SURGERY IN THE TREATMENT OF PARKINSON'S DISEASE

Introduction

The mainstay in the treatment of idiopathic Parkinson's disease is medical, with the provision of levodopa being the cornerstone of that treatment. Other medications are frequently prescribed as adjuncts to levodopa therapy, and a review of current medical trends has been published in MODERN MEDICINE (May 2003). As the disease progresses the effectiveness of drug therapy becomes less pronounced, medication no longer provides adequate relief of the disabling symptoms of Parkinson's disease and the side-effects of prolonged levodopa medication emerge. It is at this stage in the disease that surgical treatment may be considered in carefully selected patients. The resurgence of surgical treatment of Parkinson's disease is due to the emergence of these long-term complications of L-dopa therapy, as well as improvements in stereotactic techniques, brain imaging, the improved understanding of basal ganglion pathophysiology, and the development of deep brain stimulation technology.

Surgical treatment of idiopathic Parkinson's disease involves the very accurate stereotactic targeting of the various basal ganglion nuclei that play a part in the genesis of the Parkinson's disease symptoms. The target site may be modified in its function either by producing a destructive lesion (ablation) or by implanting an electrode system that imparts an electrical stimulus that alters neural function (deep brain stimulation). In either event, the neural circuitry responsible for the Parkinson's disease symptoms is disturbed and thus there is an amelioration of the patient's symptoms.

Pathophysiology of Parkinson's disease.

Research into the pathophysiology of Parkinson's disease was given a major boost with the unfortunate emergence of the contaminant 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, (MPTP) in a designer street drug MPPP, an analogue of meperidine. The first recorded case of MPTP intoxication causing Parkinson's disease occurred in 1976 when a young college student made an error in the illicit synthesis of MPPP for his own use. The MPTP contaminant produced severe Parkinson's symptoms; two years later he died of his Parkinsonism and post-mortem examination of his brain revealed cell destruction in the substantia nigra. The changes were typical of those seen in idiopathic Parkinson's disease.

A minor epidemic of similar cases occurred on the west coast of America in 1982. This led to renewed research into MPTP Parkinsonism and the use of MPTP as a tool for animal research into the function of the basal ganglia as they relate to Parkinson's disease followed.. The full understanding of the pathophysiology of Parkinson's disease remains elusive but a working hypothesis offers an explanation for the effectiveness of current surgical procedures.

Basic anatomy and function of basal ganglia in Parkinson's disease.

The caudate nucleus and putamen (together forming the striatum) receive excitatory afferents from the cerebral cortex with glutamic acid as the neurotransmitter. Of critical importance in the genesis of Parkinson's disease symptomatology is the dopaminergic input from the substantia nigra compacta. Efferent projections from the striatum project to the globus pallidus interna (GPi) and globus pallidus externa (GPE) as well as substantia nigra reticulata, with gabba-aminobutyric acid (GABBA) as the inhibitory neurotransmitter. The globus pallidus externa sends inhibitory projections to the subthalamic nucleus (STN), excitatory projections pass from the subthalamic nucleus to substantia nigra reticulata (SNR) as well as globus pallidus interna. The globus pallidus interna and substantia nigra reticulata provide the major inhibitory output neuronal activity from the basal ganglia via the thalamic ventral intermediate nucleus (VIM). Excitatory thalamic projections pass in turn to the prefrontal, supplementary motor cortex and motor cortex.

There is modulation of motor programming through two basal ganglia circuits that act in harmony to produce what we recognise as normal motor activity. It is the failure of this harmony that causes the motor symptoms of Parkinson's disease. Cortical activity initiates these two separate pathways that influence further cortical activity in a reciprocal manner

Direct pathway

Cortical output through the direct pathway has the effect of inhibiting the SNR and GPi the VIM is thus released from the tonic inhibition it receives from these nuclei. The thalamus is thus able to provide excitatory feedback to the cortex and so sustain ongoing motor behaviour patterns.

Indirect pathway

Cortical activity passing through the indirect pathway has the reverse effect on the thalamic ventral intermediate nucleus by causing inhibition of the GPE that in turn disinhibits the STN. The hyperactive STN drives the GPi to inhibit the thalamus. This pathway tends to inhibit inappropriate motor activity.

