PARKINSON'S DISEASE

Current scientific understanding and its application on surgical treatment options

ABSTRACT

Parkinson's disease is a leading neurodegenerative disorder and will continue to grow in prevalence as our population ages. It affects about 1% of the population over 65 [3] and it is characterised by muscle rigidity, bradykinesia, tremor at rest, and postural instability. Parkinson's disease affects the basal ganglia and is unique in that the symptoms result from a single transmitter deficit due to the loss of dopamine in the substantia nigra, pars compacta. The aetiology of the disease is usually unknown (idiopathic), but chemical factors and viral infections may predispose the disease along with life events and the ageing process. It is likely that about 70-80% of the nigrostriatal neurones have to cease functioning before the symptoms appear.

For several reasons there is a renewed interest among the neurosurgical community about the surgical treatment in Parkinson's disease. Firstly, pharmacological therapy, which is the current mainstay of the management of Parkinson's disease, is not totally satisfactory in the long term. As the disease progresses, the efficacy of that treatment often decreases, and incapacitating bradykinesia, rigidity, tremor, and impairment of gait and balance are frequently observed. Furthermore, late-course deterioration is frequently associated with debilitating L-Dopa-induced dyskinesias and fluctuations in clinical response. Secondly, increased understanding of the physiology of the basal ganglia in health and disease has provided a scientific rationale to proceed with various neurosurgical strategies. Thirdly, significant improvements in neuroimaging and neurosurgical techniques have made the surgical procedures safer and more accurate.

PHYSIOLOGIC BASIS OF SURGERY

Normally, the striatum controls the activity of basal ganglia output neurones via two major routes: the direct pathway and the indirect pathway. Following the loss of striatal dopamine that occurs in Parkinson's disease, these routes fail.

It is now known that there are at least five dopamine receptors. The five known receptors can be separated into two distinct families, D1 (made up of D1 and D5) and D2 (made up of D2, D3, and D4).[24] The effect of dopamine and dopamine agonists on D1 receptors is excitatory, whereas their action on D2 receptors is inhibitory.

Neurons containing D1 receptors project from the striatum (caudate and putamen) to globus pallidus internus (GPi) and are considered part of the direct pathway. Neurons containing the D2 receptors project from the striatum to globus pallidus externus (GPe) which then projects to GPi via the subthalamic nucleus. D2 receptors are considered part of the indirect pathway.

Direct Pathway

This is the simplest pathway through basal ganglia. Striatopallidal neurones induce an inhibition via g-aminobutyric acid and andsubstance P upon internal pallidal neurones (GPi) which are themselves inhibitory to target neurones. This leads to disinhibition of the motor thalamus and to an increase in the firing rate of its cells. The proposed effect of activation of the 'direct' pathway is to support or facilitate ongoing movements.

In Parkinson's disease, the depletion of dopamine (acting mainly through D1 receptors - excitatory) from the nigrostriatal projection zones in the striatum (putamen and caudate nucleus), results in the direct pathway being underactive. This leads to decreased firing of thalamic neurones and hence inhibition of initiation of movement.

Indirect Pathway

The indirect pathway is via the subthalamic nucleus (STN). Efferents from the striatum terminate in the external globus pallidus (GPe). Activation of these efferents releases g-aminobutyric acid and enkephalin which inhibit the external pallidal neurons. The neurons themselves have an inhibitory projection to the subthalamic neucleus (STN). The STN is therefore disinhibited and its cells increase firing that leads to activation of internal pallidal (GPi) and nigral (SNr) neurones. The output from GPi to thalamus is inhibitory, reducing the excitatory thalamic input to supplementary motor areas. The indirect pathway is thought to inhibit unwanted movement.

In Parkinson's disease, depletion of dopamine (acting through D2 receptors - inhibitory) from the nigrostriatal projections in the striatum, results in the indirect pathway being overactive.

Hence, the combined hyperinhibitory outflow from GPi may account for the negative symptoms of Parkinson's disease (rigidity and akinesia). Reduction of this excessive inhibitory outflow, by lesioning or stimulating GPi or STN, can probably reverse these symptoms. In addition, since laboratory data suggest that tremor activity is generated in the ventral lateral (VL) nucleus of the thalamus, , lesions or stimulation on this region can be used to treat parkinsonian tremor.

SURGICAL APPROACHES

Before describing the neurosurgical options for the treatment of Parkinson's disease, it must be emphasised that most of these surgical approaches remain shrouded in controversy partly because the results await the evaluation of blinded, random studies and partly because there is great heterogenity in the response of patients to this kind of surgery. Futhermore, neurosurgery for Parkinson's disease is an extremely difficult procedure even for the best multidisciplinary teams. Therefore, none of the surgical procedures that will be mentioned can securely provide an effective treatment.

DESTRUCTIVE SURGERY (or LESIONING or NEUROABLATION)

Because abnormal signals from basal ganglia to the motor cortex cause most of the abnormalities in Parkinson's disease, multiple attempts are made to treat the patients by blocking these signals with a lesioning probe. The procedures are now performed using magnetic resonance-guided stereotactic targeting and microelectrode recording techniques with the patient in the 'off' state and aim in disrupting the abnormal activity of basal ganglia circuitry. Destructive surgery must be extremely precise because of its 'irreversibility'.

Only unilateral neuroablation is advised since bilateral lesioning is associated with extremely high risks (cognitive etc).

