relating to sensory symptoms (
Detailed information regarding the spread of dystonia beyond the upper face was available for a subgroup of 224 subjects who participated in a sub-study evaluating natural history (
Comparison of blepharospasm cases with and without subsequent spread.
Focal blepharospasm N = 87 | Blepharospasm with subsequent spread N = 137 |
|
|
---|---|---|---|
Age | 63 ± 10 | 63 ± 10 | 0.91 |
Age of Onset (years) | 51 ± 13 | 52 ± 13 | 0.74 |
Duration (years) | 12 ± 13 | 11 ± 14 | 0.63 |
Sex | |||
Female | 70% (n = 61) | 68% (n = 93) | 0.17 |
Race | 0.17 | ||
Asian | 7% (n = 6) | 2% (n = 3) | |
Black | 6% (n = 5) | 4% (n = 6) | |
Other | 8% (n = 7) | 4% (n = 6) | |
White | 79% (n = 69) | 89% (n = 122) | |
Family History of Dystonia | 2% (n = 2) | 14% (n = 19) | <0.01 |
Areas Affected | |||
Lower Face, Jaw, Tongue | 84% (n = 115) | ||
Larynx | 16% (n = 22) | ||
Neck | 63% (n = 86) | ||
Limbs | 26% (n = 36) | ||
Trunk | 3% (n = 4) | ||
Sensory Trick | 42% (n = 37) | 64% (n = 88) | <0.01 |
BFM Severity | |||
Upper Face | 4.2 ± 2.5 | 6.1 ± 1.6 | <0.01 |
Total | 4.2 ± 2.5 | 12.3 ± 8.0 | <0.01 |
GDRS Severity | |||
Upper Face | 4.4 ± 2.1 | 6.4 ± 1.9 | <0.01 |
Total | 4.4 ± 2.1 | 12.6 ± 6.4 | <0.01 |
BoNT Treatment | 82% (n = 72) | 79% (n = 108) | 0.46 |
BDI-II Total Score | 5.6 ± 7.2 | 9.0 ± 8.4 | <0.01 |
LSAS Total Score | 22.4 ± 26.6 | 32.0 ± 29.3 | 0.03 |
This table includes data for a subset of 224 cases in the Dystonia Coalition database who participated in a sub-study in which information regarding site of origin of dystonia was available. Abbreviations: BDI-II, Beck depression inventory version 2; BFM, Burke-Fahn-Marsden dystonia rating scale; BoNT, Botulinum neurotoxin; GDRS, global dystonia rating scale; LSAS, Liebowitz social anxiety scale.
The incorrect and frequently delayed diagnoses reported in the literature highlight the need for better awareness of the many varied clinical features of BSP. To this end, this study provides a comprehensive summary of the clinical features of BSP. Despite different strategies for inclusion and evaluation, results from the literature review are quite similar to those of the DC cohort. Like other focal dystonias [
The strengths of this study include the use of two independent cohorts, both of which were very large. The literature review included 10,324 cases taken from 41 reports from many parts of the world. The DC cohort is the largest single cohort to be reported, with 884 cases recruited in a multi-center design with 45 centers internationally. The main weakness of this study is inability to directly compare the two cohorts, because of the different methods and designs employed. Another weakness of this study is over-representation of white individuals in the DC cohort, although the results appear to be similar to cohorts of predominantly non-white individuals, such as those from Asia. Another weakness is the lack of information regarding treatment strategies or treatment outcomes, which were not collected for the DC cohort and often not presented for previously published cohorts. The final weakness is the lack of any associated biological measure such as genetics, imaging, or physiology. Unfortunately, the available genes account for <1% of most BSP cases, routine clinical imaging studies rarely reveal any consistent abnormalities, and most centers do not routinely conduct physiological studies. This omission points to the need for additional studies of relevant biomarkers.
Although the clinical features of BSP are quite characteristic, there are several reasons that might account for incorrect or delayed diagnoses. One reason may be that many individuals present first with non-motor symptoms such as irritation of the eyes and/or psychiatric concerns. Eye discomfort with excessive blinking may wrongly suggest allergies or dry eyes, which are very common in this age group. Anxiety and depression may lead to an initial psychiatric diagnosis. The reduction in BSP symptoms when talking while giving the history may wrongly suggest inconsistency or susceptibility to distraction, typical of functional (psychogenic) dystonia. Another reason may be that BSP is relatively uncommon, leading to misdiagnoses of more common disorders. However, common initial misdiagnoses also include myasthenia gravis, which is less common than BSP [
Regarding the progression of BSP, the results from the DC cohort are consistent with other studies that have revealed a high risk for BSP to spread beyond the upper face [
The importance of early recognition is underscored by the availability of effective treatments. Numerous reviews have been published [
The data analyzed in this study is subject to the following licenses/restrictions: Data are being shared upon approval of Dystonia Coalition Executive Committee. Requests to access these datasets should be directed to Dr. Gamze Kilic-Berkmen at
The study was approved by the IRBs of all participating clinical sites. All participants gave written consent for participation following the principles of the Declaration of Helsinki. The Emory University IRB and the National Institute of Health IRB approved all procedures involving human participants.
