2005 Fall Meeting
Introduction by Dr. Jeffrey Hurwitz
Dr. Hurwitz began his introduction by explaining his role as an ocular plastic specialist and his role with both Mount Sinai Hospital and the University of Toronto. Ocular plastic surgery is a sub-specialty of Ophthalmology and encompasses the diseases of the eyelids and the area around the eye. It is within this specialty that blepharospasm patients, at sometime during the progression of their disease, present themselves.
He went on to say that the idea of using botulinum toxin or BOTOX® came from the fact that it was first tried for strabismus (crossed eyes) in children, where Dr. Stephen Kraft is one of the world's leading authorities, and, it was tentatively extended to the treatment of blepharospasm. Today BOTOX® is used regularly for both of these conditions.
There are a number of issues related to Benign Essential Blepharospasm (BEB) that are extremely important and non more so than awareness. It is important to get the message out and the Foundation is doing this but the message also has to come from all levels of the medical society: from general practitioners through to specialists. Many people with eye problems see opticians and optometrists and these people as well have to be made aware of the message and its need to be disseminated.
The ocular plastic programme at Mont Sinai has five specialists who are interested in eyelids and is very interactive with a similar programme at McMaster University under Dr. John Harvey, also a specialist in ocular plastic surgery.
The group at the University of Toronto has been very fortunate in having a Fellowship in Ophthalmology that is recognized by the American Society of Ophthalmic Plastic and Reconstructive Surgery. This Fellowship has been going on for many years and has evolved from a one-year to a two-year stint. During this period of time the Fellow has to get involved not only with clinical medicine but also with teaching and research.
Dr. Hurwitz went on to relate that the programme was very fortunate to have Dr. Noelene Pang, who came from and received her medical degree in California, and, who did a residency in ophthalmology at the renowned Mayo Clinic in Rochester, Minnesota. He proudly stated that the Fellowship programme is very fortunate to have such an accomplished young doctor for the next two years.
"With the support provided by the Foundation", concluded Dr. Hurwitz, "Dr. Pang has been able to embark on a project related to BEB". He assured all that Dr. Pang's presentation would outline the nature of the project and her progress to date.
Guest Speaker - Dr. Noelene Pang
Dr. Pang began by stating that her objective was to examine the question of tachyphylaxis; that is, does the benefit of botulinum toxin diminish the more doses a patient receives. In an effort to answer this question she began an extensive review of existing literature on this very topic. The review included not only BEB patients but also those with Hemifacial Spasms (HFS), Meige and other forms of facial dystonia. What she found was that, despite repeated injections of BOTOX®, there was no decline in the benefit received by the patients.
However, for a small percentage of patients studied there was a report of tachyphylaxis in patients receiving a higher and more frequent dosing. These patients appeared in studies where a patient had been receiving botulinum toxin injections for more than ten (10) years.
At a recent meeting in Chicago, the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) demonstrated that there was a loss of botulinum toxin effectiveness for Cosmetic Facial Application from circulating neutralizing antibodies to Type A botulinum neurotoxin after repeated injections. In his study Dr. Borodic found that there was some secondary resistance in patients receiving high doses of (BOTOX®) for cervical dystonia after 3 to 6 years of usage. Similarly, there were sporadic cases of secondary resistance among BEB and HFS patients.
One case study indicated that a forty-five year old woman showed decreased effectiveness after 14 injections over a period of 5 years. The 15th injection of botulinum toxin, Type A, to her forehead showed no improvement. A subsequent injection of 100 units proved to be no better and the ELISA test showed that she had developed antibodies to the toxin. She was introduced to 200 units of botulinum toxin, Type B (MYOBLOC®), which was equivalent to 20 units of Type A (BOTOX®), and, it was found to be effective. Unfortunately MYOBLOC® may also be rendered ineffective after multiple injections from neutralizing antibodies. The key would appear to be the avoidance of excessive and frequent injections.
