Medical Therapy for Blepharospasm
Stephen G. Reich, M.D.
Associate Professor, Department of Neurology
University of Maryland School of Medicine
Co-director, Maryland Parkinson's Disease and
Movement Disorder Center
2004

Prior to the introduction of botulinum toxin in the mid 1980s, oral medications were the mainstay of therapy for blepharospasm. With little knowledge of the cause(s) or changes assumed to be present in the brain responsible for blepharospasm, therapy was (and remains) largely empirical. That's a nice way of saying we put forward our best guesses and flew by the seat of our pants. As such, a diverse spectrum of medications was tried in succession hoping to hit on one, or a combination, that would strike a balance between reducing spasm and minimizing side effects. Next to those suffering from blepharospasm and their families, no one was more frustrated than we treating physicians. Medications alone generally do not provide acceptable treatment of blepharospasm. Yet, they do have a role and while many of my patients swear off medications, there are enough who swear by them, to encourage their use. What follows is my own approach for medical treatment of BEB. It is gleaned from a combination of the very few rigorous trials of medical therapy carried out for BEB, applying what we do know about the brain changes in blepharospasm, but mostly from flying by the seat of my pants trying to help people with BEB, ever mindful to do no harm.

The most effective and best-tolerated treatment for BEB and related disorders is botulinum toxin, and I encourage all of my patients to start with it. I reserve medical therapy for patients who have an inadequate response to the toxin. What is an inadequate response? You and not your physician determine this. Simply, it is determined by how much BEB is interfering with your life, and this includes your occupation, your home life, pursuing hobbies and other pleasurable activities, or your psychological state. If you have had what you consider to be an inadequate response to botulinum toxin then before going straight to medical therapy, it is essential to first determine why the response was inadequate, as the majority of people with BEB respond well. One of the most common reasons for "failure" of botulinum toxin is inexperience of the practitioner. Although injecting botulinum toxin is relatively straightforward, experience is everything, and if you have not had a good response, make sure you are seeing an experienced "injector." Other reasons for an inadequate response include atypical blepharospasm (such as eyelid opening apraxia), unrealistic expectations (it's not a cure) or the development of resistance, which is relatively uncommon. Once these factors have been considered, then it is reasonable to combine botulinum toxin with medication(s).

There are a variety of medications used for blepharospasm, but few have been subjected to rigorous clinical trials, and therefore treatment is mostly a matter of trial and error. Therapy must be individualized - what works for one patient causes intolerable side effects in another. And, just like botulinum toxin, medications are also not a cure. Instead, the goal is to achieve improvement, evidenced by blepharospasm taking less of a toll on your normal personal and occupational activities. Unless a patient can tell me a specific way in which they are functioning better, then it's unlikely a medication is helping. Not uncommonly though, as a seemingly unhelpful medication is being tapered off, you may notice worsening of blepharospasm, proving that the medication was helping more than originally appreciated and therefore worth continuing. In addition to monitoring closely for beneficial effects, it is equally important to watch for side effects. A discussion about common and uncommon side effects should always proceed starting a medication. But, you cannot expect your physician to go over every single potential side effect, so you need to be responsible for learning about the medications yourself. By taking such an active role in your treatment, the relationship with your physician becomes a partnership rather than a paternalistic one in which you play a passive role.

Aside from critically evaluating whether a medication is helping, and being familiar with side effects, there are additional pharmacologic principles to understand. First, drugs for BEB should be started at a low dose and escalated gradually to improve tolerance. Second, when a high dose of a drug cannot be tolerated, it may be helpful to use low doses of several drugs at once. Third, most drugs should not be stopped abruptly, but instead, withdrawn gradually. Fourth, the more drugs you take, the greater the chance for interactions. This is particularly true for certain drugs such as the blood thinner coumadin, drugs for the heart, and seizure medications. Discuss potential interactions with your physician and pharmacist. Lastly, many side effects diminish or go away with time, so do not jump the ship too quickly before a drug has had a chance to work.

