Parkinson's disease is a progressive nervous system disorder that affects movement. Although Parkinson's disease can't be cured, medications might significantly improve symptoms. Occasionally, the doctor may suggest surgery to regulate certain regions of your brain and improve your symptoms.This research paper will further investigate on Deep Brain Stimulation (DBS) and evaluate the research question: To what extent is DBS an effective treatment method for adults suffering from Parkinson’s Disease, by referencing to a clinical study.
ABSTRACT
Deep Brain Stimulation is an established procedure to treat patients with Parkinson’s Disease. After a screening of the brain and finding the target points for electrode implantation, the surgery is performed. However, prior to the surgery the patient along with a neurosurgeon and neurologist weigh the risks since this procedure is only effective for patients who fit a particular criterion, depending on their symptoms and daily lifestyle.
A trial was carried out to compare the effectiveness of neurostimulation (DBS) and medication delivered to 156 patients under the age of 75 (among other criteria). A randomized pair design method was followed where the patients were randomly paired and one was given medication and the other had the DBS procedure performed on them. Data was collected over a period of 6 months and the participants were monitored according to changes in their daily lifestyle as written in their diary, and according to UPDRS-II. Their dyskinesias and motor symptoms were also under evaluation; patients in the neurostimulation group had a greater improvement in all criterion than the patients who were administered medication.
Hence, the researchers concluded that neurostimulation is a more effective treatment method than medication for patients who fit the same criteria as the ones in the study. However, this research paper also evaluates the strengths and limitations of this trial, and moreover the future of Deep Brain Stimulation.
INTRODUCTION
According to The American Parkinson Disease Association (APDA), Parkinson’s disease is a type of neurogenerative movement disorder which affects one’s ability to perform common, daily activities. It’s a highly progressive disease, and its symptoms worsen over time. It’s characterized by tremors, bradykinesia (slowing of movements), and rigidity, also known as the classic parkinsonian triad associated with dopaminergic denervation. Patients may also experience symptoms such as shuffling of steps, impaired balance and coordination, and mental and behavioral changes such as depression and difficulty in talking. [4]
In order to understand this disease and its symptoms, it’s important to gain knowledge of its etiology – a set of causes of a disease or condition. Currently, the exact cause of Parkinson’s is still under evaluation, but according to latest theories it’s a result of loss of neurons (nerve cells) in the part of the brain that produces the neurotransmitter dopamine, which is responsible in controlling the movements an individual makes as well as their emotional responses. Moreover, people suffering from this disease also lose the nerve endings that produce norepinephrine, the main neurotransmitter of the sympathetic nervous system which controls the blood pressure and heart rate of the body. This consequently leads to the development of several symptoms, such as fatigue and low blood pressure in patients. [3]
Currently, there are no specific blood tests that can be done to diagnose a patient with Parkinson’s; however, a neurological examination and analysis of the patients’ medical history helps a doctor form the basis of their diagnosis. They also conduct diagnostic tests such as DaTscans – an imaging technique used to help doctors visualize the dopamine transfer levels in the brain by injecting a radioactive agent into the patients’ bloodstream. Additionally, their response to dopamine agents and their development of motor fluctuations over time help doctors make their final diagnosis more accurately. This disease is said to be the second – most common age-related neurodegenerative disorder, and an approximate of 10 million adults worldwide suffer from it. It’s most common among elders between the ages of 55-65 years, and the prevalence is said to be higher in men than in women, with a 1.5 to 1.0 ratio. Moreover, an estimated of 4% of adults are diagnosed with Parkinson’s before the age of 50. [3]
Due to this high prevalence rate, it’s important to understand the treatment options and their effectiveness on this disease. Initially, after diagnosis, the patient should begin with exercise treatment such as stretching, balance training, and strengthening exercises. Some might also require speech therapy to improve their cognitive problems. Patients are also prescribed medications such as levodopa – the most commonly used drug, generally started by the patients’ neurologist. It’s accompanied by Dopamine Agonists responsible for activating dopamine receptors, and Monoamine Oxidase (MAO) Inhibitors that block actions of monoamine oxidase enzymes responsible for breaking down the neurotransmitter dopamine. [6] However, it’s common for several patients with Parkinson’s to not respond well to these medications and to develop symptoms such as dyskinesias, i.e., uncontrolled, excessive, and involuntary movement because of their long-term use of the levodopa drug. Thus, surgical procedures such as Deep Brain Stimulation (DBS) are known to be beneficial for these patients, and have been approved by the Food and Drug Administration (FDA) for several decades. DBS is not only an effective treatment method for patients with Parkinson’s, but also useful with mental illnesses such as depression, pain relief, and obsessive-compulsive disorder (OCD). This research paper will further investigate on DBS and evaluate the research question: To what extent is DBS an effective treatment method for adults suffering from Parkinson’s Disease, by referencing to a clinical study.
