Table of Contents  

Alesch: Neuromodulation in Parkinson’s disease

Introduction

Surgical therapies in the treatment of Parkinson’s disease (PD) have a long history. Ablative stereotactic interventions in the thalamus and pallidum (thalamotomy, pallidotomy) were common in the 1950s and 1960s.1

With the advent of levodopa (LD), people lost interest in surgical therapies.2 The number of interventions dropped rapidly.3

In 1987, Benabid and Pollak brought back surgery for the treatment of movement disorders.4 The reason for this relaunch was that tremor is often very resistant to medical therapy. On the other hand, it responds remarkably well to thalamotomy. However, lesional procedures can be performed safely only on one side. Performing them on both sides risks severe speech disorders. Therefore, after thalamotomy, patients with bilateral tremor remain with a hemitremor, which can be very disabling or at least stigmatizing. Benabid et al. combined classical thalamotomy with contralateral thalamic stimulation. The latter proved to be equally effective as its lesional counterpart. A short time after that, the team moved on to bilateral deep brain stimulation (DBS) procedures.5

Deep brain stimulation was initially developed for the treatment of severe pain conditions,6 but it turned out that its reversibility and adaptability, and the fact that it can be performed bilaterally, make it a perfect tool for treating movement disorders.

Today more than 100 000 patients worldwide have been treated with DBS.

The first papers focused exclusively on treating tremor by stimulating the ventral intermediate nucleus (VIM) of the thalamus. Progress in experimental work in monkeys allowed a better understanding of the neurophysiology of the basal ganglia and the thalamus,7 paving the way for new targets for DBS.8 The promising results from stimulating the subthalamic nucleus in animals gave rise to systematic use of DBS for patients suffering not only from tremor but also from akinesia and rigidity.9 Siegfried10 used DBS of the globus pallidus internus (GPI) based on the earlier favourable results of pallidotomy in patients.

The first DBS interventions were performed using material for spinal cord stimulation (SCS) in an off-label mode. The need for dedicated appropriate material for movement disorders soon became evident. Implants for DBS11 became available on the CE market (1995) and later approved by the US Food and Drug Administration (1999).

With the general availability of the implantable material, interest in this form of therapy increased (Figure 1).

FIGURE 1

Evolution of the scientific interest in DBS as reflected by the number of publications in PubMed.

9-2-8-fig1.jpg

The level of scientific interest in DBS is currently high. As of April 2016, 392 studies were registered at www.clinicaltrials.gov, a registry and results database from the US National Institutes of Health (NIH) listing all publicly and privately supported clinical studies of human participants conducted around the world. A total of 25% of these studies are related to PD. Other indications are tremor, dystonia, dyskinesias, memory disorders, epilepsy and pain.

Cerebral neuromodulation as described in the present paper always requires a stereotactic technique for implantation of the electrodes. Depending on the centres, these techniques may differ significantly.

Patient selection is also crucial for successful therapy, and finally the choice of the adequate implantation material has a significant impact.

Principle of deep brain stimulation

A DBS system consists of an electrode that is placed into the targeted structure of the brain. In PD, the procedure is typically performed bilaterally. The electrodes are connected to an extension that is then connected to an implantable pulse generator (Figure 2).

FIGURE 2

Principle of a DBS system: the electrodes are placed into the targeted structure of the brain; they are connected to an implantable pulse generator using a lead extension; the system is fully implanted.

9-2-8-fig2.jpg

Surgical technique

The large majority of centres implant the electrodes using a stereotactic system. These type of procedures are said to be frame based.

Alternatives to the classical stereotactic techniques are frameless, dedicated skull-based implantation devices12 and techniques allowing direct implantation using magnetic resonance imaging (MRI).13

We lack conclusive data about which, if either, is superior. The best choice is still a matter of debate. There is a strong consensus that highly accurate placement of the electrode is a prerequisite for successful therapy. Surgeons should select their preferred technique based on their training and experience and the capabilities of their institution.14

Traditionally, target calculation was done using anatomical atlas data and intraoperative ventriculography. Today, implantation using high-resolution MRI, together with peroperative computerized tomography (CT), which is best done using an image fusion technique, is the method of choice. Modern imaging techniques allow a clear and accurate definition of the targeted structure. Image fusion combines the detailed information of potentially distorted MRI pictures with the geometrically highly reliable CT data.

Many centres use micro-electrode recording (MER) techniques in addition to image-based, anatomical planning to better investigate and define the target region. The usefulness of this neurophysiological add-on is currently under debate. The scientific interest of MER is not questionable, but it is time-consuming and we lack evidence that it improves the surgical outcome.

Another ongoing debate is the need for awake surgery. This has been standard and mandatory for many years. With the advent of new imaging and planning techniques, the need for awake surgery was more and more questionable. Recent studies15 (American Society for Stereotactic and Functional Neurosurgery Meeting, Chicago, June 2016) show that therapeutic outcomes when implantations are performed under general anaesthesia (GA) are not inferior to those under local anaesthesia.

The burden for the patients is by far lower, and surgery under controlled GA is safer and allows interventions in elderly patients who would not reasonably tolerate awake surgery.