In Parkinson's disease, loss of dopamine input from substantia nigra compacta (SNC) to the striatum results in a reduction of inhibitory output to SNR and GPi. There is also loss of inhibitory output to GPE, and so the normal inhibition of the STN is lost. Failed modulation of the direct and indirect pathways within the basal ganglia thus result in the emergence of the major motor symptoms seen in Parkinson's disease. The tendency to suppress motor activity through the indirect pathway becomes overactive and so new movement is difficult to generate, producing an akinesia. Sustained movement through the direct pathway becomes under-active, thus it is difficult to sustain movements once they have commenced, producing bradykinesia. Tremor probably results from reverberations within this system, with the final common pathway for tremor being found at the thalamic ventral intermediate nucleus.

The model thus provides an explanation for the surgical targets in Parkinson's disease. These are the hyperactive globus pallidus interna, the subthalamic nucleus and the thalamic ventral intermediate nucleus.. Surgical intervention at these sites is intended to suppress their excessive activity and thus improve the modulation of cortical motor activity.

The principles of stereotactic surgery

Stereotactic surgery relies on the Cartesian principle of defining a position in space in relation to three intersecting orthogonal planes with their point of intersection being at a given zero point. The location of any point within the system can thus be defined by measuring along the three planes, usually denoted x,y and z.

If the surgeon has access to a fixed reference point and an image such as an MRI or CT scan that depicts the reference point as well as the stereotactic target, it is possible to calculate the position in space of the target in relation to the fixed reference point. There are numerous stereotactic systems in use that utilise this basic process, ranging from those that require simple manual calculations to those that involve complex computerised algorithms.

The stereotactic system consists of three parts. A rigid frame attaches to the patients head, usually by four screws that are fixed firmly to the patient's skull. This frame carries the localising system that can be adjusted according to the calculations relating to the fixed zero point and the planned target within the brain. A probe carrier is then fixed to the localising system so that when the stereotactic probe is advanced through the brain, it will arrive at the designated target. The stereotactic probe systems used in functional neurosurgery are able to carry out various functions that assist the surgical team in confirming the correct position of the probe within the target. Small adjustments in the position of the probe can then be made in order to obtain the best physiological response and to avoid damage to adjacent important neural structures. Depending upon the specific system in use, these functions include impedance measurement, temperature measurement, macrostimulation, microstimulation and microrecording.

		Laitinen Stereotactic Frame

Neurological evaluation of the patient during the stereotactic procedure is an integral part of the operation. It goes without saying that the full cooperation of the awake patient is required at this time. The surgical team evaluates the effect of stimulating the target area in order to assess the effectiveness of the procedure in controlling the symptoms that are receiving attention and also in order to identify possible unwanted side-effects due to incorrect probe position.

Intraoperative X-rays or MRI may be used in order to confirm accurate positioning of the stereotactic probe or electrode system.

Surgical interventions in functional stereotactic surgery

Having placed the stereotactic probe in the planned target area and having confirmed its correct position by neurophysiological testing as well as clinical evaluation of the patient, a radiofrequency lesion may be produced or an electrode system installed. In either event the effect is to alter neuronal function at the designated target and so ameliorate the patient's symptoms. Great care must be taken to avoid incorrect positioning of the probe as this may result in unwanted effects upon adjacent important neurological systems.

Radiofrequency ablation

The radiofrequency lesion is produced by heat coagulation of the target and is a permanent destructive process. The permanent nature of the lesion has the disadvantage of being irreversible and should there be an unwanted side-effect due to incorrect positioning of the lesion, this is likely to be permanent. This risk of a permanent injury is the major disadvantage of the ablation procedure. However, with careful intraoperative evaluation of the patient, unwanted side effects are a rare occurrence.


Deep brain stimulation

The electrode system consists of a series of four electrodes that are placed at the target and are connected to a pulse generator, rather like a cardiac pacemaker, that is buried subcutaneously in the pectoral region. The disadvantage of this device lies in the high cost of the system. This is outweighed by the great advantage of the safety of the system. The effect of stimulation is reversible and there is no evidence that the electrical stimulation over long periods of time has any detrimental effect on the patient. The stimulation parameters can be adjusted telemetrically and the system can also be controlled within fixed limits by the patient.


Tissue transplantation

Various attempts have been made to restore normal brain activity in Parkinson's disease by transplanting tissue that will survive and replace the dopamine that is no longer produced normally. These attempts have been fraught with difficulties and at this time do not represent a practical solution for the patient. However, the future of surgery for Parkinson's disease may lie in the implantation of genetically engineered autogenous cells.

Stereotactic targets in Parkinson's disease

There are three potential targets that can be used in the treatment of the movement disorders seen in Parkinson's disease. In keeping with the anatomical arrangement of the motor system, these targets will influence contralateral motor activity. Depending upon the specific requirements of the patient surgery may be confined to one or both sides of the brain.

