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Show Benign Essential Blepharospasm: Risk Factors with Reference to Hemifacial Spasm Tyler A. Hall, MD, Gerald McGwin, Jr., MS, PhD, Karen Searcey, MSPH, Aiyuan Xie, MS, Saunders L. Hupp, MD, Cynthia Owsley, MSPH, PhD, and Lanning B. Kline, MD Background: To identify risk factors associated with toms, head trauma, Parkinson disease, Bell palsy, Tourette benign essential blepharospasm ( BEB) with reference to disorder, or lack of smoking. hemifacial spasm ( HFS). Persons with BEB and HFS ex- ,, „ r „ , , , , „„„_ „ „ 0„ „ 0~ . . . , . \ ^ _, ^ ,. , ( J Neuro- Ophthalmol 2005; 25: 280- 285) penence similar physical symptoms, yet the two disorders have different etiologies. Methods: Patients with BEB ( n = 159) or HFS ( n = 91) were identified from two large neuro- ophthalmo logy clinics. _ , , • ,- i . 1 . v 1 . • JI _ ,. , - , , , • , , i i - i i D lepharospasm is a bilateral condition characterized by Demographic, medical, behavioral, and psychological char- rS - - , . , ,-., ,-, „ . - °- ,. . , r 1 . • 1 f 1 1 • U excessive involuntary closure of the eyelids generally actenstics were obtained from chart review and a telephonic ,, . it , . , . ,. , ,, ., caused by spasm of the orbicularis ocuh muscles ( 1- 4). ' Benign essential blepharospasm ( BEB), the most common Results: The average age of BEB and HFS was 66 years. form, is of unknown etiology and is considered a form of Most patients in both groups were retired, white, and focal dystonia. Initially, the spasms are mild and infrequent female. BEB patients were more than two times as likely to but symptoms typically progress and are highly disruptive meet the diagnostic criteria for generalized anxiety disorder to the patient's visual activities and quality of life ( 5- 7). than HFS patients ( odds ratio, 2.13; 95% confidence inter- Studies on the crude prevalence of BEB suggest that it val, 1.22- 3.72). There was no difference between the two ranges from 12 to 133 cases per million ( 8- 11). However, groups regarding demographics, smoking, a family history valid prevalence estimates are elusive because of under-of dystonia, Parkinson disease, Bell palsy, Tourette dis- diagnosis, misdiagnosis, and the absence of population-order, obsessive compulsive symptoms, history of head based data. It does seem, however, that BEB is more common trauma, alcohol use, or caffeine consumption. than myasthenia gravis, amyotrophic lateral sclerosis, and Conclusions: As compared to HFS, BEB was significantly . , _ . - • , i- , 1 , ^ . j - n^ n , ., ... • i- i A variety of risk factors have been reported for BEB, more often associated with generalized anxiety „. it . ., .. r .1 1- • 1 r- ^ i. id isord^ e r. • in, cl, u• d ing . f- a m• i, l y , h • is , t ory of.- d. ys. t on• ia , 1h ead. an* d rf ace trauma, Given the similarity of other clinical features of these two . ,, , ,, , ,- , ,. , . J_. 1,, , , ,, , • ^ • previous eye problems, such as blepharitis or keratocon-disorders, it is reasonable to conclude that anxiety is a cause • , • • , , , , • , , ,• , , n J- T^ T^ ^ . . • ^ i- lunctivitis, other neurological movement disorders ( Par-n_ o_ t_ a conseq\ u ence . of. B, E. B.. , C, ontrary• to previo, u• s studies, , k r. n son d,. i sease and, „ T ouret° te d.. i sord. e r), , and, itth e f„ i„ ft, h xt o s. i xitt h BEB was not associated with obsessive- compulsive symp- , , . / « 1 « 1 ~ 1 ^ c , • ^ J ., decade of age ( 9,10,12- 16). Smoking was reported to be associated with a reduced risk of blepharospasm in one Department of Ophthalmology ( TH, GM, KS, AX, co, LK), School study ( 13). Obsessive- compulsive symptoms have been of Medicine, University of Alabama at Birmingham, Birmingham, associated with an increased risk in another Study ( 17). Alabama; Department of Epidemiology and International Health ( GM), Three previously published Case- COntrol Studies ( 13- 15) School of Public Health, University of Alabama at Birmingham, found ^ h a y i n g fi^^ gree rel a tives with some form Birmingham, Alabama; Section of Trauma, Burns, and Surgical Critical r . . ,. . . r T-, TnT-, . ,,, , ,, „ „ • • f„ , „ n ^ ™ + f c ^ iv/ r. o I, i of dystonia increased the risk for BEB. Although these Care, Division ot General Surgery, Department ot Surgery ( GM), School J ° of Medicine, University of Alabama at