One of the more commonly used medications for dystonia, including BEB, is trihexyphenidyl (Artane^®). This is an anti-cholinergic, meaning that it blocks the action of the neurotransmitter acetylcholine. A neurotransmitter is a chemical messenger that allows impulses (information) to travel between nerve cells. Other anticholinergics include benztropine (Cogentin^®), and the antihistamine, diphenhydramine (Benadryl^®). These drugs are best tolerated in young people with dystonia but can occasionally be tolerated in the older adult. To be effective, a fairly high dose is required and side effects often limit its use. These include constipation, dry mouth, difficulty urinating, trouble concentrating, memory loss and confusion. If you have glaucoma, check with your ophthalmologist before using an anticholinergic. The second class of drugs to consider are the benzodiazepines, of which diazepam (Valium^®) is the prototype. Others used for BEB include clonazepam (Klonopin^®, my preference in this group), lorazepam (Ativan^®), and alprazolam (Xanax^®). How they work for BEB isn't known, but in part they function as muscle relaxers. If started at a low dose and escalated gradually, side effects are minimized, and many of them, especially sleepiness, go away with time. Other potential side effects include difficulty thinking, fatigue, and imbalance. These drugs, especially Xanax, can cause dependency, but this has been very uncommon in my practice and fear of "getting hooked" should not preclude a cautious trial of a benzodiazepine.

The anti-spasticity agents baclofen (Lioresel^®) and tizanidine (Zanaflex^®) are another class of musclerelaxing drugs to consider for BEB. Like those mentioned above, they should be started at a low dose and escalated slowly. Although not an anti-spasticity agent, cyclobenzaprine (Flexaril^®) is also a muscle relaxant. Side effects of these agents are similar to the anticholinergics and benzodiazepines.

Prior to the introduction of botulinum toxin, BEB and other movement disorders were often treated with neuroleptics, sometimes referred to as antipsychotics referring to their primary use for serious psychiatric disorders. These include, among many others, haloperidol (Haldol^®), thioridazine (Mellaril^®), and trilafon/ amitriptyline (Triavil^®). The main chemical action of these drugs is to block the neurotransmitter dopamine. Although often effective for treating involuntary movements, their use is tempered by potentially serious side effects. This includes the ability to cause parkinsonism which reverses when the drug is stopped. More importantly, they can also cause new involuntary movements, including spasm of the face and limbs, known as tardive dyskinesia or tardive dystonia, and unlike neuroleptic-induced parkinsonism, these complications may be permanent. With rare exceptions, this class of medications should be avoided today. But, experience with neuroleptics demonstrated that dopamine plays a role in blepharospasm and other dystonias. A similar reducation in brain dopamine can be achieved with the drug tetrabenazine. Unlike the neuroleptics, which block dopamine, tetrabenazine prevents the release of dopamine from nerve cells and is much less likely to cause parkinsonism and only rarely causes involuntary movements. It is not available in the U.S. but can be obtained from Canada and other countries.

In light of the side effects of traditional neuroleptics, a new generation has emerged which, like tetrabenazine, are much better tolerated and less likely to cause movement disorders. These include risperdone (Risperdal^®), olanzapine (Zyprexa^®), quetiapine (Seroqel^®), and clozapine (Clozaril^®). There is relatively little experience using these agents for blepharospasm. I have had some success with risperdone and olanzapine. Clozaril can rarely lower the white blood cell count and therefore, very frequent monitoring is required. Additional side effects of the novel antipsychotics include, among others, sleepiness, insomnia, constipation, fatigue, and confusion.

The list of other potential agents used to treat blepharospasm is long and includes, among others, Parkinson's disease drugs such as carbidopa/levodopa (Sinemet^®), seizure medications, such as carbamazepine (Tegretol^®), and the blood pressure medication, propranolol (Inderal^®). In general, these are used infrequently since the introduction of botulinum toxin.

To sum up, if botulinum toxin has not provided enough relief for blepharospasm, it is worth considering adding an oral medication. Although in general they provide only modest relief, the response is variable and some people find them very helpful. It is a trial-and-error approach to hit on the appropriate drug or combination, all the while being vigilant about side effects. I am confident that research will eventually reveal the cause of blepharospasm, at which point we will no longer have to use guesswork and fly by the seat of our pants to choose drugs. Instead, we'll roll up our sleeves and design rational, effective therapies.