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
This work was supported by grants to The Dystonia Coalition (NS065701, TR001456, NS116025) which is part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported by the Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the National Institute of Neurological Diseases and Stroke (NINDS). The Sartain Lanier Family Foundation as well as the Jean and Paul Amos Parkinson’s Disease and Movement Disorders Program Endowment also provided support for this study.
RB serves as an associate editor for Neurology: Clinical Practice; performs botulinum toxin injections at the University of Rochester (30% effort); serves/has served on scientific advisory boards for Allergan, Ipsen, Merz and Revance; receives research support from Vaccinex, Fox Foundation, and Revance; NIH (NINDS, ORDR): Dystonia Coalition Projects, Site PI; Consultant for Oscine Corporation and Abvie/Allergan; receives fees as section editor and holds stock options in VisualDx; and has served as an expert witness in legal proceedings including malpractice, not involving commercial entities. SB is currently an investigator for clinical trials sponsored by Takeda Pharmaceutical Company and Bukwang Pharmaceutical Co. Ltd. BB has received research grant support from the Dystonia Coalition (receives the majority of its support through NIH grant NS065701 from the Office of Rare Diseases Research in the National Center for Advancing Translational Science and National Institute of Neurological Disorders and Stroke), the Parkinson’s Foundation, and the VCU School of Medicine. He has received honoraria from the MedLink Corporation and the International Parkinson and Movement Disorder Society and serves on the medical advisory board of the Benign Essential Blepharospasm Research Foundation and the National Spasmodic Torticollis Association. SF Honoraria: Lundbeck, Sunovion, Biogen, Impel, Acorda, CereSpir. Grants: Medtronics, Boston Scientific, Sun Pharmaceuticals Advanced Research Company, Biohaven, Impax, Lilly, US World Meds, Sunovion Therapeutics, Neurocrine, Vaccinex, Voyager, Jazz Pharmaceuticals, CHDI Foundation, Michael J. Fox Foundation, NIH (U10 NS077366), Parkinson Foundation Royalties: Demos, Blackwell Futura, Springer for textbooks, Uptodate. Other: Signant Health (Bracket Global LLC), CNS Ratings LLC. VF receives a salary from NSW Health, has received unrestricted research grants from the Michael J Fox Foundation, Abbvie and Merz, is on Advisory Boards and/or has received travel grants from Abbvie, Allergan, Ipsen, Merz, Praxis, Seqirus, Stada, Teva and UCB, and receives royalties from Health Press Ltd. MH is an inventor of patents held by NIH for an immunotoxin for the treatment of focal movement disorders and the H-coil for magnetic stimulation; in relation to the latter, he has received license fee payments from the NIH (from Brainsway). He is on the Medical Advisory Boards of CALA Health and Brainsway (both unpaid positions). He is on the Editorial Board of approximately 15 journals and receives royalties and/or honoraria from publishing from Cambridge University Press, Oxford University Press, Springer, Wiley, Wolters Kluwer, and Elsevier. He has research grants from Medtronic, Inc. for a study of DBS for dystonia and CALA Health for studies of a device to suppress tremor. JJ has received research or training grants from AbbVie Inc.; Acadia Pharmaceuticals; Cerevel Therapeutics; CHDI Foundation; Dystonia Coalition; Emalex Biosciences, Inc.; F. Hoffmann-La Roche Ltd.; Huntington Study Group; Medtronic Neuromodulation; Merz Pharmaceuticals; Michael J Fox Foundation for Parkinson Research; National Institutes of Health; Neuraly, Inc.; Neurocrine Biosciences; Parkinson's Foundation; Parkinson Study Group; Prilenia Therapeutics; Revance Therapeutics, Inc.; Teva Pharmaceutical Industries Ltd. JJ has served as a consultant for Aeon BioPharma; Allergan, Inc.; Merck & Co., Inc.; Revance Therapeutics; Teva Pharmaceutical Industries Ltd. JJ has received royalties from Cambridge; Elsevier; Medlink: Neurology; Lippincott Williams and Wilkins; UpToDate; Wiley-Blackwell. Editorial boards: Expert Review of Neurotherapeutics; Medlink; Neurology in Clinical Practice; The Botulinum Journal; PeerJ; Therapeutic Advances in Neurological Disorders; Neurotherapeutics; Toxins; Tremor and Other Hyperkinetic Movements; Journal of Parkinson’s Disease. HJ has active or recent grant support from the US government (National Institutes of Health), private philanthropic organizations (Cure Dystonia Now), and industry (Revance Therapeutics, Inc.). HJ has also served on advisory boards or as a consultant for Addex, Allergan, CoA Therapeutics, Cavion Therapeutics, EnePharmaceuticals, Ipsen, Retrophin, Revance, and Takaha Pharmaceuticals. He has received honoraria or stipends for lectures or administrative work from the International Parkinson’s Disease and Movement Disorders Society. DHJ serves on the Scientific Advisory Boards for several private foundations including the Benign Essential