Medial Pallidotomy

Surgical lesioning of the internal (medial) globus pallidus (GPi) is mainly used in young patients in good general health in whom diskinesias are the major reasons for disability. Usually, unilateral medial pallidotomy is performed and improves mainly the 'on' symptoms (diskinesia), contralateral to the lesion. Medial pallidotomy is thought to disrupt the excessive inhibition on the thalamus.

This kind of surgery, however, carries high risks of cognitive complications.

Thalamotomy

Indication of lesioning the ventral lateral (VL) nucleus of the thalamus is long-standing tremor which is resistant to all medications available for Parkinson's disease. Published outcomes in unilateral thalamotomy for Parkinson's disease show 73% of patients enjoying total abolition of tremor and 86% significant reduction of contralateral tremor; if tremor remains absent for 3 months postoperatively it rarely occurs. Major complications include mortality (2%), intracerebral haematoma (3%) and persistent dysarthria (12%) in addition to "cerebellar" complications (7%).

Bilateral thalamotomy is not currently performed since it carries enhanced risks of cognitive disorders.

Lesion of subthalamic nucleous (STN)

The STN takes up a strategic position in the pathophysiology of Parkinson's disease because its main connections are inputs from the motor cortex and external globus pallidus and outputs to the entire globus pallidus through excitatory glutamatergic neurons. Lesions on STN have been used in monkeys with surprisingly good results. Such a lesion in humans, however, carries a great risk of persistent contralateral hemiballism ( violent choreiform movements of the limbs) and is currently performed in only a few centres worldwide.

DEEP BRAIN STIMULATION (DBS)

Deep brain stimulation (DBS) was initially developed to treat chronic pain. The goals of destructive surgery and deep brain stimulation are similar but a microelectrode with a stimulator is implanted under local anaesthesia instead of making a lesion. The positioning of the chronic DBS electrode or the lesioning probe is in exactly the same area. In fact not only do the targets (in GPi, VL and STN) for lesion-making and stimulation appear to be the same, but also so do the effects of these two different forms of treatment.

As in lesion making, DBS of GPi is being used for diskinesia.

The use of DBS at a site identical to that of thalamotomy is becoming increasingly popular for the control of tremor DBS of Vim for disabling tremor.[16]

In addition, the role of DBS of STN is under investigation and probably carries little or no risk of persistent hemiballism.

The reversibility and adaptability over time of the stimulation procedure is the main advantage over the destruction of brain tissue. Thus, the risk of permanent neurological impairment related to a misplaced or too large a lesion is avoided as is the risk of recurrence of parkinsonian symptoms related to too small a lesion. However, there is a great financial cost for the equipment of DBS (£5000/ stimulator) as well as for its long term maintenance. More importantly, DBS carries risks (about 1%) of potentially fatal intracerebral infection. DBS and lesioning are compared in more detail in the table below.

TRANSPLANTATION

In Parkinson's disease, the loss of a specific and highly specialised neuronal subpopulation is thought to underlie the disease process, and these neurones innervate a fairly restricted area (the striatum) increasing the likelihood that a reasonable number of well placed grafts might re-establish functional neural circuitry. Consequently, numerous transplantation strategies are emerging but transplantation must still be considered an experimental procedure. At present, grafting of dopaminergic cells is perhaps best suited for patients with young-onset Parkinson's disease (less than 45 years old) who are at high risk of developing complications within a short time of beginning pharmacological treatment and in whom the idea of making lesions or implanting electrodes into the brain for decades seems less appealing.

Foetal dopamine-secreting cells

Ventral mesencephalic tissue from aborted foetuses, after being matched to the patient for ABO blood antigens, is implanted stereotactically through the cudate and putamen via needle tracks in an attempt to replace the lost nigrostriatal neurones. The most dramatic improvements of parkinsonian symptoms occur in patients who receive the largest amounts of foetal mesencephalic tissue (6-8 foetuses per patient) bilaterally. In most cases, however, the cells do not persist for more than a few months, and the patients usually return to preoperative state by 12 months after surgery.

This technique is limited to a few centres around the world owing to the technical, logistical and ethical problems of obtaining and handling embryonic cells.

Autotransplantation

In the early 1990s, transplantation of autologous adrenal medulla grafts to the putamen has been performed with a good but short lived response. As in foetal transplants, the favourable effects in the patients only lasted for about 6 months and the condition returned to the preoperative state by 12 months postoperatively. The possible explanation for this is that the adrenal medulla cells secreted catecholamines for about 6 months and then either gradually stopped secretion or degenerated.

More recently, another form of transplantation - that of autologus superior cervical ganglion into the caudate nucleus - has been performed with promising results. Approximately half of the operated patients showed improvement of parkinsonian symptoms over the 3 years following transplantation, although - not surprisingly - Horner's syndrome (ptosis, miosis, flushed-dry skin) is frequently observed.

THE FUTURE

The implantation of cells genetically modified to express trophic factors and tyrosine hydroxylase for the synthesis of L-dopa from tyrosine has been proposed as a possible route for the treatment of Parkinson's disease. Already, implantation of genetically modified cells that can secrete dopamine as well as L-dopa, has achieved a long term correction of Parkinson's disease in rat models. If this technique is successfully applied to humans, it will probably be the treatment of choice in all parkinsonian patients in the near future.

CONCLUSION

The advancements in the field of genetics, the development of better imaging methods, the increasing understanding of the functional organisation and pathophysiology of the basal ganglia and the growing expertise of multidisciplinary teams will undoubtedly make surgery for Parkinson's disease safer and more effective in the future.

Until then, consideration of surgery in any given patient with Parkinson's disease should always be weighed against the risks associated with the difficulty in dealing with small and complex "circuits" within the brain.

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