Invasive+Treatments+for+Parkinson's+Disease

//Directed from: Neurodegenerative Disorders //

For certain patients with advanced **Parkinson’s disease**, pharmacotherapy is no longer an effective method to control their symptoms. Patients will likely develop dyskinesias as a result of long term levodopa use1. Deep brain stimulation (DBS) is thus used to alleviate these involuntary motor movements. A battery-powered electrode is placed at specific sites in the brain to stimulate the local nuclei. Popular sites for DBS are the subthalamic nucleus (STN) and the globus pallidus internus (GPi). Symptoms are significantly improved post surgery as long as the electrode remains implanted in the brain. Numerous mechanisms have been proposed for DBS but none is confirmed. Another option is ablation, whereby the surgeons will directly lesion target sites like the globus pallidus or thalamus. This method, though effective, is not as popular since it is irreversible and the procedure holds a greater risk than DBS2. . toc

=**Deep Brain Stimulation in Parkinson’s Disease** =

Deep brain stimulation is a fairly recent treatment method that started in the late 20th century. Since then, surgical techniques have dramatically improved and new nuclei are being considered as viable target sites. The first study on deep brain stimulation in Parkinsonian patients was published in 1989 where they noticed improvements in tremor after thalamic stimulation3. The authors sent high frequency stimulation to the ventral intermediate thalamus, of which remained effective for 2 to 14 months4. However, they also noted that their research is preliminary and more testing would be required to establish a viable treatment option. Later in 1995, it was showed that stimulating the bilateral subthalamic nuclei is indeed an effective treatment for Parkinson’s disease3. According to the authors, this is a “first demonstration in human beings of the part played by the subthalamic nuclei in the pathophysiology of Parkinson’s disease”5. Today, DBS surgery has expanded and is applied in various other movement disorders as well as psychiatric disorders such as depression.

**Patient Selection and Preparation**
Selecting patients for DBS surgery must be tightly screened to ensure effectiveness. Usually, eligible patients are at their late stages of Parkinson’s with severe, debilitating symptoms and have developed levodopa induced dyskinesias3. In addition, patients should also be screened for noticeable levels of dementia, other comorbidities and any atypical Parkinsonism symptoms that may affect the outcomes of their DBS surgery as there have been reports of neuropsychiatric complications post surgery3, 1.

Prior to the surgery, patients are asked to stop their medications overnight to monitor the severity of motor response before and after levodopa medication<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">2. This is helpful in predicting the effectiveness of the DBS surgery: patients who experience dramatic differences between the “ON” and “OFF” states after a single dose of levodopa will most likely benefit from the surgery<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">2. An “ON” states signifies that the patient is under a levodopa treatment for a specific time frame while “OFF” indicates that the medication has worn off or that the patient has stopped their drug regimen for a brief time period.



<span style="font-family: Arial,Helvetica,sans-serif;">**Surgical Procedures & Outcomes**
<span style="font-family: Arial,Helvetica,sans-serif;">Accurate placement of the DBS electrode is crucial and specific steps are taken to stimulate the appropriate nuclei. Generally, bilateral stimulation, although tougher, is more preferred to unilateral simulation<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">6. The electrode is inserted stereotactically into the patient via imaging techniques and nuclei-specific electrophysiological characteristics<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">6. CT scans and MRIs are used to provide a 3D location in the brain while the specific oscillatory activity of different nuclei determines the exact nuclei for implantation<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">6, 7. Usually, for STN-DBS, it has a neuronal firing rate of 20 – 40Hz and an irregular firing pattern that is distinctive to the nuclei<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">8. In the surgery room, the instrumentation is set up so that once the STN is accurately located, makes a series of characteristic crackling noises to let the surgeons know<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">8. The electrode is then implanted into the target nuclei with the lead inserted under the skin behind the ear and neck region<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">2. Lastly, the pacemaker is inserted underneath the skin at the chest along with the battery. The battery can last for 3 to 5 years and are usually non-rechargeable<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">2. Maintenance of the device is required on a regular basis and thus the batteries are usually changed well ahead of time to prevent any complications in the treatment<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">2. There are 4 stimulation sites (or “leads”) on the electrode each 1.5mm apart and are bipolar in nature (ie: positive/negative currents)<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">8. Other properties of the electrode can be adjusted to reach optimum stimulation level: voltage, pulse width (in milliseconds) and frequency<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">8. The electrode fires at a high frequency usually around 100Hz or higher at short regular intervals<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">8. Lastly, while both regular and irregular stimulation can override pathological circuitry, the stimulation must be regular and periodic in order to alleviate the symptoms of Parkinson’s<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">9.

<span style="font-family: Arial,Helvetica,sans-serif;">The tremor after surgery is almost always improved after thalamic stimulation<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">1. Likewise, patients will find that other cardinal symptoms such as rigidity, bradykinesia are also improved after STN and GPi stimulation<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">1. Consequently, the intake of levodopa medication can also be significantly reduced or halved after DBS surgery thus resulting in significant cost savings<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">10, 3. Today, new nuclei are being explored for their potential therapeutic properties against Parkinson’s disease. Studies show that stimulation of the pedunculopontine nucleus (PPN) improves stability patients; something that is not attributed to STN-DBS<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">11. Research

ers at the Toronto Western hospital conducted a study to examine the results of PPN stimulation and its response to gait and stability. While dopamine replacement treatments to suppress symptoms are still required after STN-DBS, they reported a “significant reduction in falls in the ON and OFF medication states”<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">11. Their study is further supported where another group found restoration of reaction times involved with “gait and postural disturbance” post PPN stimulation<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">12. The concept of PPN stimulation to increase stability will provoke further research with other nuclei for targeted relief of specific symptoms that regular STN-DBS cannot provide.

