The initial use of Botulinum Toxin at Denmark Hill and Queen Square by Prof Philip Thompson ( Adelaide, Australia)

In order to understand how Botulinum toxin therapies were introduced it is helpful to go back 30 years to the 1980s.

Several things happened at the time.

 

Prof David Marsden and its research group-Denmark Hill 1984

Prof David Marsden and fellows-Denmark Hill 1984

 

First was the appearance of specialist “Movement Disorder” clinics. At that time there were only a handful of such clinics and in London these were at Kings College Hospital and the Institute of Psychiatry, Denmark Hill, lead by David Marsden and The National Hospital Queen Square with Andrew Lees. Because there were few subspecialist Movement Disorder clinics, these clinics attracted patients from all over the UK presenti
ng with a wide variety of movement disorders especially the dystonias.

As a result, the dystonias, particularly focal dystonia, “re-emerged”.. Although clearly described more than 80 years previously, the adult onset focal dystonias had repeatedly been portrayed as psychological disorders in textbooks of the time, and as a result rather neglected by neurologists. David Marsden and Stan Fahn in New York were influential in bringing the field of Movement Disorders to modern Neurology and in particular highlighting the dystonias. Through a number of influential papers that attracted much attention, contemporary views about the dystonias changed.

David was a brilliant clinician scientist and an inspirational teacher, and attracted increasing numbers of research fellows from all over the world to work in his department and attend his clinics. These clinics were heluntitledd in the Maudsley Hospital on a Friday. It was a very exciting time. The patients were fascinating, presenting with conditions many of which we had never seen before. The nuances of clinical analysis and discussion of pathophysiology were a revelation. All the fellows were fired with enthusiasm by his suggestions prompting research into the physiological and pharmacological mechanisms along with the possibility of therapeutic intervention.
The therapy of dystonia at that time was unsatisfactory. A variety of approaches were available but the outcomes were usually poor. One surgical approach, peripheral denervation, had been tried repeatedly for blepharospasm and spasmodic torticollis but the procedures were complicated and difficult with variable outcomes and not widely available.

It was at this time the concept of using botulinum toxin injections to weaken muscles was attracting increasing attention. This idea had been considered before but was fraught with the difficulties inherent in using such a potent neurotoxin in humans. The feasibility of this was demonstrated by Alan Scott an Ophthalmologist in California who produced localised paralysis of extraocular muscles in the treatment of strabismus, controlling the duration and severity of weakness by dose. With some foresight he predicted it might be useful in treating blepharospasm and a number of conditions with muscular hyperactivity. Between 1977 and 1982 he injected extraocular muscles for strabismus, lid muscles for blepharospasm and hemifacial spasm, thigh adductors for spasticity and the neck for torticollis.

Mr John Elston

Mr John Elston

Soon after, John Elston in London demonstrated the efficacy of this approach in blepharospasm and hemifacial spasm using toxin from the Centre for Applied Microbiology and Research at Porton Down an agency of the Ministry of Defence. The use in other dystonias soon followed.

In 1986 Joseph Tsui in Canada reported the successful treatment of spasmodic torticollis by injecting neck muscles with Botulinum toxin. David Marsden suggested that Rick Stell and I speak to John Elston who was familiar with the Porton Down toxin and undertake a study in spasmodic torticollis. David was keen to explore better treatments for torticollis and had recently held discussions with Claude Bertrand the Montreal Neurosurgeon who had been refining the posterior primary ramicectomy procedure that was the latest revision of the 50 year old Dandy operation for denervating neck muscles. Bertrand distinguished a variety of forms of torticollis on the basis of the nature of the movements and the muscles involved. Each required a different surgical approach and EMG was routinely used to define the muscles involved and decide which to denervate. We attempted to follow this approach in planning the site of botulinum injections.

This preliminary study showed considerable benefit, though at the side effect of dysphagia. The patterns of muscle activity and the muscles involved were indeed complex. In simple rotational torticollis the injection sites were straightforward but with complex head positions, EMG was invaluable in localising the muscles involved.

It is interesting to reflect that these studies were seemingly done without an extensive ethics review. The vials of toxin were provided by the Vaccine Research and Production Laboratory from the Centre for Applied Microbiology and Research at Porton Down. The initial vials were unmarked as I recall, though as clinical efficacy became apparent this changed as did ownership of toxin manufacture. Patients were admitted for 3 days of observation after injection- a scenario completely untenable in the world of hospital medicine today.

As is so often the case, we discovered that observations on the complexity of movements in torticollis had bepodivinskyen described previously in the literature. Dandy, the Neurosurgeon had pointed this out in 1930 and the patterns of muscle activity in torticollis were recorded in the papers of Podivinsky in the 1960’s, notably in his chapter in the Handbook of Clinical Neurology.

The variety of patterns of muscle activity in torticollis are of course typical of dystonia with long duration spasms, repetitive jerky movements and tremor. It is interesting to note the recent revision of the definition of dystonia encapsulates this perfectly: “…sustained or intermittent muscle contractions causing abnormal often repetitive movements and postures. Dystonic movements are typically patterned twisting and may be tremulous”.

The complexity of torticollis and the results of our preliminary treatments meant we had to refine the muscle targets with greater precision.

In the late 1980s we moved to Queen Square after David was appointed to the Chair of Clinical Neurology at the Institute of Clinical Neurology. By that time a Botulinum Toxin clinic had been established. The results from this clinic were published again as a guide to treatment, rather than a justification for treatment that we felt had already been established. We discussed the adverse effects, largely related to dysphagia. These could be minimised by some simple strategies.

I have not discussed the doses or relative dosing between different toxins at the time. The definitive examination of this came later as did new toxin formulations.

In 1993, an audit of this clinic was conducted at the NHNN. The efficacy of treatment was beyond doubt. At that time, the major concern was the cost of treatment. It is of interest that between 1992-3 the NHNN toxin clinics used 50% of the toxin use in the UK.

EMG cervical dystonia, Thompson

Electromyography of neck muscles in spasmodic torticollis,, Thompson et al 1990

Since that time, there have been many studies throughout the world demonstrating similar efficacy in torticollis, the benefits of EMG and the importance of precisely identifying the muscles responsible for the head and neck posture and movements. Many of these studies were initiated by David’s fellows on their return home.

By 2005, a critical review of the literature on Botulinum toxin injection for the treatment of torticollis concluded that it was effective. Further studies continue today examining new methods of muscle localisation (ultrasound) and deciding on the muscles responsible for subtle but complex postures of the head and neck. These new observations continue to provide a fertile field for those treating torticollis.

In the 30 years since the first clinical use of Botulinum toxin the indications have expanded beyond anyone’s imagination. It is unlikely there is now a Neurology service without a Movement Disorder and Botulinum toxin clinic. Finally, the conjunction a series of events lead in a short space of time to the  demonstration of the efficacy of botulinum toxin injections and arguably the most significant advance in the treatment of the focal dystonias to date.