Blepharospasm Research Foundation, Cure Dystonia Now, the Dystonia Medical Research Foundation, the Tourette Association of America, and Tyler’s Hope for a Cure. He also is principle investigator for the Dystonia Coalition, which has received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). The Dystonia Coalition has received additional material or administrative support from industry sponsors (Allergan Inc. and Merz Pharmaceuticals) as well as private foundations (The Benign Essential Blepharospasm Foundation, Cure Dystonia Now, The Dystonia Medical Research Foundation, and The National Spasmodic Dysphonia Association). CK has active or recent grant support from the DFG, BMBF, and the MJFF. She serves as a medical advisor on genetic testing reports to Centogene and on the Scientific Advisory Board of Retromer Therapeutics, and the Else Kroener Fresenius Foundation. IM has participated in research funded by the Parkinson Foundation, Tourette Association, Dystonia Coalition, AbbVie, Boston Scientific, Eli Lilly, Neuroderm, Prilenia, Revance, Teva but has no owner interest in any pharmaceutical company. She has received travel compensation or honoraria from the Tourette Association of America, Parkinson Foundation, International Association of Parkinsonism and Related Disorders, Medscape, and Cleveland Clinic, and royalties for writing a book with Robert Rose publishers. JM performs compensated consulting services for Biocircuit Technologies. He receives research funding from NIH and the McCamish Foundation. JP has provided medical legal consultation to Wood, Cooper and Peterson, LLC and to Simmons and Simmons LLP. JP serves as Director of Medical and Scientific Advisory Committee of the Dystonia Medical Research Foundation, Chair of the Scientific Advisory Committee of the Parkinson Study Group, Chair of the Standards Committee of the Huntington Study Group, member of the Scientific Advisory Board of the APDA, Chair of the Scientific and Publication Committee for ENROLL-HD (honoraria from this one), and member of the Education Committee of the Huntington Study Group (honoraria from this one). He has received honoraria from CHDI, Huntington Disease Study Group, Parkinson Study Group, Beth Israel Hospital (Harvard group), U Pennsylvania, Stanford U.; U Illinois in Chicago (box of biscotti was my honorarium); Boston University. JP has received research funding from National Institutes of Health NS075321, NS103957, NS107281, NS092865, U10NS077384, NS097437, U54NS116025, U19 NS110456, AG050263, AG-64937, NS097799, NS075527, ES029524, NS109487, R61 AT010753, (NCATS, NINDS, NIA), RO1NS118146, R01AG065214, Department of Defense (DOD W81XWH-217-1-0393), 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, Cure Huntington’s Disease Initiative, and G. Williams Fund. He is also co-director for the Dystonia Coalition, which has received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). ER served on scientific advisory boards for Orkyn, Aguettant, Merz-Pharma, Allergan; received honoraria for speeches from Orkyn, Aguettant, Merz-Pharma, Everpharma, Elivie, International Parkinson and Movement disorders Society; received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Allergan, Everpharma, Fondation Desmarest, AMADYS, Fonds de Dotation Brou de Lauriè re, ADCY5. org, Agence Nationale de la Recherche, Societé Française de M#233; decine Esthé tique; received travel grant from Vitalaire, PEPS development, Aguettant, Merz-Pharma, Ipsen, Merck, Orkyn, Elivie, Adelia Medical, Dystonia Medical Research Foundation, International Parkinson and Movement disorders Society, European Academy of Neurology, International Association of Parkinsonism and Related Disorders. LS has received grant support from the Dystonia Medical Research Foundation. She also serves as an investigator in clinical trials for Addex, Neurocrine, and Boston Scientific. TW is a consultant for Linden & Associates, Sherrard, Roe, Voigt, and Harbison. AW-S reports grants from the NIH and has received grant support from Benign Essential Blepharospasm Research foundation, Dystonia coalition, Dystonia Medical Research foundation, National Organization for Rare Disorders and grant support from NIH (KL2 and K23 NS092957-01A1) as a PI. She receives support from NIH RO1 R01NS121120-01 as a Co-I. AW-S has received consultant fees from Merz and Acadia. She is the current Vice President for the Tremor Research Group. ML owns, and is president of, Veracity Neuroscience LLC.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Additional DC investigators contributing to the recruitment of subjects for these analyses included Marian Evatt, Michael Johns, Rachel Saunders-Pullman, Alberto Espay, Alex Pantelyat, Sarah Pirio Richardson, William Ondo, Susan Fox, Natividad Stover, Stephen Reich, Claudia Testa, Daniel Truong, Oksana Suchowersky, Samuel Frank, Pinky Agarwal, Julie Leegwater-Kim, Tanya Harlow, Allison Brashear, Stephen Grill, Fatta Nahab, Christopher Groth, Sylvain Chouinard, Andres Deik, Charles Adler, Kailash Bhatia, Tao Xei.