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AAN Issues New Guideline for Botulinum Neurotoxin for Blepharospasm, Cervical Dystonia, Adult Spasticity, and Headache

ARTICLE IN BRIEF

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The lead author of the AAN practice guideline update on botulinum neurotoxin discusses the findings on the therapy for blepharospasm, cervical dystonia, adult spasticity, and headache.

In an update of its 2008 guideline on botulinum toxin, the AAN Guideline Development Subcommittee has released a new practice guideline regarding the therapy's use for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache.

The new guideline, which was published in the April 18 online issue of Neurology, offers several major changes in treatment guidance.

Neurology Today spoke about the new guideline with lead author David M. Simpson, MD, FAAN, professor of neurology at the Icahn School of Medicine at Mount Sinai.

WHY WAS IT DETERMINED THAT NOW WAS THE RIGHT TIME TO RE-ASSESS THESE GUIDELINES?

We published the last set of guidelines concerning botulinum toxin for a wide range of neurological disorders back in 2008. That was a multi-year project. Over the subsequent years, there has been a fair number of newer studies that appeared in some of the indications that we had covered in 2008. Importantly, some of the newer studies resulted in changes in conclusions and recommendations concerning some of the indications that we covered in 2008.

Additionally, we took a different strategy in the current guideline than we had done before. In 2008, we considered all of the formulations of botulinum toxins as a group, and discussed botulinum toxins generically. We incorporated the data from all four of the toxins available in the US, resulting in unified set of conclusions and recommendations. In this current guideline update, we have separated the individual formulations and reviewed the evidence for each toxin formulation independently.

[For the specific recommendation based on the evidence, see the sidebar, “Evidence-Based Recommendations for Efficacy for Botulinum Neurotoxin Indications.”]

COULD YOU DESCRIBE THE FOUR FOOD AND DRUG ADMINISTRATION-APPROVED PREPARATIONS OF BOTULINUM TOXIN, AND WHY DIFFERENT PREPARATIONS HAVE DIFFERENT EFFECTIVENESS, DEPENDING ON THE ILLNESS?

There are two serotypes of botulinum toxin that are used for human therapeutics in the US, type A and the type B. In the commercial market in the US, there are four marketed forms of botulinum toxin: three for type A and one for type B. Each of those toxins has different properties in terms of how they are manufactured, potencies, and dilution characteristics. The data concerning their efficacy and safety differs among these formulations. Therefore, we determined that it was important to review each drug independently for each of the indications. Furthermore, the Food and Drug Administration (FDA) label for these drugs states that these are not interchangeable and data on efficacy and safety as well as unit potency cannot be extrapolated from one formulation to another.

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EFFECT OF BOTULINUM NEUROTOXINS ON NEUROMUSCULAR TRANSMISSION: Botulinum neurotoxin binds to protein and sialoganglioside receptors on the presynaptic neuron membrane resulting in endocytosis of the toxin. After endocytosis, the translocation domain changes conformation, resulting in release of the catalytic domain into the cytosol. Depending on the toxin serotype, the catalytic domain cleaves one or more members of the soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) protein family. SNARE cleavage prevents formation of the SNARE complex and fusion of the vesicle with the membrane. As a result, acetylcholine is not released.

WHAT ARE SOME OF THE MAJOR CHANGES?

One of the major changes is our review of each botulinum toxin. In addition, we have updated data for the indications that we covered.

For example, in 2008, not enough evidence was available to make any recommendation on the use of botulinum toxin for chronic migraine. Since then, there have been randomized, double-blind, placebo-controlled studies that have examined onabotulinum toxin A, also known as Botox, in the treatment of chronic migraine. The results showed a reduction in headache days in the group treated with onabotulinum toxin A compared with those receiving placebo.

It's important to note that the magnitude of this change is small. In the four weeks after the first treatment, patients who took onabotulinum toxin A had about 15 percent fewer headache days compared with those receiving placebo. However, that was statistically significant and resulted in a change in our conclusions and recommendations concerning the use of onabotulinum toxin A in chronic migraine. In addition, these studies resulted in FDA approval of onabotulinum toxin A in the treatment of chronic migraine.

WHAT CHANGES DO YOU CONSIDER MOST SIGNIFICANT IN TERMS OF CLINICIAL AND PATIENT OPTIONS?

Numerous studies of different formulations of botulinum toxins for adult spasticity have resulted in an upgrading of our recommendations for the individual toxins.

Randomized double-blind, placebo-controlled studies — so called class 1 studies — have been performed for several of the formulations. Three formulations have upgraded recommendations, including onabotulinum toxin A, incobotulinum toxin A, also known as Xeomin, and abobotulinum toxin A, or Dysport. These three formulations are now concluded to be effective in reducing excess muscle tone. We recommend that they should be offered in the treatment of upper limb spasticity. In lower limb spasticity, we concluded that two formulations — abobotulinum toxin A and onabotulinum toxin A — are effective, based on multiple class 1 studies, and should be offered for treatment.

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DR. DAVID M. SIMPSON: “In the current environment of insurers frequent denials for many treatments, having a solid evidence-base to support ones use of botulinum toxin is an important consequence of having high-quality data.”

