Deep Brain Stimulation Surgery for Parkinson's Disease

Release Date: January 1, 2012

Expiration Date: January 31, 2014

FACULTY:

Joshua J. Neumiller, PharmD, CDE, CGP, FASCP
Assistant Professor of Pharmacotherapy
College of Pharmacy, Washington State University Pharmacy Advocates, LLC
Spokane, Washington

FACULTY DISCLOSURE STATEMENTS:

Dr. Neumiller has no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-12-002-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To familiarize pharmacists with deep brain stimulation surgery and its role in the management of Parkinson's disease.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Recognize deep brain stimulation (DBS) surgery as an FDA-approved surgical treatment for select patients with
    Parkinson’s disease (PD).
  2. Identify PD patients who may or may not be optimal candidates for DBS surgery.
  3. Describe the potential benefits and risks associated with DBS surgery in this patient population.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, with an estimated 1 million individuals in the United States, and 5 million individuals worldwide, living with the disorder.1 These estimates correlate to PD affecting approximately 0.3% of the overall population and 1% to 2% of individuals over the age of 60 years.2 PD is associated with a severe loss in function of dopaminergic cells within the substantia nigra, which project to the striatum, a major component of the basal ganglia.1 Progressive degeneration of these nigrostriatal projections leads to the hallmark motor features of PD such as tremor, rigidity, bradykinesia, and postural instability.1 PD is additionally associated with nonmotor symptoms including autonomic dysfunction, depression, anxiety, and sleep disturbances.3

Given the progressive nature of the disease, as well as the numerous complications associated with PD, this population has been shown to utilize more health care resources compared to individuals without PD. Evidence suggests that PD patients utilize outpatient and nursing home resources at a higher frequency,4 and a variety of studies have shown that PD patients are more frequently hospitalized when compared to people without PD.5-7 Additionally, PD patients accumulate more inpatient days over their lifetime when compared to those without PD, with longer average hospital stays.4,5,8-12 Given the significant morbidity and cost associated with PD, interventions aimed at improving functionality and quality of life are of major importance.

Initially, PD patients are often well managed with medication therapies to control the motor symptoms of their disease. As the condition progresses, however, medication therapy is frequently intensified as the management of motor symptoms becomes increasingly difficult in light of increasing motor fluctuations. Motor fluctuations can include periods of being “On,” during which the individual with PD enjoys a good response to medication, and “Off ” periods, when the person experiences a worsening in the classic motor symptoms of PD, such as tremor, rigidity, bradykinesia, and postural instability. While these “On” periods can be associated with a good response to therapy as noted above, they can also be associated with excessive involuntary movements, or dyskinesias, that can likewise adversely affect functionality. It is estimated that an approximate 50% of PD patients receiving levodopa therapy for 5 years experience some degree of motor fluctuations and dyskinesia,13 with these symptoms being particularly common in those with young-onset PD. Motor fluctuations characteristically become more pronounced as the disease progresses, leading to increased difficulty in managing the motor symptoms of PD with dopaminergic medications.

An increasingly utilized treatment modality for the management of people with advanced PD whose disease is complicated by disability from motor fluctuations and dyskinesias despite an effort to intensify medication therapy is deep brain stimulation (DBS) surgery. This review will outline current evidence and opinions regarding the use of DBS in PD with the goal of familiarizing pharmacists with DBS surgery and its role in the treatment of PD (SIDEBAR 1).

tbl1

What Is Deep Brain Stimulation Surgery?

DBS is the most frequently performed surgical procedure for the treatment of advanced PD at the time of this publication.14 DBS surgery in PD can improve symptoms of tremor, rigidity, bradykinesia, and dyskinesia. Symptoms associated with gait, balance, speech, and cognition, in contrast, do not generally respond well to DBS treatment (see Clinical Data on DBS in PD). DBS surgery itself involves the implantation of a neurostimulation system that is composed of two wires (a lead and an extension wire) connected to a neurostimulator device (implantable pulse generator [IPG]), not dissimilar to a pacemaker, to control heart rate. The IPG, which is implanted in the patient's chest, delivers electrical impulses to an electrode located at a target site within the brain. The surgical procedure for DBS is typically performed in two stages that are done approximately 1 week apart. The first surgery involves the implantation of the lead wire into the brain, and the second surgery involves the implantation of the neurostimulator and extension wire. Patients can undergo unilateral or bilateral DBS lead placement depending on whether symptoms are bothersome on both sides of the body or not.

Currently, the most common target for DBS in PD is the subthalamic nucleus (STN), as STN DBS has been shown to improve the cardinal symptoms of bradykinesia, rigidity, and tremor in people with PD.15-17 In patients where bradykinesia or rigidity are not the primary symptomatic concerns, other anatomical targets for DBS may be appropriate (TABLE 1). DBS lead placement in the ventralis intermedius nucleus of the thalamus (Vim), which is a common neurostimulation target utilized for the treatment of essential tremor, is also an effective target for patients with tremor-dominant PD.18-20 Significant overall improvements in PD patients treated with DBS of the globus pallidus internus (GPi) have also been shown. In terms of the mechanism of action of DBS for the treatment of PD, it is currently unknown if neurostimulation with DBS at these target sites induces neurons to fire normally, or if stimulation prevents abnormal neuronal output from traveling to downstream nuclei.21 Evidence suggests that DBS of the STN and GPi provides a beneficial clinical effect for up to 10 years following electrode implantation.22-25

tbl1

Following completion of DBS surgery, the programming process takes place. This consists of determining the stimulation settings for optimal control of the patient's symptoms.26 Programming is performed using a device that communicates with the neurostimulator remotely. DBS programming is aimed at fine-tuning the amount of electrical stimulation delivered (i.e., optimizing the voltage delivered, pulse width, and frequency) to the DBS electrodes, and is generally conducted by a neurologist or other professional trained in the operation of the DBS device. Patients are additionally provided with a controller device and/or a special magnet such that they can turn the neurostimulator device on and off if needed. The battery life of the neurostimulator generally ranges from 3 to 5 years, but varies based on the device and stimulation intensity settings.