1) Thalamic ventral intermediate nucleus (VIM)

The thalamic target is the classical target that was used by early stereotactic surgeons before the advent of levodopa therapy. Many thousands of these operations were carried out during the 1950s and 60s. The thalamic target is especially effective in treating tremor but does not address the other aspects of Parkinson's disease and so is not the ideal target for the majority of patients. Bilateral thalamic ablation is not performed as there is a significant danger of disturbing speech function.


2) Globus pallidus interna (GPi)

The ventro posterior portion of the globus pallidus interna as a target was reintroduced by Laitinen after the pathophysiological basis for many of the Parkinson's disease motor symptoms had been identified. This led to a renewed interest in the surgical treatment of the condition. The GPi is particularly effective in treating the dyskinesias that occur as a complication of prolonged levodopa therapy, but it also improves rigidity, tremor and to a degree, bradykinesia. Bilateral pallidal lesions carry a risk of speech and swallowing dysfunction but this problem is not a feature of bilateral deep brain stimulation.

Brain slice showing GPi target position		MRI scan showing GPi target position

3) Subthalamic nucleus (STN)

The subthalamic nucleus offers the possibility of improving rigidity, bradykinesia and tremor. To a lesser extent levodopa-induced dyskinesias are improved, as STN deep brain stimulation often makes it possible to reduce the dose of anti-Parkinson's medication. This target is generally regarded as not being amenable to lesioning as the target is small and important adjacent structures preclude the creation of a permanent lesion; deep brain stimulation electrodes are usually positioned bilaterally. The limbic connections related to the STN may lead to cognitive and behavioural problems as a postoperative complication, thus any suspicion of a preoperative disturbance in cognition is a contraindication to intervention at this site. In most centres subthalamic deep brain stimulation is now the preferred surgical procedure for Parkinson's disease.

DBS electrodes in subthalamic nucleus

Complications in stereotactic surgery for Parkinson's disease

General surgical risks

As stereotactic surgery involves passing a probe into the depths of the brain through a burr hole the general risks to the patient include the formation of an intracerebral haematoma, sepsis and epilepsy. These risks are dependent upon the surgical technique and the systems that are used. Symptomatic intracerebral haematomas occur in about 1% of functional stereotactic procedures.

Target-related risks

Each basal ganglion target carries its particular risks that relate to the anatomical relationships of the target; the risks of permanent injury are greatest with ablative techniques.

Thalamic ventral intermediate nucleus

Paraesthesiae may occur if the sensory portion of the thalamus is affected. Adjacent motor fibres may result in motor and balance disturbances while in the dominant hemisphere dysarthria may occur.

Globus pallidus interna

This target lies in close proximity to internal capsule and the optic tract, thus hemiparesis or hemianopia respectively are the greatest risks.

Subthalamic nucleus

The close proximity of many important structures to the subthalamic nucleus and the small size of the target discourage the use of this area for ablative surgery. Potential complications include diplopia due to oculomotor nucleus involvement. Paraesthesiae may occur due to medial lemniscus spread and motor dysfunction due to spread of the stimulus to the internal capsule. Hypothalamic involvement may cause vertigo or nausea. Limbic involvement may initiate depression, hypomania and other behavioural disturbances. Ataxia occurs with spread to the brachium conjunctivum.

Stimulation device-related risks

The insertion of the deep brain stimulation electrodes, the electrode leads and the pulse generator carry specific risks.

The long operative procedure and the insertion of the foreign material increase the risk of infection. This is unit- and technique-dependent and has been reported as between 2,5% and 23%. Skin ulceration over implants may occur.

Hardware-related complications include electrode migration (5-14%), lead fractures (3-5%) and pulse generator malfunction (2%-8%).

Conclusion

Data collected from numerous studies on the stereotactic treatment of Parkinson's disease provide compelling evidence regarding the relative safety and efficacy of the procedures that are now available. When patients are carefully selected, and the procedure is well tailored to the predominating symptoms experienced by the patient, the majority of patients who undergo surgical treatment can hope for a significant improvement in their motor symptoms.

Responses that are anticipated at various basal ganglion targets for Parkinson's Disease Surgery

Excellent +++
Good ++
Moderate +
Poor 0

*GPi Globus Pallidus Interna

*STI Subthalamic Nucleus

*VIM Thalamic Ventral Intermediate Nucleus

Information For Patients wishing to travel to Cape Town for Surgery and Assessments. Questionnaire included.
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