Abstract
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.1,2⇓ 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.3 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.4-6⇓⇓ 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.7 BEB reduces the quality of life of those affected8 and appears to be associated with a reactive depression.9
Epidemiology and genetics.
The prevalence of BEB has been determined as 12 per million in Japan,10 17 per million in Rochester, MN,11 30 per million in North England,12 36 per million in the Epidemiologic Study of Dystonia in Europe,13 and 133 per million in a region in Southern Italy.14 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.13,15⇓ 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.16,17⇓ Trauma of or near the eye often seems relevant and even dental procedures appear to predispose.18 Conversely, there may be a decreased risk of developing BEB with cigarette smoking.16 BEB does not predispose to developing PD,16,19⇓ 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.20 Whereas both genetics and environment appear to play a role in the genesis of BEB, the genetic factor appears stronger.16,20⇓
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.21
Most epidemiologic studies suggest that BEB is an autosomal dominant disorder with reduced penetrance of about 5%.22 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.
Anatomy of eyelid innervation.
The OO muscle is innervated unilaterally from the facial nucleus and the levator palpebrae (LP) muscle is innervated bilaterally from the central caudal subdivision of the oculomotor nucleus. The synaptic circuitry of the input to these brainstem nuclei is being worked out.23,24⇓ Primary sensory afferents from the cornea and eyelid terminate most densely in the medullary spinal trigeminal nucleus. The pars caudalis of the spinal trigeminal nucleus sends excitatory projections to the OO motoneurons, ipsilaterally. The principal trigeminal nucleus sends excitatory projections to the OO motoneurons and inhibitory projections to the LP motoneurons, bilaterally. This is the appropriate circuitry for the trigeminal blink reflex, which should occur with OO contraction and levator inhibition.
There has been a new breakthrough in understanding the cortical innervation of the eyelids. Whereas there has been the clinical notion that there is bilateral innervation from the primary motor cortex, anatomic studies have failed to show either contralateral or ipsilateral innervation.25 In a study of rhesus monkeys, the musculotopic organization of the facial nucleus was defined by injecting fluorescent retrograde tracers into individual muscles of the upper and lower face.26 Then, anterograde tracers were placed in different motor regions of the cortex to see the innervation of these defined regions of the facial nucleus. The OO region was innervated mostly by the rostral cingulate motor region (called M3). Such a pattern explains the upper face sparing in typical middle cerebral artery stroke because the descending axons from the rostral cingulate motor cortex would likely be spared.
Physiology of blinking.
The physiology of spontaneous blinking and voluntary blinking is not well known. There have been detailed investigations, however, of the blink reflex. Most commonly, the reflex is elicited with electrical stimulation of the supraorbital nerve. The OO blink reflex consists of two components: an early, first response (R1) and a late, second response (R2) (figure 1). R1 is a brief unilateral response, ipsilateral to the stimulated side, with a latency of about 10 msec. R2 has a latency of about 30 msec, is longer in duration, and appears bilaterally. The common afferent limb of OO R1 and R2 is the ophthalmic (first) trigeminal division, whereas the common efferent limb is the facial (seventh) nerve and its intermediate subnucleus of the facial nucleus.
Figure 1. Silent periods, SP1 and SP2, of the right levator palpebrae muscle (upper traces) and the responses in the right orbicularis oculi (OO) muscle (lower traces) after stimulation of the right (R*) or left (L*) supraorbital nerve. Stimulation of the supraorbital nerve causes a bilateral SP1 regardless of the stimulation side, whereas the R1 response appears only in the OO ipsilateral to the side of stimulation. Figure from Majid Arahmideh, MD.
In close connection with the excitatory OO responses the LP acts antagonistically with an inhibitory response. To record from LP, a bipolar needle electrode can be inserted through the skin in the middle portion of the upper eyelid and directed toward the LP while the subject looks downward and keeps the eyelids gently closed. The subject is then asked to open the eye. This maneuver results in tonic EMG activity of LP. The inhibitory LP response can be examined together with OO responses and consists of two silent periods (SP): an early, brief, bilateral first SP (SP1) and a late, longer, bilateral second SP (SP2) (see figure 1). Ipsilateral to the stimulation, R1 of the OO response occurs during SP1, whereas the contralateral SP1 has no R1 counterpart. SP2 appears bilaterally and concurrently with the bilateral R2.
