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Closely Spaced Stressful Life Events Precede the Onset of Benign Essential Blepharospasm and Hemifacial Spasm

Johnson, Lenworth N MD; Lapour, Ryan W MD; Johnson, Gabriella M BS; Johnson, Patricia J BS; Madsen, Richard W PhD; Hackley, Steven A PhD

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Journal of Neuro-Ophthalmology: December 2007 - Volume 27 - Issue 4 - p 275-280
doi: 10.1097/WNO.0b013e31815c4233
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Abstract

In 1947, Campbell and Keedy (1) published the first report of vascular compression of the facial nerve as a cause of hemifacial spasm (HFS). Microvascular decompression surgery for HFS was then reported by Gardner and Sava (2) and popularized by Jannetta (3). It is postulated that the facial nerve at the root entry zone becomes demyelinated due to mechanical stress from repeated pulsations of the vascular loop, most often by the anterior inferior cerebellar artery (4-7). Ephaptic transmission, or false crosstalk, subsequently occurs between axons of the facial nerve fibers (8-11). Because microvascular decompression abolishes the facial spasms in 80-90% of cases of HFS, one might conclude that vascular compression of the facial nerve is the root cause of HFS (6,7).

However, Aoki and Nagao (12) reported a case of HFS that improved immediately after posterior fossa exploration even though no vascular contact or other abnormality was identified at surgery. More importantly, neuroanatomical examination of 50 cerebellopontine angles has shown vascular loops compressing the facial and vestibulocochlear nerves in all cases, yet none of these patients had HFS (13). This would indicate that vascular compression alone is not sufficient to cause HFS. Other factors must be present before HFS occurs.

There are many similarities between HFS and benign essential blepharospasm (BEB), which is considered to be a disorder of the basal ganglia. Both BEB and HFS are debilitating disorders characterized by progressive involuntary spasms of the facial and neck muscles (14,15). These focal dystonias often begin as infrequent twitches or fasciculations of the orbicularis oculi muscles with subsequent spread to the lower face, jaw, and neck. Most cases have their onset in the sixth and seventh decades, being rarely observed at a younger age. Both disorders have a 60%-70% female preponderance and the two conditions may coexist in the same patient (14,16-19).

These similarities suggest that BEB and HFS represent entities with a common pathogenesis, although HFS is unilateral and BEB is bilateral. Consequently, in the following study we have grouped these two conditions.

The inciting cause of BEB and HFS is uncertain. We have encountered patients with BEB and HFS who had sustained major life stressors, involving the loss of a close relative or termination of a close relationship, shortly before the onset of the BEB or HFS. Major life stressors can lead to complicated grief or depression. Complicated grief, which has only recently been described, occurs in approximately 10%-20% of individuals who have experienced the loss of a loved one (20-24). We hypothesized that major life stressors and the development of complicated grief or depression might play a role in the pathogenesis of BEB and HFS. Accordingly, in the current case-control study we assessed the frequency of major life stressors and the prevalence of complicated grief and depression among subjects with BEB and HFS compared with control subjects.

METHODS

The study was approved by the institutional review board (IRB). Participants with BEB and HFS had been evaluated by one of the authors (L.N.J.) in the Neuro-Ophthalmology Clinic during the past 15 years. Control subjects consisted of individuals who had been evaluated by one of the authors (L.N.J.) during the past 2 months in the General Ophthalmology Clinic for refraction (eyeglasses) and were of approximately the same age as the participants with BEB/HFS. Potential participants were initially contacted by telephone. They were told the purpose of the study and that we would administer a questionnaire regarding their emotional state, in particular, how having lost people close to them or having ended close personal relationships affected them. They were also told that we wished to monitor changes in their mood and body temperature over a 14-week period (the latter components being the subject of another report). Written informed consent was obtained from study participants in accordance with the IRB.

