Botox Reduces MS-Related Upper Limb Tremor

Pauline Anderson

July 06, 2012

July 6, 2012 — Injections of botulinum toxin type A reduce the severity of upper limb tremor in patients with multiple sclerosis (MS) and significantly improve functional tasks such as writing, drawing, and pouring, a new study has shown.

The results are "quite novel" as botulinum toxin (BT) has not previously been tested as a treatment for MS-related tremor, study author Anneke van der Walt, MBChB, consultant neurologist at The Royal Melbourne Hospital, and research fellow with the University of Melbourne, Australia, told Medscape Medical News.

Dr. Anneke van der Walt

"The importance of the study is that it allows for a new way to approach MS-related tremor and sets the stage for larger and more long-term studies."

Results are published in the July 3 issue of Neurology. The study was supported by institutional funding from Box Hill MS Research Fund and the Royal Melbourne Hospital Neuroscience Foundation.

Main Outcomes

The double-blind crossover study included 23 patients with secondary progressive or relapsing-remitting MS, each of whom was asked to perform certain movements and tasks such as writing and pouring water, so investigators could identify which muscles were most likely causing tremor. These muscles were then injected with saline placebo or 100 IUs of BT (Botox; Allergan Australia Inc.) at baseline, and the reverse at 3 months. Patients received between 3 and 6 injections per arm.

Participants were assessed 5 times, 6 weeks apart, over a period of 6 months. Main outcomes included improvement in Bain tremor ratings score (0 - 10, with 10 being most severe), writing a standardized sentence, and drawing an Archimedes spiral on a predrawn pattern with the dominant hand. Patients were also assessed while drinking from a cup with each hand and while pouring liquid.

Tremor components were assessed while patients were sitting using a 0 to 4-point scale, with 4 being most severe. Investigators assessed postural (occurring when the arm is held against gravity), kinetic (during any voluntary movement), and intention (during target-directed movements) tremor types, as well as dysmetria (inability to properly measure distances associated with muscular acts).

In addition, researchers assessed quality of life and performed subjective global assessments (eg, patients were asked to rate feeding, drinking, hygiene, dressing, and anxiety).

An independent neurologist observed videotaped tremor assessments made every 6 weeks.

Highly Significant

Results showed that compared with placebo, differences in all primary outcomes after BT at 6 and 12 weeks were highly significant — including median composite Bain score for tremor severity (P = .0005 at 6 weeks; P = .0001 at 12 weeks), writing (P = .0001 at 6 weeks; P = .0003 at 12 weeks), and drawing (P = .0006 at 6 weeks; P = .0002 at 12 weeks).

Pouring ability was improved at 6 but not 12 weeks, and drinking from a cup improved at 12 weeks.

"We observed an average of 30% improvement in patients' ability to write and draw at 6 weeks and 3 months after receiving [BT] compared to placebo," said Dr. van der Walt. "This meant that patients could perform better at work and be more functional at home. When activities of daily living were assessed by a neurologist who was unaware of what treatment the patients had received, there was improvement in patients' ability to feed themselves, drink, [and] attend to hygiene and dressing."

Dr. van der Walt noted that improvement was particularly apparent for postural and kinetic components of tremor. "Both of these tremor components are critical when performing any functional task."

"There was no significant improvement in quality of life, but this could be because it was too small to detect such changes," said Dr .van der Walt. "As well," she said, "the quality of life scale used in the study was designed to assess essential tremor and does not adequately assess patients with MS."

More patients developed weakness after BT (42.2%) than after placebo (6.1%; P = .0005), but for the most part, it was mild or moderate, was nonimpairing, and resolved within 2 weeks. Dr. van der Walt described a patient who reported having to use 2 hands instead of 1 when placing a full roasting tray into the oven, and another who had difficulty transferring into and out of her wheelchair for a few weeks. But she noted that despite the weakness, limb function overall was better after treatment.

Rather than paralyze muscles, as a larger BT dose does in a cosmetic procedure, researchers believe that the injection blocks the release of acetylcholine, thereby preventing stretching of the muscle and modifying the sensitivity of gamma motor neurons in the muscle (muscle spindles) to fire.

"This change in the muscle-nerve interaction then affects the way the brain interprets the signals and decreases the severity of the tremor," said Dr. van der Walt.

Other Muscles

"Although the study used a dose of 100 IUs of BT, a somewhat larger dose may be more effective for a tremor that involves muscles around the shoulder, and at the elbow and wrist," said Dr. van der Walt.

Although the study followed patients for only 6 months, BT treatments may last longer. "From our experience with this group, it appears that patients often only need injections every 4 to 6 months," she noted.

The study was too small to identify patterns of MS patient response to BT treatments. Dr. van der Walt commented, "A larger study is essential for identifying which particular patients will respond best to these injections."

Currently, no treatments are specifically targeted to tremor in MS patients, and none of the standard MS treatments are effective for this tremor. "In general, the benefits of medications such as propranolol or epilepsy treatments such as carbamazepine and topiramate, are 'marginal,' " Dr. van der Walt explained.

"Neurosurgical procedures such as implantation of electrodes in the brain that may be an option in severe cases are invasive, and although they can improve tremor, the benefit can be short-lived," she said.

The current study sets the framework for a larger and longer study of BT in MS patients that could establish this treatment as a first-line therapy. "Such future studies should also include patients with other types of MS such as the primary progressive form," suggested Dr. van der Walt.

Asked to comment on the study, Lily Jung Henson MD, medical director at the Neurology Clinic, Swedish Neuroscience Institute, Seattle, Washington, discussed that although it was small, the results are "exciting."

"They offer our MS patients an option which does not subject them to the side effects they might get from medications, and improves their function," she told Medscape Medical News.

The study was supported by institutional funding from Box Hill MS Research Fund and the Royal Melbourne Hospital Neuroscience Foundation Dr. van der Walt has received travel support from Bayer Australia and Sanofi-Aventis. She receives a scholarship from the National Health and Medical Research Council of Australia. She has received unrestricted grants from Bayer Australia and Biogen Idec. She was awarded postgraduate research grants from GlaxoSmithKline, Sanofi- Aventis, and Merck Serono. She is an investigator on a National Multiple Sclerosis Society (USA) Project Grant. For conflict of interest information on other authors, see original article.

Neurology. 2012;79:92-99. Abstract.


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