DOUBLE-BLIND, PLACEBO-CONTROLLED, PILOT TRIAL OF BOTULINUM TOXIN A IN RESTLESS LEGS SYNDROME

The hallmarks of restless legs syndrome (RLS) are a desire to move the limbs due to sensory discomfort, motor restlessness, and worsening of symptoms during rest or at night.¹ Sensory symptoms cause the greatest discomfort,² and are commonly localized to muscle.

Sensory and motor symptoms can be improved with dopaminergic medications, some anticonvulsants, opioids, and to a lesser extent with GABA-active hypnotics. Botulinum toxin has been suggested as a potential therapy for refractory RLS, based on its ability to reduce peripheral and central sensitization to pain.³ In an unblinded observational study by Rotenberg and colleagues, IM injections of 70–320 mouse units (mU) of botulinum toxin type A (BTX-A; Botox, Irvine, CA) were injected into the legs of three patients with RLS and demonstrated symptom improvement, reduced medication use, and a reduction in daytime sleepiness.⁴ Based on these findings, we conducted a randomized, placebo-controlled, double-blind, crossover study.

Methods.

Patients.

We enrolled six patients from June to July 2007 who were age 18 or older, had a diagnosis of primary RLS based on International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria,¹ had a minimum score of 11 (at least moderate severity) on the IRLSSG rating scale (IRLS),⁵ and were stable on medications for greater than 6 weeks prior to enrollment. Patients were excluded for an abnormal neurologic examination, abnormal laboratory test results, a dermatologic disorder precluding leg injections, pregnancy/lactation, incapacity for informed consent, taking medications which could interact with BTX-A, or on anticoagulants. This study was approved by the National Institute of Neurological Disorders and Stroke Institutional Review Board and all patients provided written informed consent.

Study design.

Patient assessment included a medical history, neurologic examination, and baseline ratings. Eligible patients were evaluated by a second investigator who documented symptom location. A standard set of muscles were selected as potential targets: quadriceps femoris (QF), tibialis anterior (TA), gastrocnemius (GCS), and soleus (SOL). Injections were conducted under needle-EMG guidance.

After baseline ratings, patients were randomized to receive BTX-A or saline. Each 100 mU vial was reconstituted with 2 mL of preservative-free normal saline (5 mU/0.1 mL). The maximum dose was 90 mU per leg, distributed in the following sites (number of injections): QF-40mU (4); TA-20mU (2); GCS-20mU (2); SOL-10mU (1). At week 12, patients received the alternate compound with continued monitoring.

We used the IRLS and the Clinical Global Improvement scale (CGI) to assess efficacy. To monitor adverse effects (AE), patients were asked to rate from 0 (no symptoms) to 10 (severe symptoms) the presence of weakness, pain, swelling, and redness based on the preceding 2 weeks. Ratings were completed at baseline (weeks 0 and 12), and 2 and 4 weeks postinjections.

The primary outcome measure was mean change in IRLS from baseline at 4 weeks postinjection. Secondary outcomes included mean IRLS change from baseline at 2 weeks postinjection, mean CGI scores at weeks 2 and 4, and reported AEs. We performed a power analysis using standard treatment and placebo response rates reported for pramipexole.⁶ We estimated a mean difference from baseline between placebo and BTX-A of 10 points ± 3 (SD) on the IRLS. We therefore required a sample size of 3 patients per group (power = 0.80, α = 0.05).

Results.

Seven patients were screened, with one excluded due to leukocytosis on laboratory testing. All remaining patients completed the study. Five patients were on stable doses of a dopamine agonist, and one patient was on a stable dose of clonazepam. No patient had received prior BTX treatment. Group demographics were as follows: 57.7 ± 8.8 years of age, equal male-female ratio, 33.5 ± 14.4 years disease duration, and an IRLS score of 27 ± 4.8. All patients received the maximum BTX dose of 90 mU/leg with the exception of one patient who had no symptoms in the proximal legs and did not receive injections into his QF. At week 2, placebo-treated patients noted a 5.0 ± 5.1 point improvement on the IRLS vs a 1.0 ± 3.5 point improvement in the BTX-arm (p = 0.06). At week 4, placebo-treated patients maintained only a 2.7 ± 5.9 point improvement from baseline, whereas BTX-treated patients showed a 5.0 ± 6.0 point improvement (p = 0.24). The CGI showed similar findings for the BTX-arm with scores of 4.3 ± 0.8 at week 2 (p = 0.01) and 3.7 ± 1.4 at week 4 (p = 0.74), compared to placebo-arm scores of 2.8 ± 1.2 at week 2 and 3.8 ± 1.7 at week 4. We compared baseline scores at week 0 and week 12 to assess for any carryover effect in the BTX-arm and found no differences (p = 0.55). Reported AEs were similar between groups, with mean placebo AE scores of 1.5 ± 2.5 at baseline, 3.2 ± 5.4 at week 2, and 5 ± 7.4 at week 4, while BTX-A scores were 1.8 ± 3.3 at baseline, 6.3 ± 7.1 at week 2, and 4.5 ± 5.6 at week 4. Two patients reported mild weakness following both placebo and BTX-A injections.

Discussion.

This study showed no significant improvement in IRLS and CGI at week 4 for BTX-A. A statistically significant benefit was noted on the CGI secondary endpoint for the placebo group at week 2. AEs were similar between the groups. Any future studies should be powered to account for the significant placebo response while exploring higher doses without unmasking controls.

ACKNOWLEDGMENT

The authors thank Elaine Considine for her tireless efforts.

Sponsored by the Division of Intramural Research, National Institute of Neurological Disorders and Stroke.

Disclosures: Botulinum toxin was provided by the NIH Clinical Center pharmacy with no outside funding support. Dr. Hallett has received personal compensation for activities with Neurotoxin Institute, John Templeton Foundation, Cambridge University Press, Springer Verlag, Taylor & Francis Group, Oxford University Press, John Wiley & Sons, and Elsevier as an advisory board member, an editor, or a writer. Dr. Hallett has received license fee payments from the National Institutes of Health for the H-coil, a type of coil for magnetic stimulation. Dr. Hallett holds stock in Agilent Technologies, Amgen, Amylin Pharmaceuticals, Merck & Co., Monsanto Co New Del, Sanofi Aventis Adr., Coventry Health Care Inc., Sigma Aldrich Corp., Warner Chilcott Ltd., Pfizer Inc, Genentech, Inc., United Health Group, St. Jude Medical, and Eli Lilly & Company.

Received January 17, 2008. Accepted in final form May 1, 2008.

Address correspondence and reprint requests to Dr. Fatta B. Nahab, Assistant Clinical Investigator, Human Motor Control Section, NINDS/NIH, 10 Center Drive, Bldg 10, Room 5N226, Bethesda, MD 20892-1428; nahabf@ninds.nih.gov