Of the 106 potential participants (49 with BEB, 21 with HFS, and 36 control subjects) contacted by telephone, 46 subjects (16 with BEB, 7 with HFS, and 23 control subjects) were recruited to participate in the study. Almost all subjects who participated in the study lived within 25 miles of the medical center. Nearly all subjects who did not participate in the study lived more than 75 miles away from the medical center. Subjects who did not participate indicated that transportation to the medical center for the study was problematic. There were 31 (67%) women (12 with BEB, 6 with HFS, and 13 control subjects) and 15 (33%) men (4 with BEB, 1 with HFS, and 10 control subjects). Of the 46 participants, 3 (7%) were single, 28 (61%) were married, 2 (4%) were divorced, and 13 (28%) were widowed. There were 42 (91%) self-identified white participants, 1 black (2%), 1 (2%) Asian, and 2 (4%) combined white-Native Americans.

Study participants completed a questionnaire consisting of baseline demographic information including age, gender, marital status, health status, and mood. Participants then completed the Beck Depression Inventory-II (BDI-II) and the Inventory of Complicated Grief (25). Because the Inventory of Complicated Grief was originally developed to assess grief related to bereavement, we modified the Inventory of Complicated Grief to account for grief related to the loss of a close relationship as in “I feel myself longing for the person who died (or the relationship that ended)” (25).

Participants subsequently underwent a structured interview in which they were queried as to major stressful life events that they felt had caused significant personal distress, in particular, the death of a loved one or ending of a close relationship (26). The approximate month and year that these major life stressors occurred were recorded so that the time interval between two major stressful events could be computed. A BDI-II score of 10 or greater was defined as being associated with depression (10-18 mild depression; 19-29 moderate depression; 30-63 severe depression), whereas a score less than 10 indicated an absence of depression. An Inventory of Complicated Grief score greater than 25 was defined as being associated with complicated grief, whereas a score less than 25 indicated an absence of complicated grief (25). Participants found to have complicated grief or depression or for whom questions provoked disturbing thoughts or feelings were referred for psychological counseling if they were not already under the care of a mental health specialist.

Statistical analyses were performed using SAS (version 9.1; SAS Institute, Inc., Cary, NC). Proportions are given for qualitative or categorical variables such as gender, marital status, and depression. When the control group and the BEB/HFS group are compared relative to quantitative variables that are approximately normal, two-sample t-tests were used. For distributions that were skewed or strictly ordinal, Wilcoxon rank-sum tests were used. For qualitative or categorical variables, χ2 tests were used. When variables related to the number of stressful life events are considered, it is logical to assume that the number could depend on the age of the subject. Consequently, when groups are compared relative to stressful life events, Cochran-Mantel-Haenszel (CMH) methodologies were used to allow for stratification by age group. Similarly, the shortest time between two stressful life events will depend on the total number of stressful life events experienced by an individual (the interval will most likely be shorter if there are more stressful life events within a specified time period). Three participants had reported only one stressful life event before the onset of BEB. The values for these participants were considered censored as of the time of onset of BEB. Analysis for shortest time between major lifetime stressors was done using a Cox proportional hazards model with total number of stressful life events as a covariate. Because multiple tests were performed, an adjustment in the significance level was implemented using the false discovery rate (FDR) at a 0.05 level (27). Controlling the FDR is less conservative than using a Bonferroni adjustment for multiple tests. For the set of tests using the FDR, FDRs (denoted by Pf) are reported rather than the raw P values.

RESULTS

The mean elapsed time from diagnosis of the facial spasm for the 23 participants with BEB/HFS was 8.7 ± 5.7 years (median 7.2; range 1.8-23 years). All participants with BEB/HFS had been treated with botulinum toxin injections over the years. There was no significant difference in gender distribution for the 23 participants with BEB/HFS (18 women and 5 men) compared with the 23 control subjects (13 women and 10 men). The mean age of the participants with BEB/HFS was 69.4 ± 11 years (median 72; range 43-84 years), and the mean age of control subjects was 69.0 ± 9 years (median 71; range 53-84 years). As expected, there was no significant difference in the mean ages of participants with BEB/HFS and control subjects (Table 1).

