Benign essential blepharospasm (BEB) is a rare focal cranial dystonia neurological disorder characterized by involuntary contractions of orbicularis oculi muscle contractions, resulting in involuntary eye closure in which affected patients experience involuntary muscle spasms and contractions of the muscles around the eyes. These spasms come and go (intermittent). Symptoms may begin as eye twitching and blinking and there may be symptoms of eye irritation. Eventually, BEB causes involuntary closure of the eyes. The exact cause of BEB is unknown. The disorder is one of a group of disorders collectively known as adult-onset focal dystonias.
Benign essential blepharospasm (BEB) is a progressive neurological disorder characterized by involuntary muscle contractions and spasms of the eyelid muscles. It is a form of dystonia, a movement disorder in which muscle contractions cause sustained eyelid closure, twitching or repetitive movements. BEB begins gradually with increased frequency of eye blinking often associated with eye irritation. Other symptoms may include increasing difficulty in keeping the eyes open, and light sensitivity. Generally, the spasms occur during the day, disappear in sleep, and reappear after waking. As the condition progresses, the spasms may intensify, forcing the eyelids to remain closed for long periods of time, and thereby causing substantial visual disturbance or functional blindness. It is important to note that the blindness is caused solely by the uncontrollable closing of the eyelids and not by a dysfunction of the eyes. BEB occurs in both men and women, although it is especially common in middle-aged and elderly women.
Symptoms
In the early stages, benign essential blepharospasm is characterized by frequent or forced blinking and eye irritation that is often worsened by certain stimuli including bright lights, fatigue, emotional tension, and environmental factors such as wind or air pollution. BEB virtually always affects both eyes (bilateral).
The frequency of muscle spasms and contractions may increase causing involuntary narrowing of the opening between the eyelids or closure of the eyelids. It may become progressively harder for affected individuals to keep their eyes open. In severe cases, the spasms may intensify to the point where the eyelids are closed for several hours at a time. Although an individual’s vision remains unaffected, prolonged closure of the eyelids may cause a person to become functionally blind.
BEB may occur in association with dystonia of the lower part of the face, mouth, or jaw. In these cases, BEB may be associated with jaw clenching, grimacing, or tongue protrusion. This is called Meige syndrome of cranial dystonia. BEB may also be associated with abnormally dry eyes.
In most patients, spasms and contractions occur during the daytime and disappear while the individual is sleeping, only to recur the next day. Symptoms of BEB may be temporarily alleviated by a variety of activities including singing, laughing, yawning, and chewing.
Other activities may worsen symptoms. Such activities include reading, walking, watching television, exposure to bright lights, and driving. Stress may also worsen symptoms.
Causes
The cause of benign essential blepharospasm is unknown. Researchers speculate that the cause of BEB may be multifactorial (e.g., caused by the interaction of certain genetic and environmental factors).
Malfunctioning of a region of the brain known as the basal ganglia may play a role in the development of BEB. The basal ganglia are structures composed of nerve cells located deep in the brain. The basal ganglia are involved in the regulation of motor and learning functions. The exact problem(s) associated with the basal ganglia in individuals with BEB is unknown.
In some cases, BEB runs in families. In these rare instances, it is more obvious that BEB may be inherited. More study is required to determine the exact role genetics plays in the development of BEB.
In some cases, affected individuals may have a history of local eye disease such as eye trauma. However, no proven relationship between local eye disease and the development of BEB has been established. In most affected individuals, BEB develops spontaneously with no known precipitating factor.
Blepharospasm may also occur secondary to other disorders such as tardive dyskinesia or generalized dystonia, Wilson disease, and various parkinsonian syndromes. Blepharospasm may also occur secondary to the use of certain drugs, specifically the drugs used to treat Parkinson’s disease.
Non-inherited Risk Factors
There are many environmental risk factors that are associated with an increased risk of developing benign essential blepharospasm. These include high levels of urbanization and those working ‘white-collar’ jobs associated with a stressful lifestyle.