THE PROCESS OF DEEP BRAIN STIMULATION
This surgical procedure is minimally invasive, however like any surgery, it carries its potential risk of complications. Thus, it’s important to weigh the pros and cons with a doctor before moving forward with the procedure. A screening for deep brain stimulation is done, in the presence of a neurologist, neurosurgeon, and neuropsychologist to address the risks visive the benefits, followed by several medical tests to ensure this surgical treatment is the most appropriate one for the patient.
The process begins with detailed brain imaging studies such as Computed Tomography (CT) scans, or Magnetic Resonance Imaging (MRI) scans to help map the exact areas of the brain where the procedure will take place. This is accompanied by a stereotactic head frame to help keep the patient’s head still and to provide reference points for targeting. Usually, the most commonly targeted sites are the nuclei in the basal ganglia, which includes, the sub-thalamic nucleus and the internal segment of globus pallidus of a patient’s brain since this is where the most degenerative change occurs.
All Parkinson’s medications are stopped 12 hours prior to the surgery, and in most cases no general anesthesia is used so that the patient’s behavioral responses during the electrode implantation can be monitored. However, local anesthesia is used to numb the patient’s scalp, but not the brain itself since it has no pain receptors. [1]
Next, one or more electrodes (a thin, insulated wire) attached to leads are implanted in the previously determined areas of the brain. The implanted electrodes act on the cells and fibers closest to it, by inhibiting the cells and exciting the fibers. Moreover, DBS also changes the firing rate of individual neurons in the basal ganglia, and the electrical current in the electrodes act as synapses and trigger nearby astrocytes to release calcium and neurotransmitters adenosine and glutamate. Lastly, this procedure also increases blood flow and stimulates the process of neurogenesis (forming new and improved neurons in the brain) in the patient.
*An image of the electrode implantation process [13]
The second part of the surgery involves implanting the pulse generator under the patient’s chest, near the collarbone, under general anesthesia. It’s connected to the wires from the electrodes implanted in the patient’s brain and is programmed to send continuous electrical pulses to it. The generator can be easily controlled, and switched on or off when needed. All these stimulations are controlled by the doctor, and are conditioned to the patient’s symptoms and diagnosis.
Patients who have undergone the DBS surgical procedure experience a variety of results. It’s not guaranteed that one’s symptoms will improve and they might still need to carry forward with medication. However, if successful, doctors have seen a great improvement in their patients’ symptoms and their overall lifestyle.
*An image labelling parts of the brain and the equipment required for DBS [14]
CLINICAL EVIDENCE
In order to further investigate DBS and its effect in the real-world context, there are several clinical studies that have been carried out to determine whether this treatment method is an effective one for patients suffering from Parkinson’s disease, and this will be explored in the second part of this research paper.
PART I: BACKGROUND AND AIM
Neurostimulation is known to reduce levodopa-related motor complications in patients. A randomized, controlled trial was conducted, comparing this process of DBS in the subthalamic nucleus with the best medical management over a period of six months.
PART II: SAMPLE
To be a part of this study, participants were required to fulfill a variety of pre-requisites. They needed to be under 75 years of age, had to have received a clinical diagnosis of idiopathic Parkinson’s Disease at least 5 years prior to the study, according to the British Parkinson’s Disease Society Bank Criteria; had to be suffering from dyskinesias but no dementia or major psychiatric illness, and lastly should have no constraints to surgery. Each participant was also required to take state-of-the-art antiparkinsonian medication, administered by neurologists.
PART III: METHOD
The study followed a randomized pair design and an unblinded trial method and was conducted in Germany and Austria at 10 academic centers. Ethical obligations were followed; participants signed an informed consent prior to the procedure & the study was approved by the ethics committee at each center.
PART IV: PROCEDURE
The procedure was as follows: 156 participants were randomly paired in groups of two, with one patient assigned to the DBS procedure within six weeks of enrollment, and the other prescribed to the best medication treatment.