Based on analysis of human lesions, the central pathways through which OO responses are mediated are relatively well known, whereas the pathways for the LP responses are not (figure 2). Impulses for R1 and R2 enter through the first trigeminal division into the pons. For R1 they are conducted through the pons and are relayed via an oligosynaptic arc consisting of one or two interneurons located in the vicinity of the main sensory trigeminal nucleus. From there, fibers impinge upon motoneurons within the intermediate subnucleus of the motor facial nucleus. For R2, afferent impulses are conducted through the descending trigeminal spinal tract in the pons and dorsolateral medulla oblongata before they reach the caudal spinal nucleus. From there, impulses are relayed via a medullary-ascending pathway ipsilateral to the stimulated side and an ascending route that crosses the midline before it ascends contralaterally. Both routes connect with the facial nerve nucleus in the pons on the two sides. The trigemino-facial connections are thought to pass through the lateral tegmental field medial to the spinal trigeminal nucleus. The ascending pathways originate at the level of the lower medulla oblongata and the crossing of the contralateral path takes place at the level of the lower third of the medulla oblongata. The OO reflex can be influenced by suprasegmental structures, including the cortex and basal ganglia.
Figure 2. Schematic drawing of the possible central pathways involved in the generation of inhibitory responses of the levator palpebrae and excitatory responses of the orbicularis oculi (OO) muscle during electrically induced blink reflex (Aramideh et al., unpublished, 2000). CCN = central caudal nucleus; LRF = lateral reticular formation; MRF = medial reticular formation; VII = facial nucleus. Figure from Majid Arahmideh, MD.
For the inhibitory LP reflex, preliminary data derived from patients with vascular brainstem lesions suggest that impulses mediating SP1 travel through the midpons and those for SP2 through the medullary spinal trigeminal tract (Ongerboer de Visser and Aramideh, unpublished, 2000). A midbrain lesion may impair impulses ascending to the LP motoneuron nucleus. With such a lesion, antagonistic actions between LP inhibition and OO excitation are disturbed. Cerebral infarction may reduce or even remove SP2 inhibition similar to the effects on R2.
Dystonia and brain plasticity.
Whereas the etiology of dystonia is unknown, one concept of considerable interest is that dystonia arises from aberrant brain plasticity.27-29⇓⇓ The brain is capable of changing by processes such as altering synaptic strength and rewiring synaptic connections. Changes ordinarily occur for a number of reasons; for example, the learning of a new motor skill or repetitive use of a body part. It would then be possible for some plastic changes to be aberrant. For example, writing for 5 hours per day might lead to deranged organization of the motor system and dystonic hand movements. Plastic changes are facilitated by reduction in the amount of inhibition in brain circuits, so that if inhibition were for any reason diminished, there might be a propensity for increased change and possibly aberrant change.
Animal models.
A possible animal model of dystonia was created in nonhuman primates with synchronous, widespread sensory stimulation to the hand during a repetitive motor task.30,31⇓ Over a period of months, the animals’ motor performance deteriorated. After development of the movement disorder, the primary somatosensory cortex was mapped, and each cell was analyzed for the region of the body that activated the cell—its “receptive field.” Receptive fields in area 3b were increased 10- to 20-fold, often extending across the surface of two or more digits. The investigators suggested that synchronous sensory input over a large area of the hand can lead to remapping of the receptive fields and subsequently to a movement disorder. However, these tasks also involve repetitive movements, which can lead to remapping of the motor system directly.
Some trigger appears to initiate BEB in individuals genetically or environmentally predisposed to dystonia. Animal models of blepharospasm mimic this pattern by artificially creating a “predisposing neuronal environment” and then testing various triggers. The predisposing condition in a rat model of blepharospasm32 is an approximately 30% unilateral loss of dopamine-containing neurons in the substantia nigra pars compacta. In the presence of the reduced inhibition within the trigeminal blink circuits created by this dopamine loss,33 weakening the OO muscle triggers spasms of lid closure and other symptoms characteristic of blepharospasm in humans. Recent studies have examined how OO weakening might be a trigger for blepharospasm.
Weakening the OO creates two difficulties that initiate compensatory motor learning by blink neural circuits. First, the difference between the planned and the actual eyelid movement caused by OO weakness increases the drive on reflex blink circuits to compensate for muscle weakness. In other words, the nervous system learns a new relationship between blink-evoking stimulus magnitude and the motor drive required to generate the correct size blink. Second, muscle weakness decreases tear film distribution across the cornea, which leads to corneal irritation. Corneal irritation and dry eye profoundly alter trigeminal reflex blink circuits. Normally, a single trigeminal stimulus elicits a single reflex blink. With dry eye, however, this same trigeminal stimulus elicits a reflex blink and a series of additional blinks that occur with a constant interblink interval—blink oscillations (Evinger, unpublished, 2000). Dry eye might be a model for the eye irritation that appears to trigger blepharospasm. The blink oscillations created by the trigeminal complex in response to eye irritation may be a slower version of the repetitive OO contractions that characterize spasms of lid closure in some patients with blepharospasm (figure 3). Eye irritation may also be responsible for photophobic responses.
