Battling Blepharospasm: Addressing Treatment Challenges

Introduction
Benign essential blepharospasm (BEB) is an uncommon, but disabling movement disorder of the eyelids for which diagnosis is commonly either missed or delayed by 4 to 10 years.[1] An estimated 20,000 to 50,000 people in the United States are affected by BEB, with symptoms ranging from dry eye and increased blink rate to near functional blindness due to an inability to open their eyes. The range of possible symptoms can obfuscate the appropriate diagnosis. However, without a correct diagnosis, these patients can remain markedly impaired. Although formerly considered a manifestation of psychiatric disorders, BEB was classified as a focal dystonia in the late 1970s.[2] Nonetheless, it can still be misdiagnosed as a psychiatric disorder today.[3] Ophthalmologists, neurologists, as well as psychiatrists may be the first health care providers sought out by patients with BEB.[1]

BEB Is a Primary Dystonia

BEB is a primary dystonia that involves spasmodic contraction of the orbicularis oculi muscles.[1] Primary dystonias are movement disorders that are classified as having no identifiable exogenous cause as well as no association with another inherited or degenerative disease.[4] However, heredity may play a role in BEB; a genetic predisposition was found in almost 10% of cases in one of the first large studies of 264 patients.[5] Clinical features of BEB include a mean age of onset of 55.7 years and a female preponderance (2-3:1 ratio).[2,6] Although muscle contractions may begin in one eye at the onset, the second eye always becomes involved (Figure 1).[7] The eye contractions in BEB are seldom isolated and are often accompanied (in more than 50% of patients) by dystonic movements of adjacent muscles.[2] These are often subtle and not reported by

the patient. Oromandibular dystonia consists of involuntary contractures of the muscles around the mouth and, when present with BEB, is known as cranial dystonia.[6] Figure 1: Patient With BEB[6]

Patients with BEB can appear as if they are squeezing their eyes shut.

Diagnosis of BEB
BEB is considered an adult-onset focal dystonia and the etiology is unknown.[2,8] Subjective dry eye and photophobia are two common complaints of patients with BEB. [9] Early symptoms of BEB can include:

Increased blink rate Eyelid spasms Eye irritation (described as a "gritty" feeling) Photophobia Midfacial or lower facial spasm Brow spasm

These nonspecific symptoms necessitate that ophthalmologists and neurologists should be aware of BEB to be able to make an accurate and timely diagnosis. BEB is a diagnosis of exclusion, so awareness, careful clinical assessment, and patient history are important for ruling out other causes.[10,11] The clinical assessment should include observation of the eyelid position in different gaze directions and the blink rate. [12] The presence of blepharoclonus (rhythmic contractions within the lids) when the lids are gently closed, the latency and speed of voluntary eye movements on command, as well as the presence of additional spasms in other regions of the face should also be evaluated. Also, a diagnosis of BEB can be supported if the patient displays a tactile or proprioceptive sensory trick, such as talking, singing or humming, yawning, or pulling on an eyelid (also known as geste antagoniste), that alleviates the dystonic movements.
[7]

Other pathologies that can produce involuntary blinking or eyelid closing and need to be excluded include Bell's palsy, allergic conjunctivitis, dacryocystitis, eyelid myokymia (twitching of muscle fibers), and nongranulomatous anterior uveitis.[9] Tardive dystonia, which is a secondary dystonia that can occasionally mimic signs and symptoms of BEB and results from exposure to drugs that block dopamine receptors, is ruled out during the patient history.[7] Other causes of secondary blepharospasm are brain injury, lesions, or neurodegenerative disorders such as multiple sclerosis, parkinsonian conditions,

