Elsevier

Progress in Neurobiology

Volume 59, Issue 5, December 1999, Pages 509-532
Progress in Neurobiology

Review
From experimentation to the surgical treatment of Parkinson’s disease: prelude or suite in basal ganglia research?

https://doi.org/10.1016/S0301-0082(99)00015-5Get rights and content

Abstract

Parkinson’s disease remains one of the greatest challenges facing those who work in the field of neurological research. Although the development of levodopa treatment revolutionised management of this debilitating diseases, no effective long-term therapy has yet been found.

With recent advances in the understanding of basal ganglia physiopathology and the experimental demonstration of the efficacy of certain surgical procedures, there is a renewed interest in the surgical approach.

This paper provides a chronological overview of the history of parkinsonian surgery and discusses the principal surgical options at our disposal today. These take three main forms: ablation (thalamotomy, pallidotomy and subthalamotomy); cell graft and gene therapy (mainly in the striatum); and deep brain stimulation (of the thalamus, globus pallidus pars internalis and the subthalamic nucleus).

Our knowledge of basal ganglia function and our conception of how motor information is processed by this network have evolved parallel to the development of surgical techniques.

Recent results from both clinical and experimental studies underline the complexity of the physiopathological mechanisms which generate parkinsonian symptomatology and lead us to question our assumption that each class of clinical signs (tremor, akinesia, rigidity, levodopa-induced dyskinesias…) is produced by a specific and separate mechanism.

In the same way, comparison of the electrophysiological and biochemical effects of the different techniques induced in brain function vary considerably.

This complex world of interaction and interconnection is a labyrinth that we are still far from comprehending in its entirety. All the more reason, in consequence, for extending experimental investigation into the impact of any new therapy before proposing its clinical application.

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder which is observed in 1% of the population over 55, the mean age at which the disease is first diagnosed. It was first characterized by James Parkinson (Parkinson, 1817), and consists of syndromes including tremor, rigidity, postural abnormalities and bradykinesia. The principal pathological characteristic of PD is the progressive death of the pigmented neurones of the substantial nigra pars compacta (SNc) (Hassler, 1938), which have since been identified as the nigrostriatal dopamine (DA) neurones (Ehringer and Hornykiewicz, 1960). Other areas of the brain can also be affected: the locus coeruleus, Meynert’s nucleus basalis and even the hypothalamus (Foix and Nicolesco, 1925, Javoy-Agid et al., 1984, Agid et al., 1987, Cash et al., 1987, Jellinger, 1987, Halliday et al., 1990).

From the nineteenth century up until 1960, the only therapeutic approach possible was surgery since no effective pharmacological treatment existed. Various operations on the central and peripheral nervous system were introduced into clinical practice but these were often based on insufficient knowledge and had no effect on symptoms [for review, see Siegfried (1980)]. The accuracy of this prestereotactic neurosurgery left much to be desired and imaging technology was virtually non-existent.

The discovery in 1960 that the death of dopamine neurones of the SNc that causes parkinsonism (Ehringer and Hornykiewicz, 1960) marked the end of this pioneering period and opened the way for the development of pharmaceutical therapies regulating DA synaptic transmission. These have included levadopa treatment (Birkmayer and Hornykiewicz, 1961, Birkmayer and Hornykiewicz, 1962, Yahr et al., 1968, Lees, 1994), the administration of dopaminergic agonists (Lieberman and Goldstein, 1985, Goetz, 1990) and the use of inhibitors of monoamine oxydase-B and cathecol-O-methyltransferase (Kingdom, 1993, Olanow, 1993, Kingdom, 1995, Ruottinen and Rinne, 1996). It has recently been suggested that an association of different glutamatergic antagonists can prevent levodopa-induced dyskinesia [for review, see Starr, 1995, Blandini et al., 1996, Lees, 1996].

There remains, however, the problem of therapeutic escape, a state of inurement which sets in inevitably after a certain time of treatment. The delay can vary considerably from one patient to another but inevitably all patients require at some stage a heavy increase in drug dosage and very often begin at this stage to present the first signs of dyskinesia (Lesser et al., 1979, Marsden et al., 1982, Lees and Stern, 1983, Rajput et al., 1984, DeJong et al., 1987). The severity of this problem has led to a renewed interest in the surgical approach, rendered all the more interesting by the enormous advances made in recent years in stereotactic surgery and brain imaging.

We are still far from the ideal therapy but progress has been made. Each new technique has added to our knowledge of the physiopathology of the basal ganglia motor loop. This paper provides a chronological overview of the different treatments that have been used since the disease was characterised and considers the contribution each has made to the improvement of care and the advancement of brain motor research.

Section snippets

The prestereotactic era

Although lobotomy was proposed and even used to treat Parkinson’s disease (Barük et al., 1953, Gros et al., 1955) on the grounds that emotional factors intensify tremor, the early surgical approach to the treatment of parkinsonism was based overall on the assumption that the pyramidal system was the principal protagonist in the genesis of motor abnormalities. Since it was important to prevent any pathological information from reaching the periphery, the pyramidal tract needed to be interpreted.

Adrenal and mesencephalic transplants

The successful development of a dopaminergic pharmacotherapy for PD inevitably focused research for a number of years on the striatal homeostasis [for reviews, see Zigmond et al., 1990, Bezard and Gross, 1998]. Advances in fundamental research into the functioning of the central nervous system and, in particular, its capacity of regeneration [e.g. see Stenevi et al., 1976, Stenevi and Björklund, 1978, Björklund and Stenevi, 1979b] found a practical application in the expanding field of

The comeback of surgical ablation

However effective the pharmacological arsenal of which we now dispose, the problem of therapeutic escape remains. This state of inurement requiring an increase in drug dosage and often accompanied by the appearance of dyskinesia and ‘on-off’ phenomena (Lesser et al., 1979, Marsden et al., 1982, Lees and Stern, 1983, Rajput et al., 1984, DeJong et al., 1987) appears ineluctably after a certain length of treatment, usually within 3–10 years (Miyawaki et al., 1997). It is at this stage that the

Stimulation of the thalamus

The idea that the electrostimulation of deep brain structures may constitute an effective therapy for certain chronic diseases is not a recent one [e.g. Betchereva et al. (1975); McLellan (1982)]. The technique was already used in the sixties for target determination prior to lesion of the Vim thalamic nucleus, the surgical procedure used for the alleviation of tremor (see Section 4). Since stimulation inhibited parkinsonian rest tremor and postural tremor it was recommended that surgeons use

Concluding remarks

It is clear that our theoretical knowledge of basal ganglia function has evolved in parallel with advances in the neurosurgical treatment of PD, and vice versa. The advances made in one field have always engendered progress in the other. In this common quest we can distinguish four main stages; at each stage our conception of how the neuronal message is processed within the basal ganglia has undergone significant modification.

  • 1.

    In the 1930 s it was the concept of ‘irritation’ or ‘excessive

Acknowledgements

The compilation of this review was funded by the CNRS and the IFR of Neuroscience (INSERM No. 8; CNRS No. 13). E. Bezard received MESR Grant No. 95523629. The authors apologise to the many authors whose work could not be quoted because of limited space. They wish to thank Christelle Imbert and Stéphane Guitraud for their very important help with the bibliography.

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