Figure 3. Reflex blinks and blink oscillations evoked by a single stimulus to the supraorbital branch of the trigeminal nerve (SO) in a subject with benign essential blepharospasm (top traces) and a subject with dry eye (bottom traces). Each trace is a single trial showing the position of the upper eyelid. Calibration bars are 5 degrees for blepharospasm records and 15 degrees for dry eye records. In both patients, there is an initial reflex blink followed by blink oscillations (Evinger, unpublished, 2000).
Pathophysiology.
A human correlate to the rat model32 is the observation of patients with facial palsy who developed blepharospasm.34,35⇓ If this is a good model, then facial weakness should cause an increase in the excitability of reflex blinking. The size of the R2 response on the normal side in 30 normal volunteers and 68 patients with idiopathic or herpetic peripheral facial palsy was investigated.36 In patients, the reflex R2 responses were larger when the stimuli were applied to the contralateral trigeminal nerve than when the stimuli were applied to the ipsilateral trigeminal nerve. This was significantly different from what was observed in control subjects, who showed larger responses to ipsilateral than to contralateral nerve stimulation. A second study reported the blink reflex recovery curve in normal subjects and patients with Bell palsy who either recovered facial strength or had persistent weakness.37 Blink reflex recovery was enhanced in patients with residual weakness but not in patients who recovered facial strength. Facial muscles on both the weak and unaffected sides showed enhancement. In patients with residual weakness, earlier blink reflex recovery occurred when stimulating the supraorbital nerve on the weak side. Sensory thresholds were symmetric. The authors concluded that enhancement of blink reflex recovery is dependent on ongoing facial weakness. Faster recovery when stimulating the supraorbital nerve on the paretic side, similar to the results of the other study,36 suggests that sensitization may be lateralized, and suggests a role for abnormal afferent input in maintaining sensitization. Interneurons in the blink reflex pathway are the best candidates for the locus of this plasticity.
The observations in animals and humans that OO weakness may predispose to BEB raises a point of concern about the use of botulinum toxin for therapy. Might not induced weakness of the eyelids make the situation worse? From clinical experience, however, botulinum toxin certainly improves most patients and the improvement can be sustained for as long as the drug is given, in many patients more than a decade. The current conclusion is that although weakness might help trigger the development of BEB, further weakening does not appear to aggravate the condition.
Patients with BEB may have a sensory trick, such as, touching the face, that improves their eyelid spasms. The physiology of these tricks is unknown. The R2 of the blink reflex is reduced, but the blink reflex recovery curve is not affected, during a sensory trick.38 Patients who have a sensory trick are more likely to have a significant effect of prepulse inhibition with sensory stimulation of the hand.39 This appears to indicate a greater influence of sensory input on eyelid control.
Neuroimaging studies support the general concept that there is pathology in the basal ganglia and its circuitry. PET studies have identified movement-free patterns of covariance in fluoro-deoxyglucose (FDG) uptake in the brains of people who are nonmanifesting carriers of an autosomal dominant childhood onset torsion dystonia with defects in the DYT1 gene, as well as in manifesting carriers of DYT1.40 A similar covariance pattern, involving basal ganglia, was also seen in patients with essential blepharospasm.41 Both of these studies identified the abnormal covariance pattern in sleeping subjects, thereby eliminating the confound of the afferent effects of the movement on local brain metabolism. When blepharospasm is active during the scanning, then there are increases in glucose metabolism in pons and cerebellum, suggesting that these regions either are important in generating the movements or are involved in afferent activity produced by the movements.41 In another study of BEB, increased glucose metabolism was found in the striatum and thalamus.42 An MRI study found approximately 10% enlargement of putamen in people with either hand or facial dystonia,43 and a magnetic resonance spectroscopy study showed a loss of N-acetylaspartate in basal ganglia.44
Several clues from neuroimaging studies implicate striatal dopamine dysfunction or changes in striatal-cortical pathways in dystonia. Relevant findings come from animal studies as well as from neuroimaging studies in humans. Nonhuman primates treated with intracarotid MPTP developed transient hemidystonia prior to chronic hemiparkinsonism.45 This transient dystonic phase corresponds temporally with a decreased striatal dopamine content and a transient decrease in D2-like receptor number.46 The reduction in striatal dopamine receptors matches closely the reductions of in vivo striatal dopamine receptor binding found in humans with primary focal cranial or hand dystonia47 and subsequently confirmed in cervical dystonia.48 These changes suggest dysfunction of the D2-like receptor mediated indirect pathway in the basal ganglia with a loss of ability to inhibit unwanted motor activity “surrounding” an intended movement.49
PET can be used to measure the brain responses to specific dopamine agonists. Early studies have demonstrated appropriate dose response and specificity of such techniques for specific D2 and D1 dopamine agonists.50-52⇓⇓ These pharmacologic activation methods may provide additional insights into the function of selected dopaminergic pathways in dystonia, as they have already in PD.53
There have been few functional neuroimaging studies of sensorimotor processing in patients with focal dystonias, including blepharospasm. In these studies, several different groups of patients with dystonia have reduced vibration-induced blood flow responses in sensorimotor cortex and supplementary motor area.54,55⇓ Motor activation paradigms in focal or generalized dystonia also show abnormal activation in cortical regions,56,57⇓ but there have not been studies in patients with BEB. These studies do not yet tell a clear story.