T1-5
TABLE 1:
Features of the 23 participants with benign essential blepharospasm (BEB) and hemifacial spasm (HFS) and 23 control subjects

Thirteen (57%) of the 23 participants with BEB/HFS (8 with BEB and 5 with HFS) and 11 (48%) of the 23 control subjects scored in the depression range on the BDI-II. Of these 13 participants with BEB/HFS, 8 (62%) scored in the mild depression range (4 with BEB and 4 with HFS), 3 (23%) in the moderate depression range (2 with BEB and 1 with HFS), and 2 (15%) in the severe depression range (2 with BEB). Of the 11 control subjects, 9 (82%) scored in the mild depression range, 1 (9%) in the moderate depression range, and 1 (9%) in the severe depression range. Four (17%) of the 23 participants with BEB/HFS (2 with BEB and 2 with HFS) had complicated grief on the Inventory of Complicated Grief; all four also had scores indicative of depression on the BDI-II. Four (17%) of the 23 control subjects had complicated grief on the Inventory of Complicated Grief; 1 of the 4 control subjects with complicated grief did not have concomitant depression on the BDI-II. Seven (54%) of the 13 participants with BEB/HFS (3 with BEB and 4 with HFS) and 6 (55%) of the 11 control subjects with scores suggestive of depression on the BDI-II (which included one control individual with concurrent complicated grief) were unaware of their depression or complicated grief. The 7 participants with BEB/HFS and 6 control subjects had depressive symptoms with scores in the mild depression range on the BDI-II. These latter 13 individuals were offered a referral for appropriate therapy. There was no difference in the rate of depression (Pf = 0.717) or complicated grief (Pf = 1.00) between participants with BEB/HFS and control subjects. The odds ratios (ORs) (odds of outcome for participants with BEB/HFS relative to odds for controls) and 95% confidence interval (CI) for the OR were 1.42 (95% CI: 0.44, 4.53) and 1.00 (95% CI: 0.22, 4.59) for depression and complicated grief, respectively.

All 46 participants reported having had at least one major lifetime stressor that caused significant personal distress. Among the stressors were death of a loved one, divorce, serious marital problems and infidelity in a relationship, serious illness or injury, serious difficulties at work, fire destruction of a home, and profound financial loss. The mean number of total stressful life events for participants with BEB/HFS was 4.4 ± 1.9 events (median 4; range 2-11 events) and for control subjects was 4.1 ± 1.6 events (median 4; range 2 -7 events). There was no significant difference in the total stressful lifetime events between participants with BEB/HFS and control subjects (Pf = 0.68). Participants with BEB/HFS on average had 3.3 ± 1.5 major stressful life events (median 3; range 1-7 events) before the onset of the facial spasms. Facial spasms began within 1 year of a major stressful life event for 16 (70%) of the 23 participants with BEB/HFS. There were 3 participants with BEB who reported only 1 stressful life event before the development of facial spasms (although all 3 participants with BEB had at least 2 total stressful life events). Subsequent analyses below regarding the shortest time interval between stressful life events treat the values as censored as of the date of onset of the facial spasms.

The shortest time interval between two stressful life events was identified for each subject. This time interval was significantly shorter (P = 0.0048, Cox proportional hazards model with number of stressful life events as a covariate) for participants with BEB/HFS (median 0.3 years) than for control subjects (median 3.0 years). Eighteen (90%) of 20 participants with BEB/HFS had had two major stressful life events separated by 1 year or less. In contrast, only 7 (30%) of 23 control subjects had had two stressful life events separated by 1 year or less. The proportion of participants who had suffered two stressful life events separated by 1 year or less was significantly greater (P = 0.0007) for participants with BEB/HFS than for control subjects. Nine (50%) of the 18 participants with BEB/HFS with two stressful life events separated by 1 year or less developed BEB/HFS within 1 year of experiencing the double stressful life event.

DISCUSSION

We found a significant relationship between the interval between major life stressors and the development of BEB and HFS. Both types of facial spasms began within 1 year of a major stressful life event in 70% of cases.

