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Volume 59 • Number 9 • November 12, 2002
Copyright © 2002 American Academy of Neurology
Mark Hallett, MD
From the Human Motor Control Section, NINDS, NIH, Bethesda, MD.
From a workshop sponsored by The Benign Essential Blepharospasm Research Foundation and National Institute of Neurological Disorders and Stroke, November 16–17, 2000, following up a previous workshop (see reference  ). A listing of workshop participants is available at the online version of this article (access www.neurology.org).
Received December 31, 2001.
Accepted in final form June 11, 2002.
Address correspondence and reprint requests to Dr. Mark Hallett, Human Motor Control Section, NINDS, NIH, Building 10, Room 5N226, 10 Center Dr, MSC 1428, Bethesda, MD 20892-1428; e-mail: firstname.lastname@example.org
Benign essential blepharospasm is a common focal dystonia characterized by involuntary eyelid closure. Its etiology, supported by animal models, appears to be multifactorial, representing the influence of a genetic background and an environmental trigger. The genetic background could be responsible for the reduced brain inhibition, identified with physiologic studies that would set up a permissive condition for increased brain plasticity. Reduced D2 receptors identified with PET might be an indicator of this reduced inhibition. The trigger could be repetitive use or local ocular disease. Although symptomatic therapy is available, better approaches are needed and will likely become available as the genetics and pathophysiology become well understood.
Blepharospasm is a focal dystonia characterized by excessive involuntary closure of the eyelids. Typically, this is due to spasm of the orbicularis oculi (OO) muscles. Involuntary closure of the eyelids can also be caused by failure of levator contraction, a condition known as apraxia of lid opening or motor persistence of the OO muscles.   These two conditions may coexist. It is important to determine the contribution of apraxia of lid opening because this condition does not respond well to botulinum toxin injections.  Primary, essential, or idiopathic blepharospasm, often called benign essential blepharospasm (BEB), is not associated with any known etiology, whereas secondary blepharospasm is due to an identifiable neurologic or ophthalmologic disorder or documented pathologic lesion. Lesions associated with blepharospasm have been documented in the basal ganglia, brainstem, and thalamus, and more recent case reports confirm this.    Most of the relevant research relates to BEB.
BEB is present spontaneously, but can be aggravated by bright lights or irritants to the eyes such as wind or smoke. Eye closure can be so severe as to make vision difficult. BEB is often accompanied by dystonia of the lower face and jaw, called Meige syndrome, or other focal dystonias such as cervical dystonia.
Photophobia is a symptom complex in which patients avoid light because of pain or discomfort in the eyes, and appears to be the reason for light aggravating eyelid closure. Although photophobia is often seen in disorders of the iris and anterior segment of the eye, photophobia is also reported in conditions with a normal appearing anterior segment, including migraine, meningitis, subarachnoid hemorrhage, head injury, and neurasthenia, as well as BEB. The mechanism of photophobia is not completely understood but is thought to involve the trigeminal pathway with possible input from the occipital lobe and thalamus. The term photo-oculodynia—pain in the eye out of proportion to the stimulus of the light—may be more applicable.
BEB is typically a chronic disorder, but up to about 10% of patients may have a spontaneous remission, most within the first 5 years.  BEB reduces the quality of life of those affected  and appears to be associated with a reactive depression. 
Epidemiology and genetics.
The prevalence of BEB has been determined as 12 per million in Japan,  17 per million in Rochester, MN,  30 per million in North England,  36 per million in the Epidemiologic Study of Dystonia in Europe,  and 133 per million in a region in Southern Italy.  It is not clear whether these geographic differences are real; the discrepancies may simply reflect acquisition bias. Women are 2.3 times more likely to be affected than men, and are on average 4.7 years older.   There is an increased risk with a family history of dystonia or postural tremor, a history of head trauma with loss of consciousness, and prior eye disease such as blepharitis or keratoconjunctivitis.   Trauma of or near the eye often seems relevant and even dental procedures appear to predispose.  Conversely, there may be a decreased risk of developing BEB with cigarette smoking.  BEB does not predispose to developing PD,   but patients with PD may have blepharospasm and apraxia of eyelid opening. Older age at onset, female sex, and prior head/face trauma increase the possibility of spread of dystonia to adjacent body regions, which usually occurs during the initial 5 years.  Whereas both genetics and environment appear to play a role in the genesis of BEB, the genetic factor appears stronger.  
Given that local eye disorders seem to be related to BEB and that older women seem predisposed, it is of interest that dry eye is particularly common in postmenopausal women. Dry eye may be a potent trigger as suggested from model studies (see below). Recent evidence suggests that dry eye might be more common in postmenopausal women taking estrogen replacement therapy. 
Most epidemiologic studies suggest that BEB is an autosomal dominant disorder with reduced penetrance of about 5%.  It does not seem to be a forme fruste of the generalized dystonia resulting from a gene defect at the DYT1 site. Given the low prevalence, reduced penetrance, and the likely genetic heterogeneity, it will be very difficult to find genetic linkage unless some families are found with three to five affected members or a biological marker is identified. An alternative strategy is to study a large number of sibpairs, and it was estimated that 200 to 400 such pairs might be needed.