There are other factors that are loosely associated with an increased risk of developing blepharospasm, such as reading, watching television, and computer screen use.[rx] It is believed that eye strain whilst watching television, reading, or using the computer may lead to aggravation of blepharospasm.[rx]
Furthermore, patients suffering from psychiatric conditions such as obsessive-compulsive disorder, depression, and anxiety appear to have an increased risk of developing blepharospasm.[rx]
It has been shown by Conte et al. that 40% to 60% of patients present with ophthalmic symptoms such as burning, dryness, or grittiness, which precedes the development of blepharospasm. Furthermore, there is an association between diseases of the anterior segment such as keratoconjunctivitis/blepharitis and an increased risk of developing blepharospasm, although this is more correctly termed “secondary blepharospasm” as the condition improves when the underlying conditions have been appropriately treated.[rx][rx][rx]
Inherited Risk Factors
Genetic contribution to the disease is suggested by the finding of multiple affected individuals within families. In such cases, the inheritance pattern appears to be autosomal dominant with reduced penetrance. GNAL, CIZ1, TOR1A, DRD5, and REEP4 are genes reported to play a role in the development of BEB.[rx][rx][rx]
- GNAL: The GNAL gene encodes for the G alpha subunit of the G protein receptor. It is found in the olfactory epithelium and helps to mediate odorant signaling.[rx] It is also expressed in striatal neurons found in the basal ganglia. Mouse models have shown that it has a role in the coupling of adenyl cyclase in response to dopamine and adenosine via the Drd1 and Adora2a receptors.[rx] Mutations in the GNAL gene have been shown to be associated with autosomal dominant dystonia-25, and it is thought that mutations in GNAL leading to abnormalities in the function of DRD1/Adora2a contribute to the development of dystonia.[rx]
- CIZ1: The CIZ1 gene encodes for the CKDN1A-interacting zinc finger protein 1.[rx] This protein interacts with CIP1 to regulate the distribution of CIP1. CIZ1 has been found to be associated with autosomal dominant cervical dystonia.[rx]
- TOR1A: The TOR1A gene encodes for torsin-1A, otherwise known as DYT1. This is an adenosine triphosphatase that aids with a wide range of cellular activities.[rx] TOR1A has high levels of expression in melanized neurons found in the pars compacta (substantia nigra), dentate gyrus, cerebellum, and stratum pyramidale of CA3 (hippocampus).[rx] It is thought that a mutation in the TOR1A gene may lead to changes in interactions involving TOR1A in the nuclear envelope.[rx] Therefore, it is thought that mutations in TOR1A contribute to dystonia through defects in the structure and function of the nuclear membrane. TOR1A mutations are associated with torsion dystonia and are inherited in an autosomal dominant pattern.[rx]
- DRD5: DRD5 encodes for the dopamine receptor D1B. DRD5 functions to increase adenylate cyclase activity leading to the accumulation of intracellular cAMP.[rx] Polymorphisms in the D5 receptor gene have been shown to be associated with blepharospasm.[rx][rx]
Diagnosis
No laboratory tests exist to make a definitive diagnosis of benign essential blepharospasm. A diagnosis is made based upon a thorough clinical evaluation, detailed patient history, and identification of characteristic symptoms.
BEB is an underdiagnosed entity. A study performed in Japan reported that 60% of patients see at least five physicians before they receive a definitive diagnosis. One-third of patients are diagnosed within the first year of symptom onset, one-third in a period between one and five years, and in one-third of patients, it takes more than five years before they are diagnosed with BEB.[rx]
Precipitating Factors
Lee et al. have shown that 42.6% of patients experienced some sort of stressful life event before the onset of symptoms. This included major life events such as divorce (19.8%), problems at work (13.9%), illness of a family member (2%), death of a parent (1%), moving house (1%), head trauma (1%), traffic accident (1%) and cerebral infarction (1%). In a study performed in Tokyo that involved 1,116 participants, 9.7% reported symptoms to occur following surgery: the most common surgery performed was cataract surgery.[rx][rx]
Motor Manifestations
The spasm associated with blepharospasm tends to be synchronous, bilateral, and affects the orbicularis oculi muscle.