Patients undergoing neurostimulation underwent bilateral stereotactic surgery, where their subthalamic nucleus was targeted by means of MRI scans, microelectrode recording, ventriculography, or a combination of any or all of these. The techniques used at each center varied, depending on the institution’s surgical protocols. The target coordinates for the electrode implantation were: 0 to 3mm behind the midcommissural point, 4 to 6mm below the intercommisural line, and 11 to 13mm lateral to the midplane of the third ventricle. Lastly, the final implantation point was the position with the most pronounced effect on rigidity and general symptoms of Parkinson’s – obtained during intraoperative testing. After the final electrode and pulse generator were implanted, neuroimaging confirmed its position. Post-operation, patients’ antiparkinsonian medication and treatment were altered, depending on their response to the surgical procedure. However, the standard pulse setting on the generator was 60µsec at 130Hz, but the voltage was adjusted accordingly.
The participants assigned to medication were treated with optimal drug therapy by following the German Society of Neurology guidelines, but they were constantly adjusted depending on the patients’ needs.
Patients in both conditions were also required to keep a diary that separated their day into half-hour sections. They were trained to record their mobility three days prior to, and six months after admission, and rate their condition for each of the following; ‘sleeping’, ‘immobile’, ‘neither fully mobile nor fully immobile’, ‘mobile with troublesome dyskinesias’, or ‘mobile with no dyskinesias’.
PART V: DATA COLLECTION
To assess the effectiveness of neurostimulation and medication on patients, changes in their quality of life were monitored using the Parkinson’s Disease Questionnaire (PDQ-39) summary index, and in the patients’ motor symptoms while not taking any medication, assessed by the Unified Parkinson’s Disease Rating Scale, Part III (UPDRS-III). In both, PDQ-39 and UPDRS-III, a higher score indicates a poorer condition, and can range between 0 to 100 and 0 to 108 respectively. The patients were also assessed while they were actively taking the medication, and 12 hours after their withdrawal from the same.
The secondary criteria to assess patients included noting any changes in the dyskinesias scale and in the activities done by the patient in their daily lifestyle, measured by the Unified Parkinson’s Disease Rating Scale, Part II (UPDRS-II) and the Schwab and England Scale. For the dyskinesias scale (0 to 28) and UPDRS-II (0 to 52), a higher score indicates poorer function/severe dyskinesias, however, for the Schwab and England Scale (0 to 100), a higher score indicates better function. Additionally, patients were evaluated on their motor functions while taking medication using UPDRS-III, their health related quality of life according to the Medical Outcomes Study SF-36 General Survey (with a higher score indicating a better quality of life), their neuropsychiatric function according to the Montgomery and Asberg Depression Rating Scale and the Brief Psychiatric Rating Scale (a higher score indicating poorer mental health), and lastly their cognitive function according to the Mattis Dementia Rating Scale (lower scores indicating more severe dementia).
The patients’ self-reported data in their diaries were also taken into account, calculating the total amount of time each of them spent in each category (sleeping, mobile and so on) and the differences over 6 months were compared amongst both groups. Their safety was also evaluated by taking note of any new symptom or worsening of symptoms and were categorized as an ‘adverse event’.
PART VI: RESULTS
The results of the study were as follows: patients who underwent the DBS surgery showed a better improvement in their scores on PDQ-39 and UPDRS-II than the ones who were given medication, with a score improvement of 41.8±13.9 to 31.8±16.3 and 39.6±16.0 to 40.2±14.4 respectively. There was approximately a 25% improvement in the neurostimulation group and almost no improvement seen in the medication group – it actually worsened by 5%. Moreover, the DBS group was also seen to have a 22% improvement in their summary score of SF-36, a greater improvement was seen in 51 of 60 pairs according to their UPDRS-III score, and the dyskinesias scale also showed an improvement in their scores while not taking medication: 6.7±5.3 to 3.1±3.5 (54%). Meanwhile, the results either showed no change or almost insignificant change in the medication group. Participants emotional and cognitive ability did not significantly improve/worsen in either group; however, the Schwab and England Scale (measuring impairment) showed an improvement in patients’ scores who underwent neurostimulation, and a deterioration in patients who were given medication.
Lastly, the patients in the neurostimulation group showed significant improvement over 6 months as per their diaries. Their immobility reduced by 4.2 hours, their mobility without dyskinesias increased by 4.4 hours, they spent longer hours sleeping (approximately increasing by 0.7 hours), and their mobility with dyskinesias also showed significant reduction.
