Blepharospasm － A review and updates. Part I.
Blepharospasm － A review and updates. Part I.
Hirofumi Emoto MD1,2, Yukihisa Suzuki MD, PhD1,2, Motohiro Kiyosawa MD, PhD1
1 Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan
2 Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
Essential blepharospasm (EB) is a form of common focal dystonia that is characterized by involuntary closure of eyelids. EB was thought to be a rare disorder, however, it is more recognized as a result of clinical use of botulinum toxin and increased publicity. Blepharospasm can be classified into three groups; essential, secondary, and drug-induced blepharospasm. Essential blepharospasm is the most common form of unknown origin. Symptomatic blepharospasm is known to occur as a consequence of the central nervous system disorders such as Wilson’s disease, Parkinson’s disease and progressive supranuclear palsy. Lesions in the basal ganglia and upper midbrain (stroke, multiple sclerosis, tumor and hydrocephalus) have been rarely reported in blepharospasm. Drug-induced blepharospasm (DIB) is associated with psychotropic medication such as neuroleptics, dopaminergics, antihistamines, calcium-channel blockers, and noradrenalin and serotonin reuptake inhibitor. EB has three major symptoms: motor, sensory, and psychiatric symptoms. The motor symptoms are excessive blinking and difficulty keeping the eyes open with or without apraxia of eyelid opening. Apraxia of eyelid opening is a syndrome characterized by difficulty in initiating the act of eyelid elevation. The sensory symptoms are eye discomfort such as irritation of the eyes and photophobia. These symptoms are often confused with dry eye which frequently precedes and coincides with EB. The photophobia in EB patients is a complex symptom associated with discomfort or pain. The main psychiatric symptom is depression. High incidence of concomitant depression and reduced health-related quality of life has been reported in EB patients.
Key Words: essential blepharospasm, drug-induced, apraxia of eyelid opening, photophobia, positron emission tomography
Reprint request to: Hirofumi Emoto, Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, JAPAN
Essential blepharospasm (EB) is a form of common focal dystonia that is characterized by involuntary closure of eyelids. It is typically caused by spasmodic contractions of the orbicularis oculi muscles, occasionally with failure of levator palpebrae contraction, a condition known as apraxia of eyelid opening1-5. The etiology remains unclear, but the lesions or abnormal function associated with EB have been documented in the basal ganglia and thalamus6, 7 [Fig. 1]. EB was thought to be a rare disorder, however, it is more recognized as a result of clinical use of botulinum toxin and increased publicity3. The prevalence of blepharospasm was estimated to be 17 per million in 1988 in the US3, 8, but 133 in 2001 in Italy9. Fukuda et al reported it was 16 per million in 1993 in Japan, but it became 4 times higher to 65 per million in 200310.
Thus, EB is more recognized, however, 44% of the patients needs more than 2 years to be diagnosed11.
We present here a review and updates on blepharospasm.
Blepharospasm can be classified into three groups; essential, secondary, and drug-induced blepharospasm.
EB is the most common form of unknown origin1-6. It usually begins during the 5th or 6th decade, and generally persists throughout life3, 5, 12. It affects women more often than men at a ratio of about 3:13, 5, 12, 13. The mean age at onset is characteristically higher than other focal dystonias: blepharospasm; 55.7 years vs writer’s cramp; 38.4 years, cervical dystonia; 40.8 years, and spasmodic dysphonia; 43.0 years14. However, different forms of focal dystonia seemed to be related to each other15. They may coexist in the same individual as the result of spread or they are positive in the family history16-18. Peckham et al reported that focal dystonia is the most common in family history in the EB patients (27%9 ~ 32%11), followed by Parkinson’s disease and dementia11. Of the focal dystonias, EB was the most commonly reported at 21%: 16% in a first-degree relative and 5% in a second-degree relative11. Other dystonias in family history were focal hand dystonia (4%), spasmodic dysphonia (3%), cervical dystonia (2%), and foot dystonia (1%)11. The majority of patients had symptoms in a first-degree relative and this may indicate that EB is inherited in autosomal dominant fashion with reduced penetrance15.
In various forms of dystonia, over 14 different gene loci have been reported19. A single mutation in DYT1 gene which is expressed in the dopaminergic cells of the substantia nigra pars compacta cause early-onset torsion dystonia20, 21. And a multiallelic polymorphism of the D5 dopamine receptor gene (DRD5) is associated with EB22. Clarimon et al investigated common variability within these two genes in two independent cohorts of Italian and North American patients with EB19. No significant association was identified, however, analysis of the Italian group separately revealed an association with the same risk genotype in DYT1 as previously described in an Icelandic population19. Defazio et al speculated that common genes underlie the pathophysiological mechanisms shared by the various forms of adult-onset focal dystonia and that additional genes and/or environmental factors determine the clinical and neurophysiological differences in the various forms of dystonia18. They studied the influence of the TOR1A gene polymorphism on the risk of dystonia spread in two cohorts of Italian and North American patients with EB23. In both groups, patients carrying the T allele (G/T or T/T) in the rs1182 polymorphism were more likely to have dystonia spread as compared with the homozygous carriers of the common G allele23. These genetic factors may contribute to the spread of EB23.