Symptom severity is highly variable, and it can range from mild symptoms with increased blinking rate, to functional blindness due to persistent muscle contraction. In many cases, the course of the disease is progressive, initially presenting with contractions limited to the orbicularis oculi muscles and later extending to the musculature of the lower face and neck, which is known as Meige syndrome.[rx]
Apraxia of Eyelid Opening
Some patients suffering from blepharospasm may also present with apraxia of eyelid opening (AEO). This presents with an inability to reopen the eyes in the absence of orbicularis oculi muscle spasm. This occurs as a result of spasm of the pretarsal orbicularis oculi muscle, which acts against the opening of the eyelid.[rx]
Non-motor Manifestations
It is important to keep in mind that depression and anxiety are commonly present in patients with BEB. These occur either before the disease or as a consequence of it. This should be sought during evaluation and psychiatric consultation considered.[rx]
Half of the patients with BEB have accompanying ocular symptoms, most reporting eye dryness and photophobia.[rx]
Relieving Factors
There are particular things some patients can do to help relieve their blepharospasm. This includes resting (35.6%), concentrating on work (12.9%), and various other things such as singing, talking, eating, sleep, and exercise, which were all reported at a rate of 2%. However, 31.7% of patients could not identify a relieving factor.[rx]
Aggravating Factors
Things that have been shown to aggravate the symptoms of blepharospasm include fatigue (55.4%), stressful events (46.5%), watching television (27.7%), bright lights (18.9%), dry eye symptoms (14.9%), feeling sick (10.9%) or reading a book (8.9%).
Clinical Assessment
A clinical history determining the nature of the eyelid spasm is highly important. Patients suffering from blepharospasm will complain of bilateral, synchronous, stereotyped spasm of the orbicularis oculi muscle. These spasms may present with brief and repetitive blinking or persistent closure of the eyes leading to functional impairment. There is a diagnostic algorithm that is based on the presence of bilateral, synchronous, and stereotyped movements of the orbicularis oculi muscle, the presence of a sensory trick, or increased blinking. This diagnostic algorithm has been shown to have a sensitivity of 93% and a specificity of 90% in differentiating BEB from other similar conditions.[rx][rx][rx]
Furthermore, as mentioned before, patients suffering from blepharospasm may also suffer from related non-motor manifestations such as psychiatric disorders, sleep disorders, sensory symptoms, and cognitive disturbances.
Sensory symptoms such as a sensation of dry eye or photophobia have been identified to be associated with a specificity of 94% and a sensitivity of 77% in patients suffering from BEB.[rx]
Psychiatric disorders, such as anxiety and depression, are associated with BEB. However, other related conditions are also associated with higher rates of anxiety and depression.[rx]
Severity Assessment
In order to assess the severity of the disease, many scales have been developed. These include The Jankovic Rating Scale (JRC), The Blepharospasm Severity Scale (BSS), The Blepharospasm Disability Scale (BDS), and The Blepharospasm Disability Index (BDI).[rx]
The most widely used scale is the Jankovic Rating Scale. This is commonly used during the initial assessment and to monitor treatment response during patient follow up. This scale assesses severity and frequency separately, giving a score of 0 to 4 for each one of these, as shown in Table 1.[rx]
There also exist scales for severity grading of focal dystonia not specific for blepharospasm, but that are commonly used by some physicians when assessing patients with BEB. These include The Global Dystonia Rating Scale, The Burke-Fahn-Marsden Dystonia Rating Scale, and The Unified Dystonia Rating Scale.[rx] Direct comparison of these grading scales has not been performed, and which one to use is determined by physician preference.