Birmingham, Birmingham, previous studies provide intriguing candidate ideas about Alabama; and Vision Partners LLC ( SH), Mobile, Alabama. potential Causes, their methodological shortcomings limit Address correspondence to Lanning B. Kline, MD, Department of the ability to generate reasonable directions for etiologic Ophthalmology, School of Medicine, University of Alabama at Birming- hypotheses. For example, most Studies included patients ham, 700 South 18th Street, Suite 601, Birmingham, AL 35294- 0009; - f, , , • r- 1 • 1 T ^ ™ • n , . x, , „ , . n , , with dystonia, of which BEB comprises a small subset, b- mail: lklme( g) uabmc. edu J ' r ' This research was funded by NIH R21 EY14071, Research to Prevent making it difficult to know whether results are applicable to Blindness, inc., and the Eyesight Foundation of Alabama. BEB per se or to other forms of dystonia. Relative risks are sometimes described as crude rather than adjusted esti- behavioral, medical, and psychological characteristics mates, thereby raising the question about the potential role from participants. Socio- demographic characteristics were of confounders in reported associations. Two studies have collected with standard items addressing age, sex, race, been published only as abstracts, making it difficult to education, marital status, total annual family income, and evaluate results ( 18,19). employment status. Behavioral risk factors were assessed The case- control study is the most efficient design through questions concerning cigarette smoking, alcohol when the disease of interest is rare, as is the case with BEB. use, and caffeine intake. Health history information was In the approach taken here, study cases are denned as obtained from questions regarding whether the respondent persons with BEB ( but not other types of dystonia). The had ever had various chronic and acute conditions and sur- " control group" is comprised of persons who have been geries, head trauma, or certain neurological conditions ( Bell diagnosed with hemifacial spasm ( HFS). The logic under- palsy, Parkinson disease, or Tourette disorder) or a family lying selection of this control group is that HFS is charac- history of these conditions. General health was assessed by terized by clonic- tonic contractions of the orbicularis oculi the number of chronic medical conditions reported on a stan-muscle with eventual involvement of other muscles on one dard questionnaire ( 25). The number of surgeries in the previ-half of the face, and it shares with BEB patients many ous three years was also reported. symptoms and social consequences because of the invol- The telephone version of the Short Portable Mental untary lid closure. However, HFS usually has a known Status Questionnaire was used to assess cognitive status cause ( peripheral facial nerve irritation caused by vascular ( 26,27). Obsessive- compulsive symptoms were assessed compression), whereas BEB remains idiopathic. Unlike using the University of Hamburg Obsession- Compulsion BEB ( 2,20- 23), HFS has not been associated with basal Inventory ( 28). The presence of a generalized anxiety dis-ganglia dysfunction ( 24). Only once before has BEB been order was evaluated by asking about the presence of compared with HFS in a small sample study of 26 cases ( 17). six symptoms during the past six months, as described in the Diagnostic and Statistical Manual of Mental Health, fourth edition ( DSM- 4) ( 29). The presence of at least four mrTTmnc symptoms was necessary to meet criteria for a generalized IVlrL 1 HLHJJ> ,. , anxiety disorder. Case Selection A research interviewer ( KS) experienced in the admin- Cases were identified from the clinics of the Depart- istration of telephone questionnaires administered the sur-ment of Ophthalmology, University of Alabama at Binning- vey The interviewer was not masked as to the diagnosis of ham, Birmingham, AL and Vision Partners LLC located in the participant. If the participant was unavailable during the Mobile, AL. These two clinics constitute the most popular initial phone call, up to four subsequent phone calls were tertiary referral centers in the state of Alabama for persons attempted on different days and at different times during the suspected of having BEB or HFS. Cases were initially day to maximize the chance of contact, identified from electronic records obtained from