PART VII: CONCLUSION
This study supported Deep Brain Stimulation as a form of treatment for Parkinson’s Disease for patients under the age of 75 with severe dyskinesias and fluctuations in mobility. They were observed to have a more significant improvement post-operation than the ones who were only given medication regularly. Patients not only improved in their motor control, but also in their daily quality of life – such as in sleep time, activities done, and emotional well-being. They were able to have longer periods of bodily comfort and less severe dyskinesias. This was supported by a 10-point change in the PDQ-39 summary index, which was used to estimate the effectiveness of the treatment method. Such changes were not seen in the medication group. Thus, through this study one can conclude that patients who fit the same or similar criteria as these participants will most likely benefit from neurostimulation, however it should also be weighed against the complications that arise due to this surgery.
PART VIII: DISCUSSION
This Parkinson’s trial had several strengths and weaknesses which I’ll be exploring in the last part of this study. Unlike previous studies which have been conducted on neurostimulation and focused on motor scales, this study had a broader criterion. Patients’ quality of life was the primary measurement, including factors that affected it: motor function, medication, complications of surgery and so on. The researchers also investigated whether cognitive differences, mood changes, depression, and behavior were related to the surgery or the medication intake by patients.
However, even though this study was an effective way to determine and answer the research question ‘To what extent is Deep Brain Stimulation an effective treatment method for adults suffering from Parkinson’s Disease’, it also has its set of limitations. The study did not consist of any control group/placebo group to compare the results with the surgical or medication group. Furthermore, a placebo could have been administered in patients who were not actively taking any medication to compare results between stimulation and non-stimulation conditions. A sole comparison between Deep Brain Stimulation and medication is not correct either since stimulation of the brain requires a smaller dosage of medication to prevent any side effects related to motor control and cognition/behavior. Moreover, a large number of participants also left the trial throughout the experiment, leaving only 156 patients for the final comparison. This makes the study seem unreliable, and less generalizable and representative since it has a small and specific sample size. Lastly, standardization of the medication for patients was not performed, making it less comparable.
SUPPORTING STUDIES
To support the results and conclusions of the above study, three subsequent trials were carried out, following a similar method and experimental design as the one mentioned above. Here, the sample consisted of 255 patients from the US, who either underwent the surgical procedure or were given medication. The results showed that the neurostimulation group gained a mean 4.6 hours of “on” time per day, visive 0 hours gained by the medication group. A 6-month follow up of the patients also showed the surgical group benefiting in their daily lifestyle more than the medication group.
In another trial with 366 patients from the United Kingdom, the neurostimulation group had a PDQ-39 score of 32.5, versus medication group having a score of 38.1 – meaning, the neurostimulation group was showing more improvement.
Lastly, another trial conducted in US adds to the hypothesis that DBS is an effective treatment method for Parkinson’s since the neurostimulation group was seen to have an “on” time of 11.2 hours per day, whereas the group which underwent electrode implantation without activation was seen to have an “on” time of only 8.9 hours per day.
CONCLUSION
To conclude, Deep Brain Stimulation is an effective treatment method for patients suffering with Parkinson’s Disease, under the age of 75. It not only improves one’s symptoms and provides a sense of relief, but also significantly changes their daily lifestyle – allowing them a longer sleeping duration, positively changing their behavior, and improving their cognition. Whereas with medication, the efficacy of treatment is shorter and no significant change is observed in their lifestyle.
However, it’s also important to note that the neurostimulation procedure is only effective for particular patients with specific symptoms, and not all can be eligible for the procedure. The benefits and the risks need to be carefully weighed with a neurologist and neurosurgeon to determine whether this is a correct treatment option for someone. Moreover, the target point for the implantation of the procedure also needs to be carefully evaluated, based on the patient’s symptoms and where it’ll be most effective.
I believe that after careful consideration, a Deep Brain Stimulation procedure can be very helpful for patients with severe dyskinesias and motor function.
FUTURE OF DBS
The exact mechanism through which DBS alleviates the symptoms of Parkinson’s are still undergoing investigation, and further research is required. A refinement in patient selection, target implantation point, and a higher value MRI might improve the future of this surgical procedure. A change in equipment and stimulation to deliver a different type of electrical signal is also being evaluated. It has been noticed that 5 years post-operation, the procedure’s effectiveness decreases and symptoms begin to degenerate quickly. Thus, a new implantation point, or further therapy after DBS might still be required, and is currently under evaluation. However, DBS is currently the most promising form of therapy we have.
BIBLIOGRAPHY
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