Neurophysiology
Electromyography
Dystonia presents with the contraction of antagonistic muscles. Electromyography studies can be used to identify such abnormalities. However, in practice, this is not always used.
Blink Reflex
Assessment of the blink reflex is useful in the evaluation of BEB. The tapping of the forehead (glabella reflex) may be done to induce reflexive blinking. By repeatedly tapping the forehead, it is possible to assess the patient’s ability to inhibit the glabella reflex. This is known as Myerson’s maneuver.[rx] Another way to induce reflexive blinking is the use of a startling stimulus such as visual or auditory stimuli.
In practice, the most frequently used method of inducing the blink reflex is electrical stimulation of the supraorbital nerve whilst performing an EMG on the orbicularis oculi muscle.[tx] As mentioned earlier, the trigemino-facial blink reflex consists of an early ipsilateral R1 component and a late bilateral R2 component. The R1 component is facilitated by the pons, whereas the R2 component is dependent on both the pons and the lateral medulla.
The blink reflex can be assessed by using the paired shock technique. Both of the supraorbital nerves are stimulated with an impulse of identical intensity.[rx] The first stimulus used induces a change in the excitability of the reflex circuits (conditioning), whereas the second stimulus (test), which is delivered at varying intervals (100 to 1000ms), is used as a probe stimulus. The size of the induced response is measured, and the test stimulus is compared to the conditioning stimulus. This is done for varying stimulus intervals. A normal patient will present with no R2 response during small intervals (100 to 200 ms), whereas patient suffering from blepharospasm may have an R2 response at small intervals (100 to 200ms).[rx]
This test does not have high specificity for dystonia, but can be used to rule out psychogenic dystonia which will present with normal features.
Treatment
Treatment of BEB consists of oral drug therapy, focal injections of botulinum toxin (four different brands are available in the USA), or surgery to remove eyelid muscle, used alone or in conjunction with the botulinum toxin injections.
Approximately one-third of affected individuals are treated with oral medications (drug therapy) specifically anticholinergic drugs and with dopamine depleters such as tetrabenazine. The results of these drug treatments are usually moderate or unsatisfactory and often temporary. Additional drugs that have been used to treat BEB include clonazepam, trihexyphenidyl, diazepam, and baclofen.
Photochromatic Modulation
It has been shown that patients suffering from blepharospasm are able to tolerate light intensities similar to those tolerated by patients without blepharospasm. However, when particular wavelengths were blocked out using lens tints, the patients suffering from blepharospasm were no longer able to tolerate similar light intensities. This implies that photophobia in blepharospasm is dependent on both light intensity and wavelength.
Multiple studies have shown symptomatic improvement in patients treated with photochromatic modulation.[rx] In particular, the FL-41 lens tint has been shown to reduce symptoms of photophobia in patients suffering from blepharospasm.[rx][rx]
Botulinum Toxin injections
Botulinum toxins:
There are seven serotypes of the botulinum toxin (A, B, C, D, E, F, G), but only serotypes A and B are available for use.[rx] In the United States, the only botulinum toxin products approved for use in blepharospasm are abobotulinumtoxinA, onabotulinumtoxinA, and incobotulinumtoxinA.[rx] Studies have shown that abobotulinumtoxinA may have a longer duration of action compared to incobotulinumtoxinA.[rx]
Botulinum toxin has been approved by the Food and Drug Administration (FDA) as a treatment for blepharospasm and has become the primary form of treatment. The technique of injecting small amounts of botulinum toxin into the orbicularis oculi weakens these muscles for approximately three months, after which time the procedure must be repeated. Botulinum toxin injections have been helpful for many individuals with blepharospasm, but some people do not respond well. Botox, distributed by Allergan, and Xeomin, distributed by Merz Pharmaceuticals, are type A botulinum toxin products that are FDA approved for the treatment of blepharospasm.