Target selection

The classical target for DBS is the ventral intermediate thalamic nucleus (VIM). This target is primarily used for the treatment of tremor. Not only parkinsonian (resting) tremor can be blocked by stimulating this nucleus, but also essential and cerebellar tremor.

In cases where rigidity and akinesia are the prominent symptoms, the nucleus subthalamicus (STN) and GPI are the targets of choice. While the majority of centres today prefer the STN, there are studies suggesting that the results in both targets are similar.16 The effect on dyskinesias seems to be superior in GPI, allowing a higher dose of levodopa under stimulation, while in cases with STN stimulation less levodopa is generally reported to be needed. On the other hand, psychiatric side-effects, such as those reported by Bejjani et al.,17 seem to be absent in GPI stimulation. The choice of the best target is still under debate.

It has been postulated that pedunculopontine nucleus (PPN) stimulation may improve gait instability and freezing of gait.18 Despite significant improvement in postural instability observed in several studies,19 evidence from the current literature is not sufficient to generalize these findings to the majority of patients.20

Patient selection

Patient selection is very important. Careful preoperative screening is mandatory. The screening team should include a neurologist, a neuropsychologist, a neurosurgeon and, if need be, a psychiatrist. The best results can be expected in patients with a good LD response, younger age, no or mild axial non-LD-responsive motor symptoms, no or mild cognitive impairment, and no or well-controlled psychiatric symptoms. Not respecting these criteria will increase the number of failures.21 In any case, the decision about surgery has to be taken on the basis of an individual risk–benefit evaluation. This should be done together with the family or caregivers of the patient. Patients with atypical PD are not good candidates for DBS.

Age is also an important factor and has to be considered. It is difficult to propose a generally applicable cut-off point. The availability of surgery under GA makes it easier to decide on surgery in patients of advanced age.

In earlier studies, the disease duration prior to surgery was 10–15 years. Dyskinesias and fluctuations are generally considered to be complications from medical therapy. A recent study (Earlystim Study)22 have shown that early surgery, at a time when dyskinesias and fluctuations occur, improves quality of life more than best medical therapy (mean disease duration: 7.5 years).23

Implantable material

The implantable material has significantly improved in recent years. Historically, DBS was performed with systems providing constant voltage (CV). The amount of therapy provided by this technique is very dependent on the impedance of the tissue surrounding the tip of the electrode. As this impedance is not predictable or stable, the therapeutic efficacy of CV systems varies. All of today’s stimulators provide constant current (CC) stimulation. They are completely independent of the impedance of the tissue and provide stable and predictable therapy.24 Moreover, recent systems are multisource independent constant current (MICC) (Figure 3). They allow the electrical stimulation field to be shaped according to the patient’s specific anatomy, using a total of eight poles per side.25,26 Ergonomics of handling the devices play a growing role in DBS (Figure 4).

FIGURE 3

Modern DBS systems allow personalized electrical fields for stimulation, perfectly matching the patient’s anatomy and needs. This picture shows the programming front-end of an MICC system (Vercise™, Boston Scientific, Valencia, CA, USA).

9-2-8-fig3.jpg
FIGURE 4

New platform for DBS (Infinity™, St. Jude Medical, St. Paul, MN, USA). The communication between the implanted pulse generator and the external programmer goes via Bluetooth (Bluetooth SIG, Inc., Kirkland, WA, USA), using popular handheld devices.

9-2-8-fig4.jpg

Early stimulators were not rechargeable. Today, more and more rechargeable systems are available. This not only reduces the size of the implants but also eliminates the need to replace them when the battery is depleted. Patients tolerate and comply well with the charging procedure, which is performed transcutaneously by induction using an external charger.27 Typically, patients recharge every 1–2 weeks for approximately 1–2 hours.

Traditional stimulation electrodes had four poles, with four metallic rings as interfaces to the brain. Recent models have eight poles, which can be eight rings in series or two rings combined with two rings, split in three (segmented leads). This geometry allows directional stimulation. Directional stimulation seems to be superior in matching the electrical field with the patient’s anatomy (Figure 5).

FIGURE 5

Segmented electrode: the split rings allow more focused application of the electrical current. (Boston Scientific, Valencia, CA, USA)

9-2-8-fig5.jpg

Follow-up

Follow-up is crucial after DBS. The effect of DBS has proven to be very stable, and will probably be even more stable with CC systems. However, PD is a neurodegenerative disease, and other symptoms, probably not responsive to DBS, might occur. DBS affects the symptoms very efficiently, but not the disease. DBS does not cure the disease. Even if many patients do not need antiparkinsonian drugs after surgery, regular visits to the treating neurologist are highly advisable.

Conclusion

Deep brain stimulation provides a powerful tool for the treatment of patients with PD when medical failures or severe side-effects such as dyskinesias and/or fluctuations occur. Patients with severe tremor profit equally from this therapy. Keys for success are careful patient selection, comprehensive target definition, and precise as well as safe surgery.

References

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Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991; 337:403–6. http://dx.doi.org/10.1016/0140-6736(91)91175-T

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