botulinum toxin

Sense of satisfaction

Modern academic research is largely a rather slow process taking small incremental steps. I’ve vented my frustration before about how dispiriting it can be to get lost in a fog of low-level research projects which often leave us more confused rather than enlightened. I thus feel I want to celebrate a rare occasion when I do feel a sense of completion of a substantial programme of research.

I was lucky enough to move to Belfast  shortly after Kerr Graham and Aidan Cosgrove  had completed their early work demonstrating the efficacy of Botulinum toxin injections first in hereditary spastic mice and then in children with cerebral palsy. Kerr had departed for Melbourne by the time I arrived but left Niall Eames, an orthopaedic surgeon, lined up to do some research to try and better understand the effect of the toxin. Given that the problem in CP is that the muscles are too short and that Botulinum toxin, by reducing the neural input to the muscle, allows them to elongate, we decided that we should do this by looking at the changes in muscle length. We thus started with some, by modern standards extremely crude, muscle length modelling of the gastrocnemius.

Niall graph

Response to botulinum toxin plotted against the pre-operative dynamic component (taken from Eames et al. 1999)

Having developed the model we applied it to a cohort of children with cerebral palsy having Botulinum toxin injections and were able to demonstrate that the action of the toxin was to reduce the “dynamic component” of reduced muscle length (see figure above). This makes a lot of sense as it is this component that is affected by the neural input to the muscle. The “fixed component” (contracture) is largely a consequence of changes to the composition and structure of the muscle and is unlikely to be affected by the toxin. The research also allowed us to understand that the variable response was largely due to children having a different dynamic component rather than of the toxin acting differently and led to reasonably simple prescription guidelines. Botulinum injections to the calf are most likely to be beneficial if the child has a large dynamic component (good range of passive dorsiflexion during physical examination but walking up on their toes). It further explained that the different response in children with diplegia  and hemiplegia was also attributable to them having different magnitudes of dynamic component.

Armed with this understanding I was then able to work with the pharmaceutical company Ipsen to set up a cliniucal trail to establish the most appropriate dose of the toxin. We couldn’t find enough children to study in the UK so had to extend the study to five centres in Poland. We divided children into one of four groups and injected them with either a placebo or one of three different doses. We used the same modelling technique which we had developed for the earlier study to analyse the results and came to  the conclusion that placebo didn’t work (very much) and that the middle dose was the most effective (see figure below). It was interesting that the biomechanical modelling came to clear logical conclusions whereas doctors’ subjective opinions were that the placebo was very nearly as effective as the drug and that they were so impressed by the “improvement” after placebo injection that they would have recommended repeating the process for two thirds of the children! (despite biomechanical evidence that the placebo had had no effect).

Baker graph

Reduction in dynamic component as a function of different doses of Botulinum toxin at 4, 8 and 16 weeks (Baker et al. 2002)

Having established the most appropriate dose on a single occasion the most obvious remaining question is, “How often should those injections be repeated?”. I’d moved to Melbourne to join Kerr by then and we applied to the Australian National Health and Research Council to fund a clinical trial to compare injections delivered either annually or every four months over a  two year period. Reflecting on the biomechanics we recognised that the long term goal of the injections had more to do with preventing the development of secondary fixed contractures than on the immediate effect on the dynamic component. We would have to measure relatively small changes over a two year time span and thus devised a method to standardise the measurement of passive dorsiflexion range as much as possible.

Which brings me to the stimulus for writing this post in that the results of that study have just been published . The first conclusion is that passive range of dorsiflexion was maintained over the two year period by both injection regimes. We had no true control, because by this stage it wasn’t considered ethical to inject placebo over such a long period, but these measurements were taken over an age range in a child’s life during which preserving dorsiflexion range would be extremely unlikely without injections. The second conclusion was that the more regular injections where only slightly more effective in preserving dorsiflexion range and therefore that there doesn’t appear to be any particular benefit in injecting more regularly than once a year.

Thus after nearly twenty years of research based on the application of thoughtful biomechanics to a clinical problem we finally have clear evidence of which children to inject, how much toxin to inject and how often to repeat this. As one leader of the western world was once heard to comment under less auspicious circumstances, “Mission accomplished!”