Mode of action:
Botulinum toxin injection is the standard treatment for patients with BEB. It exerts its effect by inhibiting acetylcholine release at the neuromuscular junction, which leads to decreased muscle contraction.[rx]
Technique:
Approximately 1.25-5 units of botulinum toxin are used per injection site.[rx] However, with repeated injections, increasingly larger doses may be needed due to the formation of antibodies against the botulinum toxin in a few patients, along with the worsening of the underlying condition. The injection sites that are typically used include the lateral lower and upper eyelid margins, the lateral canthi, and the medial upper eyelid.[rx] The toxin is typically injected into the procerus, corrugator, and orbicularis oculi muscles. The dose of botulinum toxin should not exceed more than 200 units (of onabotulinumtoxinA) within 30 days.[rx]
It usually takes 48 hours from injection to clinical response. However, the response to treatment is highly variable. Nevertheless, the reduction of abnormal movements is seen in all subjects. Treatment response and duration of the effect appear to be dose-related, and the latter may be as long as 170 days.[rx] On average, most patients become significantly symptomatic about 90 days after injection.
Botulinum toxin injections are recommended every three to four months. Some authors report a more intense effect seen with the first round of injections and decreasing efficacy with subsequent doses.[rx]
Potential reasons for a poor response to botulinum toxin injections include the development of antibodies against the botulinum toxin, poor injection technique, and the presence of apraxia of eyelid opening.[rx] Antibodies against the botulinum toxin are more likely to develop if there is a short interval between injections, with the use of ‘booster’ injections, increasingly larger doses over time, and an early onset of botulinum toxin injection therapy.[rx]
Oral Pharmacotherapy
Oral pharmacotherapy for BEB has failed to show persistent relief from symptoms and tends to vary in effectiveness between patients.[rx]
This includes medications such as benzodiazepines, anticholinergics (benztropine and trihexyphenidyl), levodopa, baclofen, VMAT2 inhibitors (tetrabenazine), lithium, valproate, methylphenidate, zolpidem amongst others. All of these have a limited role, but might be considered for refractory disease, before taking patients to the operating room for a more invasive strategy and as an adjunct to botulinum toxin injections. Oral pharmacotherapy is also associated with potentially undesirable side effects, which are not associated with botulinum toxin injection along with the potential risk of developing dependence of benzodiazepines.[rx][rx][rx]
Surgical Management
Surgical intervention is indicated in patients who fail to show a response to medical therapy and have persisting symptoms. Surgical management is performed with the intent to improve functionality and reduce the frequency of spasms.
In patients in whom the disease is refractory to standard measures, neurectomies, myomectomies, and deep brain stimulation (DBS) represent appropriate treatment alternatives. About half of patients treated with myomectomies or neurectomies will require botulinum toxin injection five years after surgery, but at lower doses, than previously needed. Evidence supporting the use of DBS for BEB is not robust and should be considered as a last resort.
Surgical myectomy:
Surgical myectomy consists of the resection of the protractor muscles (corrugator supercili, orbicularis oculi, procerus, and depressor supercili). Gillum and Anderson described the surgical technique for full myectomy, which succeeds in controlling blepharospasm as there is an 88% improvement in patients with blepharospasm but may be associated with postoperative lymphedema, lagophthalmos, and facial anesthesia. Currently, modified and partial myectomy is the preferred technique. This is performed in addition to correcting the effects of blepharospasm, which include brow ptosis, ptosis, dermatochalasis, and lateral canthal dystopia.[rx][rx][rx]
In the past, a procedure known as a neurectomy was performed to treat individuals with BEB. However, the complication rate is much higher than with a myectomy and this procedure is rarely used anymore. In a neurectomy, sections are taken off the branches of the facial nerve leading to the orbicularis oculi. Paralysis of the entire upper face may result, but the nerve branches tend to regenerate after months or years.
References
