Parkinson’s disease (PD) is a neurodegenerative disorder, a synucleinopathy, associated with the apoptosis of dopaminergic neurons of the substantia nigra, particularly the pars compacta, in the central nervous system (CNS). In Western Europe, the ageing population is leading to a rise in the incidence of the disease, with a current prevalence of 160 per 100,000.¹

Development of deep brain stimulation as a therapeutic for Parkinson’s

Deep brain stimulation (DBS) is a surgical procedure employed in managing the symptoms of PD, and indeed many other movement disorders – most notably essential tremor and dystonia. It helps to alleviate the symptoms of the disease, such as tremor, bradykinesia, muscle stiffness or rigidity, impaired balance, loss of automatic movements and speech changes.² However, as of yet, it is only used in cases where medications are effective but fluctuant.

Deep brain stimulation has had many contributions to its development over recent decades. In the 1960s Dr Irving Cooper, a neurosurgeon, found that after accidentally causing a patient to stroke, the patient’s tremors were improved postoperatively where the stroke had affected him.³ Later in the 1970s the emergence of MPTP, a toxin that targets specifically the neurons related to Parkinson’s, in heroin users, led to rapidly developing parkinsonian symptoms. Investigations of MPTP toxicity, in monkeys, provided a means of studying the possible pathogenesis of PD.⁴ Connections between PD, other movement disorders and the Basal Ganglia (BG) were subsequently established, between 1983 and 1990. 

In 1987, in France, Prof Benabid and his team managed to exert therapeutic effects on PD sufferers, alleviating symptoms by inputting 100Hz into the Thalamus.³ Medtronic, who had developed the pacemaker 60 years previously, collaborated with Benabid to pioneer deep brain stimulators. Clinical trials are ongoing to continue exposing the mechanisms behind the disease and therapy, the biochemical functions of which have yet to be fully understood.

The mechanism of DBS

Deep brain stimulation involves surgically inserting an electrode into the subcortical structures of the brain; most typically the BG. Magnetic resonance imaging (MRI) is typically used to determine the relevant area of the brain for electrode implantation. The electrode is an uninsulated wire, connected to a neurostimulator, also called an implanted pulse generator (IPG), that stimulates the brain with electrical impulses.⁵ The IPG is typically implanted under the skin of the chest, below the clavicle. The extension wire connecting the two is typically guided around the posterior of the ear.

In Parkinson’s the two most targeted regions are the subthalamic nucleus (STN) and the globus pallidus, both nuclei of the BG.⁶ Deep brain stimulation exerts its effects in a proportional manner in respect to proximity. Areas closer to the electrode will be greater affected. The stimuli modulate brain activity by harmonising or disrupting neural signalling patterns to better balance downstream pathways. In the majority of patients deep brain stimulation inhibits cells and excites fibres to alter firing rates and patterns, influencing pathways, circuits and other brain structures.⁷

Stimulation causes astrocytic release of calcium, promoting release of neurotransmitters like adenosine and glutamate from neighbouring astrocytes. It is believed that this could be an important mechanism for alleviating PD symptoms.⁸ It has also been shown that deep brain stimulation can cause significant changes in cerebral blood flow at the location of the electrode, which helps to alleviate motor sign.⁹ It has also been implicated that DBS stimulates neurogenesis by increasing the number of progenitor cells proximal to the electrode. This may relieve non-motor symptoms, such as olfactory disturbances and mood disorders.^10,11

In the treatment of PD, high frequency stimulation (HFS) is the form of electrical stimulation traditionally used. It is well-tolerated and is adaptable to suit the needs of the patient by altering the form of the stimulus. HFS leaves open the option of future treatment, as it is a reversible state.¹² Patients who can avail of deep brain stimulation usually have a narrowed therapeutic window of dopamine replacement drug efficacy with associated dyskinesia or tremor. Patients suffering from cognitive and/or psychiatric issues are generally restricted from receiving DBS. Also, patients with largely asymmetric symptoms may only need unilateral deep brain stimulation.¹³

The advantages of DBS over other treatment options 

DBS provides numerous advantages over both non-surgical and other surgical treatments. For example, it is preferable to lesional surgery, as it is both reversible and adaptive. This is desirable as it avoids the possibility of chronic postoperative complications, which in other surgeries might be permanent. Also, no further surgery is required if it does not improve the patient to the optimal level. The device can be adjusted without any further invasive procedures to the patient and by the patients themselves.¹⁴

Clinically, deep brain stimulation has many benefits. For example, DBS greatly improves motor symptoms, in a similar way to levodopa, yet does not require taking medication as regularly, does not cause dyskinesias and, in fact, improves levodopa-induced dyskinesias. It was shown that ‘activities of daily living’ were improved after one year of subthalamic nucleus (STN) DBS.¹¹ For example, one recent study showed that STN DBS was associated with an overall improvement in driving accuracy and a decrease in the number of errors, over both medicated and unmedicated PD patient.¹⁵ The Unified Parkinson’s Disease Rating Scale (UPDRS) is used to assess the quality of daily activities of PD patients. STN DBS showed vast improvements in the UPDRS.