clinic visits between December 6, 1999 and December 11, 2002 Statistical Analysis on the basis of the International Classification of Diseases, Comparison between the demographic and medical Ninth Revision, Clinical Modifications ( ICD- 9- CM) codes characteristics of the two patient groups was performed 333.81, 333.82, and 333.83 ( blepharospasm, orofacial dys- using t t e s t s a n d x2 t e s t s for continuous and categorical kinesia, and spasmodic torticollis, respectively). Charts con- variables, respectively. The Kruskal- Wallis test was used to taining these codes were then abstracted to confirm the compare the two groups with respect to continuous diagnosis of BEB or HFS and to collect selected demo- variables that did not meet the assumptions for the t test, graphic characteristics. In addition to having either of these For s e i e c t e d risk factorS; o d d s r a t i o s ( 0RS) with 95% diagnoses, subjects had to be at least 19 years of age. The confidence intervals ( CIs) were calculated. P- values of study design and procedures were approved by the Insti- < 0 0 5 ( two- sided) were considered statistically significant, tutional Review Board of the University of Alabama at Birmingham. Survey Questionnaire RESULTS Persons deemed eligible after chart review were con- Of the 347 subjects initially identified by ICD- 9- CM tacted by letter describing the study and later by telephone codes to be eligible, 250 completed the telephone by the research interviewer ( KS). Willing participants gave questionnaire. Ninety- seven subjects did not complete the verbal consent and were asked a series of questions by tele- questionnaire for the following reasons: 36 could not be phone to collect information regarding socio- demographic, contacted by telephone, 27 refused to participate, 13 were J Neuro- Ophthalmol, Vol. 25, No. 4, 2005 Hall et al TABLE 1. Demographic, health behavior, medical, and psychological characteristics and hemifacial spasm ( HFS) cases Demographic characteristics Age ( in years), mean ( SD) Sex, n (%) Men Women Race, n (%) White African American Education, n (%) Less than high school High school Some college College or higher Marital status, n (%) Married Non- married Income, n (%) Less than $ 20,000 $ 20,000-$ 39,000 $ 40,000-$ 49,000 More than $ 50,000 Current employment status, n (%) Currently employed Retired Disabled Unemployed Health behavior characteristics Smoker, now or in past (%) Smoker, now (%) Pack/ years cigarette smoking, mean Pack/ years cigarette smoking, mean Alcohol consumer (%) Ounces of alcohol/ week, mean ( SD) Ounces of alcohol/ week, median ( SD) ( SD), median Caffeine consumption ( in mg), mean ( SD) Caffeine consumption ( in mg), median Medical characteristics Number of medical conditions, mean ( SD) Surgical procedure in previous 3 years, n (%) Head trauma, (%) Family history of neurological conditions Blepharospasm or focal dystonia, Bell palsy, n (%) Parkinson disease, n (%) Tourette disorder, n (%) n (%) BEB ( n= 159) 65.5 ( 11.6) 44 ( 27.7) 115 ( 72.3) 147 ( 93.0) 11 ( 7.0) 23 ( 14.5) 55 ( 34.6) 36 ( 22.6) 45 ( 28.3) 103 ( 64.8) 56 ( 35.2) 46 ( 30.1) 47 ( 30.6) 14 ( 9.2) 46 ( 30.1) 55 ( 34.8) 83 ( 52.5) 19 ( 12.0) 1 ( 0.6) 58 ( 36.5) 18 ( 11.3) 8.16 ( 22.0) 0 90 ( 65.2) 6.47 ( 24.8) 0 167.80 ( 173.57) 133.0 4.16 ( 2.39) 73 ( 45.9) 53 ( 33.3) 9 ( 5.66) 11 ( 6.92) 9 ( 5.66) 1 (. 01) among benign essential blepharospasm ( BEB) HFS ( n = 91) 66.3 ( 12.6) 34 ( 37.4) 57 ( 62.6) 79 ( 86.8) 12 ( 13.2) 11 ( 12.1) 30 ( 33.0) 19 ( 20.8) 31 ( 34.1) 57 ( 62.6) 34 ( 37.4) 21 ( 23.9) 28 ( 31.8) 12 ( 13.6) 27 ( 30.7) 34 ( 37.4) 52 ( 57.1) 5 ( 5.5) 0 ( 0.00) 41 ( 45.0) 5 ( 5.5) 7.90 ( 16.5) 0 56 ( 70.0) 5.33 ( 18.5) 0 193.39 ( 230.24) 127.5 3.71 ( 2.09) 41 ( 45.1) 30 ( 33.3) 5 ( 5.49) 10 ( 10.99) 4 ( 4.40) 0( 0) P- value 0.63 0.11 0.10 0.80 0.73 0.61 0.32 0.18 0.13 0.92 0.37 0.55 0.68 0.16 0.36 0.37 0.14 0.90 0.99 0.96 0.26 0.77 0.99 Continued 282 © 2005 Lippincott Williams & Wilkins deceased, 4 had impaired mental status, 5 were too ill to anxiety disorder than did patients with HFS. Previous participate, 4 had been surgically cured of HFS, 3 had studies have not found such an association when BEB pa-hearing impairment, 2 requested to be contacted later but tients were compared to normal controls ( 30), to a small were not reachable, 1 ended the interview without