Footnote

Trials like this take so long to organise that we were not actually the first group to complete a study to establish the most appropriate injection frequency. This was actually published about 5 years ago. It was a very similar study (it had been sponsored by Ipsen as a follow-on our to earlier work and I’d had some involvement in its planning before I left for Australia) and arrived at a very similar result. Rather than feeling that there was competition here though it highlights the scientific importance of repeating studies to confirm results. With such an emphasis on innovation in modern clinical research the need to repeat and confirm earlier results, which is an important part of the scientific process, can very often be overlooked.

 

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Averaging up the profits

Here are two graphs. The first from very early in my career shows a parameter we called the “dynamic component” of gastrocnemius length. It plots the improvement in this after injection of botulinum toxin in children with cerebral palsy against the baseline score (Eames et al., 1999). I remember when Niall first showed me the graph. We’d captured a  whole load of data on these kids and were wondering what to plot to make sense of it. This was the first suggestion and I can still remember Niall’s excitement when it came up with such a strong relationship.

Eames

At the other end of my career here’s another graph from a paper that has only just been published electronically in Gait and Posture (Rutz et al. 2013). Here is the improvement in Gait Profile Score (GPS, Baker et al., 2009) for children with cerebral palsy plotted against baseline score (with GMFCS II and III children plotted separately). Again there is a strong correlation. (There are some statistical issues in plotting data this way which might lead to exaggeration of the correlation when measurement error is substantial but I’ve gone to some lengths in the recent paper to show that this is unlikely.)

rutz

When you think about it though the relationship is actually quite unremarkable. What both studies are showing is that kids with the most severe problems to start with are the most likely to show improvements. To a certain extent this is common sense – if two kids both improve by 30% then the child with the biggest problem to start with will show the biggest change in absolute units.

What interests me though is that if we only look at the average changes in each group we will reach the conclusion that the group as a whole have improved. If we are not careful we might conclude that all the group has improved. Thissimply isn’t the case. The full truth is that the kids who have the biggest problems have improved a lot those with milder problems haven’t improved very much (in absolute terms).

The Botulinum toxin study became the basis for an industry sponsored randomised controlled trial (Baker et al. , 2002). In that trial although we included baseline readings as a covariate in the statistical analysis but we only ever reported group results. That is still probably the most rigorous trials of lower limb injection of Botulinum Toxin in the literature. The message that almost everyone has taken out of that study  from the data we presented is that kids with spastic diplegia will benefit form Botulinum toxin. Had we presented the data more carefully the conclusion should have been that the more severely affected kids will benefit from Botulinum Toxin big time, but that  the milder kids may not benefit at all.

As it stands the paper is really convenient for the company because it suggests that a wider group of kids will benefit from an expensive drug than is actually the case. Given that bigger responses to treatment in more severely affected people is likely in almost all conditions that affect people across a range of severity I suspect that a similar phenomena spread across almost all of . I wonder how much profit the drug companies are making as a consequence?

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Baker, R., Jasinski, M., Maciag-Tymecka, I., Michalowska-Mrozek, J., Bonikowski, M., Carr, L., . . . Cosgrove, A. (2002). Botulinum toxin treatment of spasticity in diplegic cerebral palsy: a randomized, double-blind, placebo-controlled, dose-ranging study. Dev Med Child Neurol, 44(10), 666-675.

Baker, R., McGinley, J. L., Schwartz, M. H., Beynon, S., Rozumalski, A., Graham, H. K., & Tirosh, O. (2009). The gait profile score and movement analysis profile. Gait Posture, 30(3), 265-269.

Eames, N. W. A., Baker, R., Hill, N., Graham, K., Taylor, T., & Cosgrove, A. (1999). The effect of botulinum toxin A on gastrocnemius length: magnitude and duration of response. Dev Med Child Neurol, 41(4), 226-232.

Rutz, E., Donath, S., Tirosh, O., Graham, H.K., Baker, R. (2003). Explaining the variability improvements in gait quality as a result of single event multi-level surgery in cerebral palsy. Gait Posture, published on-line http://dx.doi.org/10.1016/j.gaitpost.2013.01.014