Wilson's disease, or Tourette syndrome. Treatment for the blepharospasm symptoms resulting from these conditions may be different than treatment for BEB. Apraxia of eyelid opening (failure of levator muscle contraction) can be a separate condition or can coexist with BEB to cause involuntary closure of the eyelids.[13] It is important to determine if there is an apraxia component because this condition does not respond as well to botulinum toxin injections, which are a key treatment option for BEB. Except for a careful patient evaluation and history, there are no other diagnostic tests necessary or useful for BEB.[7,14] However, neuroimaging is helpful in the evaluation of patients suspected of having secondary blepharospasm associated with stroke, multiple sclerosis, or other neurologic etiologies.[2,15] Receptor-binding functional imaging studies, including positron emission tomography and magnetic resonance imaging (MRI) techniques, as well as functional MRI and voxel-based morphometry, have demonstrated subtle differences between BEB patients and controls in hyperactivity and grey matter density in several regions of the brain. However, these techniques have only been explored in a research setting and do not consistently differentiate BEB.

Therapeutic Options for BEB

Patient education is an important part of the necessary comprehensive therapeutic approach to BEB.[10] The therapeutic approach that is likely to succeed for each patient will depend on the patient's understanding of how the therapy works and the options available. The BEB Research Foundation disseminates knowledge, promotes awareness, organizes support groups, obtains funding for research and education, and is an excellent source of information for patients. Goals of any therapeutic regimen for BEB are improved quality of life and alleviation of symptoms. These goals are accomplished only by optimizing the response for each individual patient.[16] For all patients, the first line of treatment should include conservative measures that can address their symptoms associated with ocular hypersensitivity.[10] These measures include wearing tinted sunglasses with ultraviolet blocking and artificial tear application. A rose-tinted lens called FL-41 has demonstrated success when used in BEB patients' sunglasses.[13] Botulinum Neurotoxin Treatment Botulinum neurotoxins (BoNTs) have been shown to be highly effective and welltolerated symptomatic treatments for focal dystonias including blepharospasm.[17,18] Blepharospasm was actually the first indication for BoNT type A and more than 90% of patients with BEB have reported significant improvement after BoNT injection. BoNT injection is now considered the treatment of choice for BEB.[17] Even though BoNTs have improved the treatment options for patients with BEB, treatment outcome is still dependent on the skill of the clinician in intramuscular injections, along with proper muscle selection and dosing.[17,19] Contraindications for BoNT injection include pregnancy and lactation; neuromuscular diseases; and use of certain medications including quinine, calcium channel blockers, penicillamine, or amino-glycoside antibiotics.[10]

Two different serotypes of botulinum toxins, BoNT-A and BoNT-B, are routinely used in clinical practice to treat patients with BEB.[17] AbobotulinumtoxinA (BoNTA1; Dysport), onabotulinumtoxinA (BoNTA3; Botox), and rimabotulinumtoxinB (BoNTB; Myobloc) are available as formulations of BoNT-protein complexes (Table 1).[20] Of these formulations, BoNTA3 is US Food and Drug Administration (FDA) approved for BEB. IncobotulinumtoxinA (BoNTA2; Xeomin) has just received approval by the FDA for BEB and is described as a BoNTA free from complexing proteins.[21,22] The formulations vary by commercial processing, dosage strength (expressed as units [U]), and size of protein complex.[23] Units of each BoNT correspond to the calculated median intraperitoneal lethal dose in mice, but units of biological activity cannot be compared nor converted between different BoNTs due to differences in manufacture and assay conditions.[20] Table 1: BoNT Formulations for BEB[1,10,17,24,25]

BoNTs act by a process called chemodenervation, which temporarily paralyzes the muscle by blocking the release of acetylcholine from nerve terminals.[20] After BoNT injection, it can take 3 to 5 days before the onset of effect is experienced, the maximal effect is expected at 1 to 4 weeks, and the duration of effect can range from 12 to 16 weeks.[7] BoNT Administration for BEB Treatment The administration of BoNT requires specialized skills and a detailed understanding of both the pharmacology of BoNT and structural and functional anatomy. The most important factors for ensuring treatment efficacy are selection of the appropriate dose and muscles and placement of the toxin.[17] For BEB, BoNTs are injected superficially (29- or 30-G needle at a flat angle) over the orbicularis oculi and also intramusculary in the corrugator or procerus muscle to act

locally around the eye (Figure 2).[1] A common injection pattern is 4 points distributed as 2 (medial and lateral) in the pretarsal portion of the upper lid, 1 near the lower lateral canthus (in the orbital orbicularis), and 1 in the procerus or corrugator muscle (near the tip of the eyebrow). However, injection locations can be individualized. Figure 2. Possible BoNT Injection Sites in the Orbicularis Oculi Muscles[26]

