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STN stimulation and neuroprotection in Parkinson’s disease—when beautiful theories meet ugly facts
  1. P C Warnke
  1. Correspondence to:
 Professor Peter C Warnke
 The University of Liverpool, Department of Neuroscience, The Walton Centre for Neurology and Neurosurgery, Lower Lane, Liverpool L97LJ, UK; p.c.warnkeliv.ac.uk

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STN stimulation does not halt progression of Parkinson’s disease

Repeated claims have been made that inactivation of the subthalamic nucleus (STN) is a neuroprotective measure.1–3 It was postulated that by suppression of the glutamatergic STN, glutamate mediated excitotoxicity exerted on the substantia nigra could be reduced, if not abolished. The paper by Hilker et al in this issue (see page 1217) deals with this topic by looking longitudinally at patients who have undergone successful STN stimulation. The investigators have taken the approach of using objective functional imaging employing 18F-DOPA positron emission tomography (PET), an established objective measure of biological progression in Parkinson’s disease, which was then correlated with clinical progression. They were able to show convincingly that STN stimulation did not halt the progression of Parkinson’s disease.

They have also shown that their technique of STN stimulation was effective both in terms of UPDRS improvement and in reducing L-DOPA or DOPA equivalent drug treatment, and was exactly within the range reported by other groups.

The PET approach to quantify disease progression will allow insights into disease biology and ways of modifying it. A critical point in using sequential PET studies is the reproducibility of quantitative ratios of L-DOPA uptake, especially in the light of huge interindividual differences in uptake in Parkinson patients. Furthermore, accurate repositioning of slices is another crucial point. Finally, patients were examined in the off-drug condition without STN stimulation but the follow up was done with deep brain stimulation turned on, though again in the off-drug condition. We have recently shown that a significant difference in dopamine transporter capacity, though not in dopamine uptake, can be seen between pre-STN stimulation and post-STN insertion but with stimulation turned off.4 Thus electrode placement resulting in a “microsubthalamotomy” could have an effect on its own.

Nevertheless STN stimulation is like other traditional functional neurosurgical ablative techniques in producing symptomatic relief without affecting the biology of the disease.

What is the cause of the discrepancy between the experimental findings and this clinical study that rules out neuroprotective effects? The experimental papers used an artificial model of Parkinson’s disease—that is, the 6-OHDA model which does not reproduce all the features of the disease. Furthermore in that model, STN ablation with kainic acid is used instead of STN stimulation to show the potential neuroprotective effects of STN suppression on the substantia nigra.

The paper by Hilker et al also raises questions about the focus of future neurosurgical approaches in Parkinson’s disease. The investigators point out quite correctly that STN stimulation, which can be carried out bilaterally, has been found to be beneficial in numerous retrospective studies. However, it clearly only provides symptomatic benefit and therefore falls into the realm of traditional functional neurosurgical approaches such as STN ablation. In this context it is worthwhile asking whether the current prospective randomised controlled trial (the PD Surg trial) comparing bilateral STN stimulation with the best medical treatment is a wise investment of money. Very likely the study is going to prove the obvious. New attempts have been made by several neurosurgical groups to modify disease biology in Parkinson’s disease and by doing so to achieve actual neuroprotection. These include attempts at the direct infusion of glial cell line derived neurotrophic factor (GDNF) using convection enhanced delivery, which seems to have long term effects in the same range as STN stimulation and looks very promising.5,6 In addition, while still in the experimental phase the elegant approach of converting the excitatory glutamatergic STN by means of gene therapy into an inhibitory GABAergic nucleus—which is currently being tested in patients after successful results in an experimental Parkinson’s model—also looks promising.7,8

Besides the worthwhile clinical information gained from Hilker’s paper, another of its merits is to point out that, while STN stimulation is highly effective and beneficial in patients with Parkinson’s disease, we should be looking for more sophisticated means of attacking the disease biology and hopefully modifying it.

STN stimulation does not halt progression of Parkinson’s disease

REFERENCES

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Footnotes

  • Competing interests: none declared

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