Symptomatic blepharospasm is known to occur as a consequence of the central nervous system disorders such as Wilson’s disease, Parkinson’s disease and progressive supranuclear palsy4, 5. Lesions in the basal ganglia and upper midbrain (stroke, multiple sclerosis, tumor, and hydrocephalus) have been rarely reported in blepharospasm5.
Drug-induced blepharospasm (DIB) is most commonly associated with neuroleptics, as well as dopaminergics, antihistamines, calcium-channel blockers, and noradrenalin and serotonin reuptake inhibitor24. In addition, Wakakura et al reported benzodiazepines and thienodiazepines can induce blepharospasm25. Although the pathogenesis of DIB remains obscure, abnormalities of cortical or subcortical neural pathways have been suggested26. In neuroleptics, supersensitivity of striatal dopamine receptors has been speculated for the mechanism27. Long-term use of neuroleptics may lead to an altered normal balance of the D1 and D2 receptors, which could give rise to a striatal disinhibition of the thalamocortical pathway and consequent dystonia28. Horie et al reported in a positron emission tomographic (PET) study that decreased dopamine D2 receptor binding might be one of the predisposing factors that lead to the motor circuit dysfunction, resulting in disinhibition to unwanted movements during blinking in DIB patients29. Another hypothesis is that neuroleptics may cause lipid peroxidation that cause neurodegeneration28. In chronic use of benzodiazepine and thienodiazepine, they may induce impairment of normal blinking as a result of down regulation of GABAA receptors in the neural circuits30. Unfortunately, these hypotheses cannot account for why some patients on neuroleptics are vulnerable to the development of DIB and other dystonias28.
There are three major symptoms: motor, sensory, and psychiatric symptoms.
The motor symptoms are excessive blinking, and/or difficulty keeping the eyes open caused by involuntary forceful contraction of the orbicularis oculi muscles, and apraxia of eyelid opening1-6, 15. Typically it starts with excessive blinking, and in some cases, it is triggered by various stimuli such as air pollution, bright light and stress5. Then, it progresses to chronic involuntary spasm in both eyes31. Its severity can range from excessive blinking to disabled functional blindness due to persistent spasmodic closure of the eyelids32, 33. EB patients may experience spread of involuntary spasms to other facial, oromandibular, pharyngeal, laryngeal, or cervical muscles4, 5. When oromandubular regions are involved, it is referred as Meige’s syndrome4, 5. Weiss et al studied 602 patients with primary dystonias and reported that EB patients were more likely to spread (31% past the head) than those with dystonia starting in the neck (9%), larynx (12%), or upper extremities (16%)17. In many cases, spread occurred in the first 1 to 2 years after onset of EB, whereas the risk of spread was relatively constant over time in other dystonias17. The rate of spread after onset varied significantly between the different groups and the EB group had significant relative risk of spread17.
Apraxia of Eyelid Opening
Apraxia of eyelid opening (AEO) is a syndrome characterized by difficulty in initiating the act of eyelid elevation34, 35. Initiation of eyelid elevation occurs with activation of the levator palpebrae superioris and the concurrent inhibition of orbicularis oculi activity36. It is non-paralytic motor abnormality and patients can open their eyes by contracting the frontalis muscles or touching their eyelids with their fingers (sensory trick) 35. This symptom is first described by Goldstein and Cogan in patients with basal ganglia disease34 and often associated with EB and occasionally seen in patients with Parkinson’s disease, progressive supranuclear palsy, multiple system atrophy, or other movement disorders35. True cases of AEO are caused by prolonged supranuclear inhibition to the levator palpebrae superioris which is proved by electromyography15, 36. EB patients are often diagnosed as AEO in error, as contraction of the pretarsal portion of the orbicularis oculi is also responsible for eyelid closure15. The electromyography of these muscles is a specialized procedure, therefore, the diagnosis remains largely based on careful clinical assessment and observation of delayed eye opening15.
The sensory symptoms are eye discomfort such as irritation of the eyes and photophobia. These symptoms are often confused with dry eye which frequently precedes and coincides with EB. Actually 57% of the patients with intractable dry eye had Meige’s syndrome37. However, objective findings are much less than the frequency of complaints in the EB patients15. The ”dry eye” in EB is different from the ordinary one, as the EB patients often have photophobia, difficulty in driving, or barge into a person while walking.
