Why Do Patients Discontinue Botulinum Toxin for Dystonia?

The treatment can markedly improve function, but a waning effect between injections, adverse events, and unrealistic expectations may affect patient satisfaction.

Neurology Reviews. 2017 June;25(6):38-39

May 24, 2017|Neurology Reviews

[[{"attributes":{},"fields":{}}]] MIAMI—Botulinum toxin injection is the first-line treatment for most focal dystonias. The therapy improves function in many patients, but registry studies suggest that discontinuation is relatively common, said Cynthia L. Comella, MD, Professor of Neurology at Rush University Medical Center in Chicago. The fact that the treatment effect may wear off between injections, which typically are administered at least 12 weeks apart, and unrealistic patient expectations may contribute to patient dissatisfaction, Dr. Comella said at the First Pan American Parkinson’s Disease and Movement Disorders Congress.

A Potent Neurotoxin

The FDA first approved botulinum toxin in 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm. Early reports also described its use in cervical dystonia, spasmodic dysphonia, oral mandibular dystonia, focal hand dystonia, and focal leg and truncal dystonias.

Four preparations of botulinum toxin—three serotype A (ie, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and one serotype B (rimabotulinumtoxinB)—are available in the United States. A 2008 evidence-based review assessed the level of evidence for botulinum toxin in movement disorders, including blepharospasm (level B), hemifacial spasm (level C), cervical dystonia (level A), upper focal limb dystonia (level B), lower focal limb dystonia (level C), and adductor laryngeal dystonia (level B). An update in 2016 incorporated additional trials for cervical dystonia and blepharospasm, and the authors separated the level of evidence by toxin type for those indications. A paucity of class I trials limits the strength of the evidence for certain indications, but botulinum toxin still is the treatment of choice for those indications, Dr. Comella said.

Blepharospasm

Studies have found that as many as 90% of patients with blepharospasm improve with botulinum toxin treatment. As in other indications, however, the treatment effect may not be sustained between injections. A retrospective chart review of 41 patients with primary blepharospasm and 23 patients with secondary blepharospasm found that the patient-reported duration of treatment benefit was less than 10 weeks. Yet early studies of immunoresistance with botulinum toxin treatment led to a recommendation that injections be given 12 weeks apart. “Perhaps we are overdoing this 12-week rule,” Dr. Comella said. “In some patients, in order to maintain their functional capacity, we may want to consider injecting sooner.” Additional research is needed to determine optimal dosing intervals.

The development of neutralizing antibodies with current formulations of botulinum toxin appears to be rare, and the effects of neutralizing antibodies are not well understood, Dr. Comella said. Brin et al studied the immunogenicity of onabotulinumtoxinA in 326 patients with cervical dystonia who received a median of nine treatments over an average of 2.5 years. Four patients (1.2%) developed neutralizing antibodies, and one of the four patients who developed neutralizing antibodies continued to respond to treatment.

Cervical Dystonia Registries

CD PROBE, a registry study of patients who received onabotulinumtoxinA for cervical dystonia, enrolled 1,046 patients. Overall, 26.2% of patients experienced adverse events, most commonly mild to moderate muscle weakness and dysphagia. Over three injection series, 52% of the patients discontinued the study. The ANCHOR-CD registry study of abobotulinumtoxinA had a discontinuation rate of 36.6%. “If [botulinum toxin] is such an effective treatment in controlled clinical trials … why did these patients discontinue [therapy]?”

Dr. Comella and Kailash Bhatia, MD, DM, Professor of Clinical Neurology at University College London, conducted an international survey of self-identified patients with cervical dystonia to assess patients’ perceptions of their illness and its management. Of the more than 900 patients who were receiving botulinum toxin, 56% were fairly or very satisfied with the treatment, whereas 25% were fairly or very dissatisfied.

A survey by Sethi et al of 136 patients with cervical dystonia found that 51% were very satisfied and 43% were somewhat satisfied with botulinum toxin treatment, but 45% would prefer a treatment cycle of 10 weeks or fewer. “The benefits of the injection wore out before the next injection was permitted,” Dr. Comella said. “That gave them two to three weeks of not doing very well, which caused some dissatisfaction.”

Evidente et al studied the effect of flexible injection intervals in the two pivotal trials of incobotulinumtoxinA for blepharospasm and cervical dystonia. After an initial double-blind, placebo-controlled period, dosing intervals became flexible during a 68-week open-label extension. During that time, patients could request treatment after a six-week interval, and physicians would administer the treatment at that time if a patient’s dystonia was at a certain level of severity. Among patients with blepharospasm, 26.5% of treatments were administered at less than 10 weeks during the flexible dosing period. Among patients with cervical dystonia, 29.5% of treatments were administered at less than 10 weeks. Flexible dosing was well tolerated, and no additional safety concerns were observed when treatment was given sooner than 12 weeks after the last injection, compared with treatment given after 12 or more weeks.