A holistic scale to determine the quality of life of PD patients was formed to assess the social and emotional aspects of the disease. The scale, Parkinson’s Disease Quality of Life (PDQL), may show a greater aspect of a PD patient’s improvement after deep brain stimulation, besides motor improvements. PDQL is evaluated using the patient’s health and their perceived quality of life. PD patients who had received STN DBS showed improvements across the board, including social and emotional factors. Patients who also suffered from depression slightly improved when tested on the Beck Depression Index (BDI).¹¹ The improvement in the PDQL correlated well with those of the UPDRS, but was independent of the BDI. This is important as mood and emotional improvements in deep brain stimulation patients are independent of motor improvements.

The disadvantages of deep brain stimulation and areas of complication

There is an inherent risk of complications associated with surgical implantation of any device. The very nature of surgery puts patients at risk of haemorrhages, especially in this case, due to the length of the wiring between the IPG and electrodes. Intraparenchymal haemorrhages were one such complication found in the surgery and this led to hemiparesis in both cases.¹⁶ Intracranial haemorrhages can cause further complications such as cerebral oedema due to hypertension, hydrocephalus, hyperglycaemia, fever, thromboemboli, seizures and epilepsy.¹⁷ The more complications that occur, above that of the haemorrhage itself, the more difficult the situation is to control.

Delayed adverse events, associated with the surgery, can be more frequent than initial complications. Malfunctioning of implanted devices could cause the patient to undergo unnecessary rebound of symptoms. This could be due to defective impulse generators, end-of-life battery failure of IPGs, migration of leads or migration of electrodes.¹⁸ If access to the healthcare system is limited, the patient’s complications could go unresolved for extended periods. 

If the problem is urgent, there may be disruption to daily life, as the patient is forced to have it investigated. Ultimately, if the device becomes unresponsive to corrective measures, the patient may be required to undergo surgery to remove or replace it.¹⁸

Device-related infection is a consistent complication of implanted devices, with incidence increasing over time. Microorganisms, especially in areas of low perfusion, can attach to foreign surfaces. The main risk of infection associated with medical devices, is that the microorganism can form a biofilm, which is a tough layer of ‘slime’, resistant to endogenous defence mechanisms and antibiotics.¹⁹ Typical examples include gram-negative bacteria, gram-positive bacteria and yeasts. Despite the obvious complications associated with infection, ie. pain and swelling, it requires the patient to undergo a strong course of antibiotics and, in the event the infection persists, the medical devices may need to be removed.¹⁹

Outstanding research questions and the future of deep brain stimulation

There are many areas of uncertainty associated with DBS. Concerns may arise over the fact that the mechanism of action is not fully understood, but there are other ambiguities. For example, it is unclear at what point in the progression of PD that a patient should be considered for deep brain stimulation.⁶ To resolve this issue, an extensive, time consuming and costly trial would have to be undertaken to evaluate the benefits of the surgery at various stages throughout the timeline of the disease. These difficulties suggest that it may be years before a trial of this proportion is merited and the time at which optimal results could be achieved will, for now, remain unknown.⁶

Another consideration is that there is currently no known advantage between locations currently used for DBS. Studies showed no significant differences between the placement of the electrodes, specifically between the STN and globus pallidus internus. Motor symptoms seemed to improve in an equal manner at both sites. However, non-motor symptoms may be a reasonable determinant of the site of electrode placement.²⁰

As for the future of deep brain stimulation, there are some possible areas of improvement. For example, the implantation of DBS devices must be performed in a two-step procedure. Desirably, this would be done in just one surgery, but the site of IPG implantation and wiring to the electrode are inconveniently obstructed by the size of the device and the stereotactic frame required to perform the implantation.²¹ It would also eliminate other inconveniences, such as placing the patient under general anaesthesia twice, the increased risk of infection with two separate operations and a reduction in the number of electrical connections. Fewer electrical connections would also lead to increased device reliability and reduced cost for replacement of parts.²¹

Conclusions

As of yet, no cure for PD has been found, but there are some advanced therapies available to help improve the quality of life of PD patients. Deep brain stimulation has become a viable treatment option as it helps to alleviate both the motor and non-motor symptoms, while decreasing medication intake. In fact in seems to have some advantages over that of levodopa therapy. However, it too has disadvantages such as cost and the risks associated with surgery and, furthermore, the procedure could be improved upon to minimise inconvenience. In summary, DBS is a surgical procedure that came into use about 25 years ago, is continuously increasing in popularity, and looks to be a therapy that will prove useful for some years to come.

References

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