Battling Blepharospasm

8/3/2019 Battling Blepharospasm

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Battling Blepharospasm: Addressing TreatmentChallenges

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 canobfuscate 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 oculimuscles.[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 notrespond 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 BEBare 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 well-

tolerated 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 receivedapproval 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 maximaleffect 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 managementtechniques 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 transcranialmagnetic 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 least12 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.

Battling Blepharospasm

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