Treatment.
The mainstay of treatment remains the use of botulinum toxin.58 Its efficacy is high and it can be used for many years without side effect or loss of efficacy. The pretarsal region may be the best part of the OO to inject,59 and a recent suggestion, that needs confirmation, is that injection into Riolan muscle, part of the pretarsal OO, is particularly effective.60 Doxorubicin chemomyectomy has provided 10 or more years of relief but has skin side effects that have limited its acceptance.61 A liposome encapsulated form of the drug that limits skin side effects is in clinical trial. Oral agents work only weakly and cannot be depended on.22
Most cases that are refractory to botulinum toxin have eyelid deformities associated with blepharospasm or associated apraxia of lid opening. These cases as well as the true nonresponders to botulinum toxin may be successfully treated with the full myectomy operation.62 In this operation the OO and corrugator superciliaris muscles are removed to relieve spasms. The levator aponeurosis is tightened to help elevate the eyelids, and in rare cases of severe apraxia of lid opening a frontalis suspension may be required. Dermatochalasis as well as other eyelid deformities can be corrected at the time of surgery. The limited myectomy operation is used as an adjunct to botulinum toxin, and the greatest relief is frequently afforded patients by both forms of therapy. Therapy should be tailored to the patient’s needs, and many patients benefit from combining all available treatments available to provide maximum benefit.
A method to reduce the light sensitivity (photophobia) associated with BEB has been the use of tinted lenses; in particular, FL-41 tinted lenses. FL-41 tint was originally described in Birmingham, England, for use in children with migraine headaches.63 The FL-41 rose-tint (as opposed to a blue-tinted lens) reduced migraines by one-half in these children after 4 months of wear. One optical shop (in Salt Lake City, UT) has dispensed FL-41 tinted glasses over the last 3 years. In a completely unscientific poll—only asking patients to “let us know” the effect of the lens—about 70% of patients have reported an improvement in blepharospasm (Digre, personal communication, 2000). More work needs to be done in this area.
Physiologic findings in dystonia reveal a decrease in intracortical inhibition measured with transcranial magnetic stimulation.64 Because rTMS delivered over the primary motor cortex at 1 Hz can induce an increase in inhibition,65 it was proposed that it might ameliorate the deficit. A study showed a normalization of the intracortical inhibition and some modest improvement in performance in patients with focal hand dystonia.66 Perhaps a similar therapeutic approach would be useful in BEB.
The photophobia of BEB may be caused by sympathetically maintained pain.67 This has led to the idea that sympathetic block might be therapeutic. Nineteen patients with photophobia and BEB were enrolled in an unblinded prospective treatment trial. Ocular surface disease was present in 18 of 19 patients, adding evidence to the idea that local eye disease is relevant in the pathogenesis. The intervention was blockade of the superior sympathetic ganglion with local anesthetic. Outcome measures included patients’ subjective report of ocular surface dryness, foreign body sensation, and eyelid spasm, as well as video recordings of eyelid movements. Of the 19 patients, 13 reported subjective improvement in BEB symptoms after cervical sympathetic blockade. Thirteen of 19 patients also had objective evidence of decreased light-induced eyelid spasm. These data are consistent with the hypothesis that in many patients with BEB there is a sympathetically maintained pain syndrome associated with external ocular disease, but the study needs to be repeated with appropriate controls. The concept of sympathetically maintained pain has not proven to be robust as an etiology for complex regional pain syndrome (reflex sympathetic dystrophy).68-71⇓⇓⇓
Footnotes
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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 22). A listing of workshop participants is available at the online version of this article (access www.neurology.org).
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Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the November 12 issue to find the title link for this article.
- Received December 31, 2001.
- Accepted June 11, 2002.
References
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