The photophobia in EB is a complex symptom associated with discomfort or pain38. 79% of 1,653 EB patients reported that bright light was the most frequent exacerbating factor and precipitates eyelid spasms39. Even after the muscle spasm is relieved, bright light still bothers EB patients1, 2, 40. Whether the wavelength or the intensity of light contributes to the photophobia is controversial and the mechanism of the photophobia remains unclear. Herz et al investigated the effect of photochromatic modulation with tinted lenses on the photophobia in the EB patients41. Even though the patients could tolerate a higher intensity of light with lens 6 (filtering light < 400 nm and between 500 and 600 nm), the majority (71%) of patients preferred the FL-41 lens (filtering < 400 nm and moderately between 400 and 550 nm) for symptomatic relief of photophobia41. These findings imply that the photophobia may be related more to the wavelength than to the intensity of light41. On the other hand, Adams et al tested thresholds of light sensitivity in the EB patients compared with migraineurs and normal control subjects42. The EB patients are significantly more sensitive to light than control subjects and as sensitive to light as migraineurs42. Both gray and FL-41-tinted lenses improved the thresholds in all groups and there was no difference in the improvement in light sensitivity between the lenses42. This study suggests that the photophobia may be related to the light intensity, not to the wavelength15. To localize regional alterations in cerebral glucose metabolism in the EB patients with photophobia, we performed positron emission tomography using [18F]-fluorodeoxyglucose (FDG-PET) and compared with the EB patients without photophobia and normal controls38. As compared to the control group, the EB patients with photophobia exhibited significant hypermetabolism in the thalamus, while the EB patients without photophobia exhibited significant hypometabolism in the dorsal midbrain, especially, in the superior colliculus38. These findings suggest that photophobia in the EB patients may be associated with abnormal hyperactivity in the thalamus38. Blink Reflex Both conditions above; the abnormal hyperactivity in the thalamus and the abnormal hypoactivity in the superior colliculus could enhance the blink reflex circuits43-45 [Fig. 2]. EB is possibly mediated by blink reflex due to dry eye or ocular irritation15, 46, 47. More than half of the patients have eye symptoms at the onset of EB1-3, and prior eye diseases (blepharitis and keratoconjunctivitis) were significantly associated with EB48. They may trigger EB in predisposed individuals15, 46, 47, however, blepharitis and keratoconjunctivitis accounted for only 18% of eye diseases in the EB cases46. As for the photophobia in EB, Peckham et al reported it was only present in 25% of patients prior to the onset of symptoms, whereas 74% of patients report this symptom when diagnosed11. Abnormal blink reflex in EB may attributable not to the ocular surface disorders, but to abnormal activity in the brain such as abnormal hyperactivity in the thalamus. Psychiatric Symptoms Depression High incidence of concomitant depression has been reported in EB patients13, 49-51. Of psychiatric disorders associated with EB, depression was the most frequent (26%), followed by anxiety (14%), and panic attacks (4%)11. The patients may have phobia, obsessive-compulsive disorder, and other emotional and behavioral disorders49, 52. 69% of the EB patients (35/51) with psychiatric disorders had one before the onset of dystonia, and the rest of patients (31%: 16/51) had after the onset51. Disabled functional blindness may impact on the patients’ social life, resulting in withdrawal, isolation, and finally depression53. Of the depressive disorders with EB, the patients have secondary dysthymia (19.3%), major depression (16.1%), and recurrent major depression (16.1%)52. There are no differences in age, dystonia severity, and duration of botulinum toxin treatment between EB patients with and without psychiatric disturbances51. Stress The development of EB was significantly related to the number of stressful life events within the preceding 1 year rather than to the total number of stressful life events54. In 70% of cases, EB symptoms began within 1 year of a major stressful life event54. More than 90% of the female patients reported the onset or exacerbation of EB within 2 years of a dramatic life change, principally involving the death of a loved one or a divorce54. Health-Related Quality of Life Studies reported that EB patients experience reduced health-related quality of life (HR-QoL)33, 50, 55-60. Depression and anxiety are the most important predictor60. Botulinum toxin treatment may improve the HR-QoL and reduces the intensity of depressive symptoms in EB53. However, Müller et al reported, HR-QoL did not improve in EB, although botulinum toxin treatment resulted in a significant improvement of the motor symptoms61. This difference may result from the severity of depression. Cognitive Impairment Alemán et al reported cognitive impairment in the EB patients which is independent from depression, anxiety, and premorbid intelligence62. The EB patients have prefrontal and parietooccipital dysfunction, both structures previously implicated in dystonia62, 63. 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