Botulinum toxin was found to improve restless leg syndrome in the largest, well-controlled study of the investigational intervention to date.
Shivam Mittal, MD
Botulinum toxin was found to improve restless leg syndrome (RLS) in the largest, well-controlled study of the investigational intervention to date.
The lead author of the report, Shivam Mittal, MD, from the department of neurology at Yale University School of Medicine, in New Haven, Connecticut, described evidence of improvement in symptoms from the randomized, double-blind, placebo-controlled crossover study. The findings should supplant mixed results from 3 previous open-label studies and a single, smaller randomized double-blind pilot study, according to Mittal.
The data were presented at the International Congress of Parkinson’s Disease and Movement Disorders, in Hong Kong.
"The results of our current...trial are encouraging," Mittal told NeurologyLive. "This study showed that botulinum toxin injections at the applied dose can reduce the severity of symptoms in RLS up to 6 weeks. Moreover, the quality of life of the RLS patient can be improved for up to 6 weeks post-injection, and pain and discomfort diminished for 4 weeks."
The study was designed with principle investigator Bahman Jabbari, MD, also from the department of neurology at Yale University School of Medicine and conducted with colleagues from departments of neurology at Mayo Clinic, in Rochester, Minnesota; Hartford Healthcare Ayer Neuroscience Institute, in Harford, Connecticut; and the Columbia Asia Hospitals, in Bangalore, India.
The investigators theorize that botulinum toxin acts in the pathophysiology of RLS involving cortical sensory-motor integration. In addition to muscle relaxation, intramuscular injection of botulinum toxin reduces the discharge of muscle spindles that signal the length and tension of the muscle to the spinal cord. There is also evidence that intramuscular or intradermal botulinum toxin can reach the spinal cord from the site of injection via retrograde/anterograde transmission and directly influence spinal cord neurons.
Mittal explained that the agent could prove particularly useful when RLS is refractory to other agents. "RLS is the most common movement disorder, a sensorimotor neurological disease. About 45% of patients have no improvement or have worsening of symptoms with the conventional RLS medications,” he said.
Mittal and colleagues screened a total of 29 subjects, with 21 completing the study. At baseline, they had moderate (n = 1) severe (n = 13) or very severe (n = 7) symptoms on the International RLS (IRLS) rating. Their mean age was 61 years and 11 were female.
Subjects were randomized to receive an injection of either saline or 100 U Incobotulinumtoxin A (IncoA, Xeomin, Merz) into the tibialis anterior, gastrocnemius, and hamstring muscle each side. They were evaluated at 4, 6, and 8 weeks, and then crossed over to the other treatment condition. Each assessment included measures with the IRLS, the John Hopkins Quality of Life Questionnaire (QoL), the Medical Outcome Study (MOS), the Visual Analog Scale for pain (VAS), and the Epworth Sleepiness Scale (ESS).
Mittal reported that improvement from severe (IRLS >21) to either mild or moderate (IRLS ≤20) score was significant at 4 and 6 weeks, but not at 8 weeks following the IncoA administration compared to placebo. Additionally, there was a significant improvement in pain score by VAS at 6 weeks and on the quality of life measure at 6 weeks with active treatment. Definite or marked improvement in the patient global impression of change was seen at 4 weeks in 7 subjects receiving the active treatment compared to 1 in the placebo group. There were no significant differences between active treatment and placebo groups on the Epworth Sleepiness Scales.
Mittal and colleagues suggest that the lack of statistical significance at 8 weeks could reflect a dose-dependent effect and that a larger dose might have lengthened duration of response. They acknowledge that, although the study was the largest to date, it was still underpowered, and the trend toward improved quality of life at both 4 and 8 weeks might have reached statistical significance beyond 6 weeks with a larger cohort.
While expanded studies with a larger cohort are needed to confirm their results, Mittal anticipates that botulinum toxin will prove to be a useful intervention. "We could offer this to patients who have severe symptoms of RLS, not well-controlled with conventional medications," he told NeurologyLive.
Mittal S, Machado D, Richardson D, Dubey D, Jabbari D. Botulinum toxin in restless leg syndrome: a randomized double-blind placebo-controlled study. Presented at: 2018 International Congress of Parkinson's Disease and Movement Disorders; Hong Kong; October 7, 2018. mdsabstracts.org/abstract/botulinum-toxin-in-restless-leg-syndrome-a-randomized-double-blind-placebo-controlled-study.