Preface

The clinical use of botulinum neurotoxin comes into its third decade of existence with many new off-label indications for a host of different medical conditions. Originally used specifically for strabismus, blepharospasm and spasmodic torticollis, botulinum neurotoxin is now commonly employed in diverse disciplines by many specialists. Its unique properties requires local application for efficacy . . . and while this is relatively simple in some locations such as the skin and superficial muscles of the face, it is much more complicated in others, at times requiring ultrasound guidance or endoscopic assistance. Not all neurotoxins are the same and, therefore, an in-depth understanding of their pharmacological actions, limitations and complications is required.

This book tries to answer many of the questions posed above with the contributions from a team of international experts. As in the first edition, the emphasis in this book is on technique, so it is richly endowed with illustrations concerning accurate access techniques to help physicians to become familiar and fully competent.

The clinical development of botulinum neurotoxin began in the late 1960s with the search for an alternative to surgical realignment of strabismus. At that time, surgery of the extraocular muscles was the primary treatment for strabismus, but it was unsatisfactory for some patients because of the variability in results, consequent high reoperation rates and its invasive nature. In an attempt to find an alternative, Alan B. Scott, an ophthalmologist from the Smith–Kettlewell Eye Research Institute in San Francisco, investigated the effects of different compounds injected locally into the extraocular muscles to chemically weaken them. The drugs tested initially proved unreliable, short acting or necrotizing (Scott et al., 1973).

About this time, Scott became aware of Daniel Drachman, a renowned neuroscientist at Johns Hopkins University and his work, in which he had been injecting minute amounts of botulinum neurotoxin directly into the hind limbs of chickens to achieve local denervation (Drachman, 1964). Drachman introduced Scott to Edward Schantz (1908–2005), who was producing purified botulinum neurotoxins for experimental use and generously making them available to the academic community. Schantz himself credits Vernon Brooks with the idea that botulinum neurotoxin might be used for weakening muscle (Schantz, 1994). Brooks worked on the mechanism of action of botulinum toxin for his PhD under the mentorship of Arnold Burgen, who suggested the project to him (Brooks, 2001). Schantz had left the US Army Chemical Corps at Fort Detrick, Maryland, in 1972 to work at the Department of Microbiology and Toxicology, University of Wisconsin in Madison. Using acid precipitation purification techniques worked out at Fort Detrick by Lamanna and Duff, Schantz was able to make purified botulinum toxins.

Introduction

Focal hand dystonia (FHD) is characterized by dystonic hand contractions that are often aggravated by purposeful actions and may be specific to a particular task. For example, a patient may have dystonia when using the hand for writing but not for other tasks such as eating or typing. The term “occupational dystonia” is used when dystonia affecting performance of the job arises in individuals with a particular occupation, usually an occupation requiring repetitive and excessive fine motor activity. The occupations particularly prone to have focal task-specific dystonia are listed in Table 10.1. Most of these hand dystonias fall under the rubric of primary focal dystonias.

This chapter discusses writer’s cramp and musician’s dystonia (cramp) in detail, the two most common occupational dystonias, followed by a discussion of other focal occupational dystonias.

Pathogenesis

The exact cause of FHD is not yet elucidated. A consistent physiological finding is excessive activation of antagonists and overflow and prolongation of muscle activation. Both of these are thought to reflect deficiency of inhibition at multiple levels of the motor system circuitry (Hallett, 2000, 2006a,b). Dopamine dysfunction has also been implicated. Although FHD is a movement disorder, somatosensory dysfunction is also present, including distorted sensory maps of the affected hand (Bara-Jimenez et al., 1998) and impaired sensory discrimination (Sanger et al., 2001). Structural MRI analyses have shown increased gray matter volume in the basal ganglia of musicians (Granert et al., 2011) and writers (Garraux et al., 2004) with FHD. Functional MRI has shown impaired activation of the primary sensorimotor and supplementary motor cortex during voluntary muscle relaxation and contraction (Oga et al., 2002). A genetic factor in the development of hand dystonia is possible, as up to 20% of patients with writer’s cramp have family members with dystonia.

Introduction

Botulinum neurotoxins (BoNTs) are proteins derived from the bacterium Clostridium botulinum that have been formulated as drug products for clinical use. These biologics are typically injected into muscles where they act locally to inhibit the release of acetylcholine at the neuromuscular junction. Botulinum neurotoxins can also act on cholinergic autonomic terminals following injection into smooth muscle, where they inhibit contractions, or nearby glands, where they inhibit glandular secretions. Additionally, they can inhibit release of inflammatory peptides at pain endings.

Synthesis and structure

C. botulinum produces BoNTs as protein complexes that contain non-toxin hemagglutinin and non-hemagglutinin proteins in addition to the neurotoxin itself. The type and number of non-toxin proteins are determined by the strain of the bacteria, and these proteins form complexes with the neurotoxin that range in molecular weight from approximately 300 kDa to approximately 900 kDa (Sakaguchi et al., 1984). Seven different BoNTs serotypes are produced by different clostridial strains, A, B, C1, D, E, F and G. Only types A and B are commercially available; types C and F have been tried in humans on an experimental basis only.