These results corroborate the findings of Diamond et al (28) in which more than 90% of the female participants reported the onset or exacerbation of BEB within 2 years of a dramatic life change, principally involving the death of a loved one or a divorce. More strikingly, our study documented that participants with BEB/HFS had a significantly shorter time interval between two major stressful life events than did control subjects. For participants with BEB/HFS, the shortest time interval had a median value of 0.3 year (approximately 4 months) whereas for control subjects it was 3.0 years. Our study also documented that 90% of 20 participants with BEB/HFS had suffered two major stressful life events separated by less than 1 year and that 50% of the facial spasms began within 1 year of these stressful life events. Double stressful life events were less common among control subjects. These findings may explain why BEB and HFS are rarely encountered at a young age, as it is unusual for individuals to experience multiple stressful events so early in life (29,30).

We did not find the rate of complicated grief or depression among participants with BEB/HFS to be different from that of control subjects. However, our study was conducted, on average, 9 years after the onset of BEB and HFS. The number of individuals with complicated grief or depression might have been higher at the onset of BEB and HFS, but no different from the number of control subjects when tested 9 years later. Recent advances in the understanding of grief and depression have identified that a major life stressor is the most significant risk factor for depression and is the sine qua non of complicated grief (20,29-36).

It is estimated that a major life stress precipitates the onset of depression in 70% of individuals without a prior history of depression and that 20% of major life stresses will result in an episode of depression (31). Through kindling, major life stressors can initiate autonomous episodes of recurrent depression (31-35). Kindling results in upregulation of gene transcription factors leading to neurochemical alterations of inhibitory and excitatory neuromodulators and sprouting and retraction of nerve terminals (31,32,35,37). Grief, when triggered by a major stressful life event, such as the loss of or separation from a loved one, may last several months.

We suspect that having a second major stressful life event, before or shortly after the resolution of grief from a prior major stressful event, may potentiate kindling mechanisms leading to BEB and HFS (33,34,38). This could occur through the activation and inhibition of brain centers, particularly in the basal ganglia, known to modulate blink reflex and mimetic facial movement (39-41).

A limitation of our study is that only 46 (43%) of 106 potential subjects participated after receiving the telephone inquiry. This could result in participant bias such that those choosing to participate did so because they believed that they had experienced either more or less stressful life events than had other individuals. However, the number of major stressful life events for both participants with BEB/HFS and control subjects was similar between the two groups and comparable with that for other studies (31-34). Most importantly, participants with BEB/HFS and control subjects were unaware that we had planned to assess the rate of two stressful life events separated by less than 1 year, which occurred significantly greater (P = 0.0007) for participants with BEB/HFS than for control subjects.

Another limitation of our study is that we relied on subjects recalling major stressful life events from the past. Recall bias could have affected the study outcome with regard to the number of events reported. Simon et al (42) have noted that recall errors more often involve underestimation of past morbidity than reporting or exaggerating episodes that did not actually occur. However, possible differences in the rate of recall would probably have been reduced because both groups were similar demographically, and the rates of depression and complicated grief were similar. Additionally, both groups had undergone similar structured interviews in which they were queried as to major stressful life events that caused significant personal distress. The striking difference between participants with BEB/HFS and control subjects with regard to the shortest time interval between two major stressful life events (median of 4 months for participants with BEB/HFS compared with median of 3 years for control subjects) suggests that recall bias most likely did not influence the outcome.

Finally, the modest number of participants in our study could falsely lead us to accept a relationship between closely spaced stressful life events and the development of BEB and HFS. A prospectively designed study recruiting subjects with recent onset of major stressful life events would eliminate the potential bias of a retrospective case-control study.

The findings in our study agree with those of Diamond et al (28) suggesting that closely spaced major stressful life events contribute to the development of BEB and HFS. The development of these focal dystonias was significantly related to the number of stressful life events within the preceding 1 year rather than to the total number of stressful life events.

ADDENDUM

A follow-up evaluation of one of the seven control subjects who had two closely spaced (within 1 year) stressful life events, but who did not have BEB or HFS at the time of the study, indicated that this subject has now developed BEB 1 year after experiencing the second stressful life event.

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