A further study, in what may prove to be a better answer, looked at the "next generation"; of high-purity botulinum Type A neurotoxins and gauged their safety and efficacy results on human subjects for the first time. This study was presented by Dr. JA Khan et al, and its basic purpose was to test a botulinum toxin with a higher-purity protein so that it would have less of an effect in the human body. The study involved 40 subjects in parallel groups. In one group the dose was increased over a period of time and the other had partially randomized placebo controls. In each group there were about 8 patients that received the ultra-pure botulinum Type A toxin: five injections from 0 to 20 units at a time. The patients were followed for about 6 months and it was found that the effectiveness was dose-related: the more toxin used the more effective the benefit with increased adverse effects.
The conclusion of this study was that a highly purified version demonstrated an expected dose-response relationship, safety and efficacy. The theoretic benefit includes a lower anti-generic protein load resulting in:
- Less immuno-resistance
- More stable formulations (longer shelf life)
- Higher potency per nanogram (use less toxin)
- More precise targeting of effect with less diffusion, and
- Increased consumer choice and price competition (in Canada for those under 65 years of age).
The specific research undertaken by the Department of Ophthalmology at the University of Toronto and McMaster University is to compare the amount of force generated by the orbital muscles before and after pretarsal and preseptal botulinum Type A injections in blepharospasm patients. In other words, if one were to use less of a neurotoxin then there would be less of a sensitizing effect in the body and hence less resistance to the toxin.
As demonstrated by the diagram (Figure 1), the muscles around the eye are seen as three distinct sections; the very outer layer (a b c and d) are known as orbital muscle, the section immediately below that (e and f) is known as the preseptal muscle, and, finally, the section adjacent to the opening for the pupil (g and h) is known as the pretarsal muscle.
The majority of injections, as demonstrated by current practice, are in the orbital and preseptal muscles. It is thought that pretarsal injections, currently being done by some physicians, would be advantageous and would require a lower dosage,
The specific aim of the study is to compare the effect of injecting into the preseptal and pretarsal muscles of the BEB patients. This will be done in the following manner:
- measure the orbicularis oculi muscle-force generation before and after pretarsal and preseptal botulinum A toxin injections in the same patient,
- compare the duration of the effect as well as any adverse effects using the Jankovic rating scale and clinical exam, and,
- assess the patient’s preference for pretarsal versus preseptal injections via a questionnaire.
The main thrust behind the study, even though some retrospective studies have shown an improved efficacy with this methodology, is to ensure that it is truly random as far as patients were concerned which was not necessarily true with the past studies. Retrospective studies dealing with both BEB and HFS patients demonstrated an increased response rate: 80% for preseptal and up to 95% with pretarsal injections. A lower dosage was required and fewer adverse effects, such as ptosis (droopy eyelid) were observed.
One study, in Japan, demonstrated an increased efficacy in muscle-force generation by increasing the toxin dose. Because the measurement of dose-response was a good objective criterion, it was felt that the same measurement criteria could be used to compare the efficacy of different toxin injection sites.
The Japanese study chose the same injection sites for all of the patients participating in the study (Figure 2).
They used a measuring device (Figure 3), which consisted of two wires located between the eyelids and connected to a device, which recorded the measurement digitally.
The measurement is in grams of force with 50 grams being the baseline measurement (Figure 4) that is, with the eyelids open.
The lower measurement is taken with the eyelids closed; that is, measures the force of contraction. The same measure is taken after the administration of the toxin and the measurement of the contractions is substantially reduced. The same device would be used in the University study.
The University study would be a single-blinded prospective study. The examiner would not be informed as to the sites selected by the person giving the injections in order to eliminate any bias. The size of the study may involve 40 or more patients with the final number to be determined by a statistician in order to ensure that project qualifies as a true study. Each patient will serve as his or her own control and will receive a preseptal injection pattern on one side and a pretarsal injection pattern on the other side (Figure 5). These two sides will be compared.
In order to be eligible for the study the patient must be diagnosed to have BEB by the oculoplastic surgery service; that is, they must have bilateral, involuntary orbicularis oculi spasm, sometimes associated with spasm of other facial muscles (Meige Syndrome), in the absence of any ocular or periocular pathologic changes responsible for secondary blepharospasm such as dry-eyes. Also patients to be eligible must be currently treated with botulinum toxin and the patients must have a Jankovic rating scale of 6 or higher. The rating scale was developed by Dr. Jankovic to gage the frequency and severity of the blepharospasms. Dr. Jankovic developed two scales: one to determine the frequency of spasms, and, the second, the frequency of the spasms (Figure 6).