finishing sample of HFS patients ( 17), or to population- based because of difficulty with Parkinson disease, 1 declared that reference values ( 31,32,34). Whether generalized anxiety the interview had lasted too long and decided to quit, and 1 disorder caused, resulted from, or may be concomitant with had too poor a command of English to be understood. BEB cannot be determined from this study. However, given Ultimately, 159 BEB cases and 91 HFS controls were the similarity in the physical symptoms and impairments enrolled in the study. Those who refused the invitation to experienced by BEB and HFS patients, a similar frequency enroll were not different from the enrollees with respect to of patients in both groups would be expected to have an age, sex, and race, and the proportion of refusers who had anxiety disorder if it were a consequence. Thus, consid- BEB versus HFS was similar to that of the enrollees. eration should be given to the possibility that generalized The average age of both groups was 66 years ( Table anxiety disorder has a role in BEB origin. Our results do not 1). Women comprised most of BEB ( 72.3%) and HFS confirm earlier reports of an association between BEB and ( 62.6%) subjects. Whites comprised 93.0% and 86.8% of obsessive- compulsive disorder or symptoms ( 17,35). Pre-the BEB and HFS groups, respectively. The two groups vious studies reporting an association had small sample were similar with respect to the distribution of educational sizes ( less than 25 BEB patients each). The larger sample level, marital status, and income level. Regardless of group, studied here suggests that an association between obsessive slightly more than 50% of the patients were retired, approx- compulsiveness and BEB is unlikely, imately 33% were employed, and the remainder was disabled We suggest the following framework as a hypothesis or unemployed. There was no difference between groups explaining how generalized anxiety disorder could be with respect to current smoking status or having ever been a involved in the etiology of BEB. Anxiety and stressful smoker or in alcohol or caffeine consumption. situations are known to trigger an acute increase in Cortisol BEB cases were more than two times more likely to levels that subsequently become downregulated during meet the diagnostic criteria for generalized anxiety disorder chronic anxiety states ( 36), resulting in hypocortisolism than HFS controls ( OR, 2.13; 95% CI, 1.22- 3.72). ( 36,37). Recently, Pruessner et al. ( 38) extended the results The two groups did not differ with respect to the of previous animal studies reporting a link between stress-number of chronic medical conditions, history of head trauma, related Cortisol levels and striatal dopamine levels by dem-family history of neurological conditions ( other focal dys- onstrating that a stress- induced increase in Cortisol produced tonias, Bell palsy, Parkinson disease, or Tourette disorder), or a corresponding increase in the release of striatal dopamine disease duration. The two groups were similar with regard to in human subjects. According to this line of reasoning, the mental status score and obsessive- compulsive symptoms. hypocortisol state induced by generalized anxiety disorder might also induce a proportionally decreased level of striatal dopamine. These factors are linked to BEB by a DISCUSSION recent study ( 39) that demonstrated that a decrease in The most important result of our study is that patients striatal dopamine would measurably increase the trigeminal with BEB had a significantly higher frequency of generalized blink reflex ( TBR), an important component of BEB p a t h o p h y s i o l o g y , in a n animal model. This r e l a t i o n s h i p 14. Stojanovic M, Cvetkovic D, Kostic VS. A genetic study of idiopathic is also thought to occur in humans ( 40). Moreover, 15 ^ 1 dystonia. Jwe » rOzi995; 242: 508- ii. 15. Defazio CJ, Livrea P, Guanti CJ, et al. Genetic contribution to T B R e x c i t a b i l i t y IS i n c r e a s e d b y Other factors c o m m o n in idiopathic adult- onset blepharospasm and cranial- cervical dystonias. BEB ( irritative eye conditions such as blepharitis and dry Eur Neurol 1993; 33: 345- 50. eye ( 39- 44)). Thus, in this hypothetical framework, the 16- Elston JS> Marsden CD> Grandas £ et al. 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