THE REVIEW FOUND THAT ALTHOUGH BOTULINUM TOXIN CAN REDUCE TONE IN ADULT SPASTICITY, THE IMPACT OF THESE INJECTIONS ON FUNCTION IS MIXED, SUGGESTING THAT POTENTIAL FUNCTIONAL GAINS ARE HIGHLY PATIENT-SPECIFIC. CAN YOU OFFER ANY TIPS TO CLINICIANS ON HOW TO CHOOSE A TREATMENT IN THESE DIFFICULT CASES?

I would begin by saying that botulinum toxin treatment is based in science, but also requires considerable art. One should begin with a firm knowledge of the literature and the evidence-base for the use of botulinum toxin. It is equally important for injecting clinicians to master this art and develop the requisite skills in order to optimize patient response. One can only go so far using the literature to guide treatment of an individual patient. Patient-specific issues include goal-setting, which varies dramatically from patient to patient. Technical issues include what muscles to inject, dosage per muscle and total body, potency, dilution, and number of injection sites. One must master techniques to target muscles accurately — such as EMG, electrical stimulation, ultrasound, or the combination of them all. Much of this skill comes from experience and training with appropriate mentorship.

WHY ARE THERE FEW COMPARATIVE TRIALS OF BOTULINUM TOXIN FORMULATIONS FOR ADULT SPASTICITY?

There are several reasons why such studies are not generally done, including the fact that such trials are often considered “high-risk” by the pharmaceutical industry, since the likelihood of demonstrating of comparative superiority is small. In the absence of such head-to-head studies, clinicians are often relegated to compare data across trials, although this is not a rigorous or scientifically appropriate way to compare drugs, given the many differences between trials.

THE GUIDELINE POINTS OUT THAT THERE ARE GAPS IN THE EVIDENCE FOR THE EFFICACY OF TWO FORMULATIONS FOR ADULT LOWER LIMB SPASTICITY. WHAT CHALLENGES ARE THERE IN ADDRESSING THE GAPS?

Botulinum toxin drug, which was initially developed by Dr. Alan Scott for strabismus in children, has now been shown to be safe and effective in a remarkably large range of indications and has penetrated many fields of medicine. I don't think that anyone could have ever predicted that botulinum toxin would have reached such a dizzying array of indications over this period of time.

On the other hand, there are major gaps in our knowledge concerning botulinum toxin. One would hope that these gaps will be filled as the years go on. However, these studies are difficult, require meticulous study methodology to answer difficult questions, and require large resources, both in money and personnel, to perform them. However, I believe that there is a bright future ahead for research in botulinum toxin.

OVERALL, HOW WOULD YOU RATE THE QUALITY OF THE RESEARCH ON THE EFFICACY OF BOTULINUM TOXIN TREATMENT IN THESE DISORDERS SINCE THE LAST GUIDELINE WAS PUBLISHED?

We can discuss a longer time frame than eight years and go back for, perhaps, 25 or more years, since the early trials of botulinum toxin. If one examines the early days of this clinical research, for example, in blepharospasm or hemifacial spasm, these trials were generally very small, and not done with the rigor of those trials in recent years. Thus our recommendations for the use of botulinum toxin in these disorders are relatively weak.

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EVIDENCE-BASED RECOMMENDATIONS FOR EFFICACY FOR BOTULINUM NEUROTOXIN INDICATIONS

It is reassuring that we now have many more high-quality studies for numerous indications. I think that most stakeholders now realize that expectations are higher now for generating these more rigorous trials, particularly if one of the aims is to receive FDA approval, for which a very high level of rigor is required. Another pragmatic issue relates to reimbursement. In the current environment of insurers' frequent denials for many treatments, having a solid evidence-base to support one's use of botulinum toxin is an important consequence of having high-quality data.

HOW DO YOU THINK THIS UPDATE WILL HAVE AN IMPACT ON THE CARE AND QUALITY OF LIFE OF PATIENTS WITH THESE ILLNESSES?

For those who would like to access an up-to-date, state-of-the-art review of the evidence base for the use of botulinum toxin in these selected indications, with the criteria for classification explicitly presented, we hope that this publication will be of considerable utility. This audience includes clinicians, researchers, patients, caregivers, as well as other stakeholders such as the FDA, and payers. In order to reach these diverse audiences, we have prepared this material in several different formats. Finally, I hope that our delineation of the considerable knowledge gaps will be a spur to further research.

LINK UP FOR MORE INFORMATION:

•. Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache. Report of the Guideline Development Subcommittee of the American Academy of Neurology http://www.neurology.org/content/early/2016/04/15/WNL.0000000000002560.short. Neurology 2016; Epub 2016 April 18.
    •. Simpson M, Gracies JM, Graham HK, et al.for the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology http://www.ncbi.nlm.nih.gov/pubmed/18458229. Neurology 2008; 70:1691–1698.
      •. Simpson M, Blitzer A, Brashear A, et al.for the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology http://www.ncbi.nlm.nih.gov/pubmed/18458230. Neurology 2008; 70:1699–1706.
        •. Naumann M, So Y, Argoff CE, et al.for the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum toxin in the treatment of autonomic disorders and pain (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology http://www.ncbi.nlm.nih.gov/pubmed/18458231. Neurology 2008; 70:1707–1714.