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<span style="font-family: Arial,Helvetica,sans-serif;">**Mechanisms**
<span style="font-family: Arial,Helvetica,sans-serif;">There is no conclusive mechanism of how DBS works on the basal ganglia circuitry in Parkinson patients. However, many studies point to towards a disruption in pathological firing activity thereby restoring regular function. In the diseased brain, inhibitory outputs from the GPi in the direct pathway are much higher than normal patients<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">3. As a result, there is an inhibition in motor control from a reduced activation signal in the ventral lateral thalamus. Similarly, the indirect pathway produces an increased excitation signal from the STN onto the GPi allowing for an increase in inhibitory output<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">3. There are two theories as to why DBS works on improving PD symptoms: the neurons in the stimulated and surrounding tissue are either silenced after DBS (similar to a lesioning effect), or that new firing activity excites and overrides the pre-existing thereby resetting the circuitry<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">13, 14. A study by Lafreniere-Roula et al (2010) supports the theory that stimulation of the target nuclei suppresses neuronal activity via “activation of GABAergic afferents”<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">15 while data from Garcia et al’s (2005) research favors an override mechanism in which stable oscillations in the STN induces regular activity<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">16. Evidently, more research is required before arriving at a consensus with DBS mechanisms.



<span style="font-family: Arial,Helvetica,sans-serif;">**Side Effects & Complications**
<span style="font-family: Arial,Helvetica,sans-serif;">There have been some cases of neuropsychiatric disorders that developed after DBS surgery. However, they seem to be treatable and reversible with the majority of patients responding successfully to the surgery<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">17. Side effects were noticed in the study by Limousin et al, (1995) where they reported confusion with bouts of hallucinations and a case of thalamic infarction which improved after several months<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">5. As well, hemiballism was noticed when the stimulation frequency was set too high though this was resolved shortly after the surgery by lowering the frequency<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">5. However, as this was one of the first few reports published on DBS surgery, it should be treated with caution as surgical techniques have improved along with a greater understanding of basal ganglia physiology. Other reported side effects after STN stimulation include a slight decline in speech fluency, depression and heightened emotional sensitivity to small stimuli<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">3. There seem to be fewer cases of side effects after GPi stimulation though the problem with word fluency still exists<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">3, 18. Apathy was also noticed in some patients, with a faster progression in adults under 65<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">19. Lastly, “//de novo// dopamine dysregulation syndrome” was reported in a few cases after DBS<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">20. They proposed that this could be due to the combined effects of their dopamine replacement regimen and the surgery allowing for an over stimulation of the limbic system<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">20. Although there are continual reports of complications after DBS surgery, extreme caution should be utilized as most of these reports stem from small sample sizes and most do not have a comparison to a control group<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">17. Screening for co-morbidities prior to surgery must be done with as much accuracy as possible since pre-existing conditions may also affect the outcomes of the surgery.

=<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">**Ablation in Parkinson’s Disease** =

<span style="font-family: Arial,Helvetica,sans-serif;">Another method is ablation whereby target sites would be lesioned to improve tremor in PD. This approach was initially proposed but later abandoned due to the discovery and success of L-DOPA and other pharmaceutical treatments. However, when side effects of pharmacotherapy became more apparent, ablation was reconsidered as the alternative treatment<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">3. Bergman et al (1990) began the revolution when they sought to confirm the proposed theory of increased STN activity in Parkinsonian brains: monkeys were injected with MPTP and contralateral motor control was improved after unilateral STN lesioning<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">2, 21. In 1992, pallidotomy was reintroduced on patients<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">2 : Laitinen et al conducted the surgery in 46 patients and noticed significant improvements in all the classic symptoms<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">22.

<span style="font-family: Arial,Helvetica,sans-serif;">A 5 year post-op study was conducted on 18 patients who received pallidotomy<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">23. As expected, it yielded robust results in their “ON” and “OFF” states with minor regressions of cognitive behaviours. Ablation, though effective, is not preferable as it is irreversible and there are higher risks associated with lesioning nuclei. In addition, it would have to be done unilaterally since bilateral lesioning will most likely lead to deficits in the patient post surgery<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">1.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">**Comparing DBS and Pallidotomy**
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">DBS surgery has gained popularity for treating Parkinson’s amongst surgeons since its inception even with its higher costs. However, ablative procedures are still conducted despite the irreversible conditions since both methods are effective in alleviating symptoms. Interestingly, research has been done to determine the effects of consequent procedures. Fishman et al (2004) examined the effects of bilateral STN-DBS after an existing pallidotomy<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">24. Patients needed a second operation due to progression of the disorder rather than a failed pallidotomy procedure. Thus, bilateral STN-DBS was administered and improvements were once again noticed in those patients suggesting that it may be acceptable to undergo DBS after pallidotomy<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">24. Similar results were also obtained by Hyam et al, 2010 where a subsequent pallidal stimulation had greater advantages than a second contralateral pallidotomy<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">25. Contralateral pallidotomy was only significant in reducing dyskinesias and pain while stimulation yielded better scores across all motor symptoms<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%; vertical-align: super;">25.

=<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%;">**Useful Links** =


 * <span style="font-family: Arial,Helvetica,sans-serif;">Neural Stem Cell Therapy
 * <span style="font-family: Arial,Helvetica,sans-serif;">Stem Cell Treatment for Parkinson's Disease
 * <span style="font-family: Arial,Helvetica,sans-serif;">[|Parkinson Society Canada]
 * [|Parkinson's Disease Foundation]

= **References** =
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