Best practice is to treat patients with the lowest effective dose and then adjust as needed for subsequent injections.[10,27] The typical starting dose for BEB therapy is BoNTA1 60 U per eye, BoNTA2 or BoNTA3 20 to 25 U per eye, or BoNTB 1250 U per eye.[1,10,24] Minimizing the dose and waiting at least 12 weeks for the next treatment reduces the chance for adverse events and immunogenicity (biological resistance).[17] Table 2: BoNT Dosing for BEB by Muscle[17,25]

Complications of Therapy With BoNTs BoNTs are usually very well-tolerated by patients.[28,29] The potential complications of treatment with BoNTs depend on the area of the body being treated. Patients treated for BEB may develop ptosis, double vision, and dry eye, usually secondary to reduced blink rate. Flu-like symptoms may be observed and are likely related to the protein complex used in the specific BoNT.[30] Nonetheless, the FDA issued a risk mitigation strategy for BoNTs in April 2009 mandating that patients should be warned of the potential adverse effects and receive an FDA-approved handout at every treatment session.[31] Some BEB patients are not adequately controlled with BoNT injections alone. Reasons for inadequate treatment with BoNT may include imprecisely targeted injections, associated apraxia, worsening of disease, or immunoresistance.[32] A test for BoNT effectiveness involves the patients being asked to squeeze their eyelids shut as forcefully as they can and then trying to force the eyelids open with their fingers at the same time. If the force of the "squeeze" has been adequately weakened, then the BoNT treatment is functioning, and there may be another reason for therapy failure.[33] Other BEB Treatments Other treatment options for BEB include a ptosis crutch, which is a set of semicircular wires that can be mounted on a pair of glasses to hold the upper eyelids open.[34] For some patients, biofeedback and other muscle relaxation and stress management techniques can be helpful, especially for those patients in whom stress exacerbates their symptoms.[7] Some patients obtain satisfactory relief with oral medications, such as trihexyphenidyl (an anticholinergic) or clonazepam (a benzodiazepine).[7] However, since oral medications are generally less effective than BoNT, it is usually reserved as a second line of treatment for spasms that respond poorly to BoNT.[10] There are no controlled trials of oral medications for blepharospasm. Patients who fail to obtain satisfactory control of their BEB with BoNT may be candidates for surgical treatment.[10,32] The mainstay of surgical treatment for BEB is eyelid protractor myectomy. Myectomy, combined with suspension of the frontalis, can successfully treat patients with apraxia; it may also be used to improve eyelid function in some patients concurrent with BoNT therapy. This procedure involves surgical

removal of portions of the orbicularis oculi muscle or the procerus and corrugator muscles. Aesthetic outcomes from the decreased tissue volume in the eye socket from myectomy can be improved with muscle grafts. Other therapies that have been shown to have benefit for BEB patients and are currently a focus of investigation are neuromodulation with low-frequency repetitive transcranial magnetic stimulation and deep-brain stimulation.[35-37]

Summary of Practice Pearls

BEB is a disabling movement disorder that remains underdiagnosed. BEB is a diagnosis of exclusion, so awareness of the disorder, careful clinical assessment, and patient history are important for ruling out other causes. Patient education resources and BoNT have significantly improved treatment options for BEB patients. BoNT dosages are not interchangeable. The formulations of BoNT currently approved for BEB include BoNTA2 (Xeomin) and BoNTA3 (Botox). Proper muscle selection and dosing of BoNT is critical for success and prevention of adverse events. Best treatment practice for BoNT is to treat with the lowest possible dose, wait at least 12 weeks, and then titrate upwards if necessary. Other treatment options, including oral drugs and surgical interventions, need to be evaluated for those patients who do not show or sustain improvement.