Patients with eyelid spasms due to ocular surface disease, which can be resolved with punctal occlusion (blocking of the tear ducts), or, the application of lubrication will be excluded. Also excluded would be patients who have undergone previous surgical treatment for their blepharospasm or hemifacial spasm. This exclusion is necessary in order to produce ‘pure’ results; that is, results that cannot be attributed to other causes.
The majority of patients will be recruited from oculoplastic practices affiliated with both the University of Toronto and McMaster University. Those who wish to participate will do so after their informed written consent is obtained. The Research Ethics Board Approval will be obtained prior to the commencement of the study.
Upon the patient’s initial visit he or she will be measured using the muscle-force generation device and the Jankovic rating scale in order to establish baseline data random pretarsal and preseptal injection patterns will be assigned to either side of the patient’s face. Measurement data will be taken by Dr. Pang, while other members of the Team will do the random injections. Although the pattern of injections will be different on both sides of the face, the dose to be used will be the same on both sides of the face and, it will be the current dose that the patient is receiving in order to ensure that the patient’s regular treatment is continued.
There will be a follow-up visit at 2 to 3 weeks after the initial treatment for data measurement using the muscle-force generation device and the Jankovic rating scale. As part of the visit the patient will be asked to state how long it took them to notice an effect and ask if there were any adverse effects such as eye irritation, blurry vision, etc. Further follow-up visits will occur in months 3, and 6 of the project. The same measurements will be made, a subjective assessment will be asked for as well as the search for adverse effects. In the sixth month or at the approximate time of their last visit each patient will be subjected to a questionnaire which will assist in determining the preference for one type of injection over the other.
Each patient taking part in the test will be seen in a clinical setting and each visit will last anywhere from 30 to 45 minutes. Patients at a minimum of eight times: more if the patient subjectively experiences functional disabilities from returning spasms. The time to complete all 40 plus test subjects will be approximately two years.
The data collected will be under pretarsal versus preseptal injection sites and consist of the eyelid-force generation and the Jankovic measurement before the initial injections, 1 to 2 weeks after the injections and at the specified third, sixth and nine month visits. The duration of the effect will be included along with the subjective analysis of the time to peak effect plus any adverse effects. A qualified statistician will perform the analysis of the data and the results will show the amount of force generated at 2 to 3 weeks after pretarsal and preseptal botulinum toxin injections of the same dosage.
In her review of the various studies Dr. Pang found a couple of patients who had pretarsal injections in the past and who had complained of more pain in the injection site compared with those further away from the lashes or in the preseptal area. Despite the pain they preferred the pretarsal injections because it gave them greater efficacy and a longer duration effect.
In anticipation of this question coming up in the study, Dr. Pang found a study done by Dr. Sami, et al in Houston, Texas, (Figure 7) which examined the efficacy of Botox injections after a local anaesthetic had been applied. Those in the cosmetic field principally use the practice of using a local anaesthetic prior to injections. In the study the examiners did not know what the patients were getting nor did the patients. One side of the face was subjected to a local anaesthetic while the other side was not. This was done for three treatment cycles and there was a crossover on each side of the face.
Bectacaine was applied to one side of the face while a placebo ointment was applied to the other. An ice-cold gauze was applied to the whole face to provide what was thought to be hopefully an analgesia or an equal decrease in pain so that the patient could not tell which side was which. Botulinum toxin was applied symmetrically to both sides of the face and interestingly the placebo treated side of the face produced better results in 90% of the time. The side treated with the Bectacaine had a deleterious effect on the toxin possibly due to a channel blockade of local motor neurons, or, the inhibition of nerve-stimulation-dependant internalization required to have the botulinum toxin function.
A possible future study may be to take a look at patients who have had botulinum toxin injections for 20 to 40 years and determine what the effects are with these long-term patients. The same questions, duration of treatment effect over time, tachyphylaxis, dosage strength and adverse effects, could be answered and contribute to the ongoing battle with BEB.
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- BOTOX® registered trademark of Allergan Corporation
- MYOBLOC®/NEUROBLOC® registered trademark of Solstice Neurosciences Inc.