Who Is A Good Candidate for DBS Surgery?

According to an expert consensus report published in 2011, the most important factor in achieving consistent DBS outcomes is appropriate patient selection.27 Findings from a retrospective analysis of DBS failures attributed more than 30% of treatment failures to DBS placement in individuals who were not optimal candidates for surgery.28 TABLE 2 provides a summary of patient-selection criteria and factors to consider when determining if a patient is a good candidate for DBS surgery for the treatment of PD, as outlined in the 2011 expert consen- sus report.27

tbl2

Preoperative levodopa responsiveness is considered the single most important predictor of symptomatic improvements following STN DBS.29-31 Levodopa responsiveness testing often involves the discontinuation of dopaminergic therapies overnight followed by an office visit the following morning to examine the individual in an “Off ” state.32 Following examination in the “Off ” state, dopaminergic medication is provided and an evaluation of the symptomatic benefits of the medication is conducted. If the patient exhibits symptomatic motor improvements with levodopa therapy, further improvements in these symptoms should occur with DBS therapy. Conversely, if improvements are not seen in the symptoms for which the individual is seeking help, DBS is unlikely to improve those symptoms. That being said, for patients in whom the tolerated dose of levodopa is limited due to bothersome dyskinesias, DBS may provide benefit when compared to subtherapeutic levodopa administration.

Another important point highlighted in TABLE 2 is the recommendation for neuropsychological testing to determine an individual's cognitive function prior to surgery. Individuals with dementia or marked behavioral symptoms are not considered good candidates for DBS due to the potential for worsening cognitive function following STN DBS.33 Additionally, an increased rate of suicide in patients undergoing STN DBS for PD has been reported, highlighting the need for diligent preoperative psychiatric assessments, treatment of comorbid depression, and diligent postoperative follow-up.27,34

Clinical Data on DBS in PD

Given the considerations noted above, what do the clinical data show regarding DBS for the treatment of advanced PD versus optimized medical therapy? Two prospective, randomized, controlled clinical trials have compared DBS to standard-of-care medical therapy.15,35

The first study was a large, multicenter, controlled trial that included 255 adults with advanced PD and motor complications.35 Study participants (mean age 62 years) were assigned at random to receive either bilateral DBS (n = 121) or best medical therapy (n = 134). In the DBS group, 60 participants received STN DBS, with the remaining 61 undergoing stimulation of the GPi. The primary outcome measure was the amount of “On” time without troubling dyskinesia at 6 months after study enrollment. Participants in the DBS group improved their “On” time by a mean of 4.6 hours per day compared to no change from baseline in the best medical therapy group. In addition, participants in the DBS group had a higher rate of clinically meaningful motor improvements when compared to the medical therapy group (71% vs. 32%), and quality of life was additionally improved as assessed by the Parkinson Disease Questionnaire (PDQ39). Despite the improvements seen in the DBS treatment group, the rate of serious adverse events was significantly higher when compared to the best medical therapy group (40% vs. 15%, respectively). Two deaths occurred in the DBS group. One death was due to a cerebral hemorrhage 24 hours following lead implantation, and the other was related to lung cancer. The most common serious adverse event in the DBS group was infection at the surgical site. An increased risk of falls and dystonia was also more common in the DBS group. Additionally, when compared to baseline, participants in the DBS group demonstrated mildly diminished performance on several measures of cognitive function at follow-up. These diminished performances were seen in measures of working memory, processing speed, verbal fluency, and delayed recall.35

The second study was an unblinded, multicenter trial that included 156 participants with advanced PD.15 Treatment centers enrolled participants in pairs, with one participant in each pair randomly assigned to receive STN DBS, and the other best medical therapy. DBS was associated with a mean 4.4-hour gain in “On” time, and demonstrated improvements at 6 months compared to best medical therapy in terms of quality of life as assessed by the PDQ39. Similar to the study outlined above, serious adverse events were more common in the DBS group (13% vs. 4%), with one study participant in the STN DBS group dying of intracerebral hemorrhage. Cognitive complications were infrequent and were not found to be significantly different between the study groups.15

The two studies summarized here outline not only the potential clinical benefits of DBS for people with PD, but also the potential risks associated with this treatment modality. The next section will discuss the potential risks of DBS surgery for PD.

What Are the Risks of DBS?

As can be anticipated with a surgical procedure involving the implantation of a medical device, there are several potential complications associated with DBS.36 TABLE 3 lists event rates for adverse events reported in clinical trials of PD patients undergoing DBS surgery.37 Selected complications of DBS are outlined and discussed individually below.

tbl3

Skin Erosion: Patients undergoing DBS are at risk for skin erosion around areas where the hardware is protruding, which may cause tension of the overlying skin. Skin erosion may also occur around the surgical incision sites. Skin erosion can present as erythema, pain, scabs, and pruritus.32 Untreated skin erosion can lead to infection of the surgical hardware and potential removal of all of the DBS hardware, depending on the site and severity of skin breakdown.38

Infection: Infection of the DBS surgical site or hardware may result in removal of the DBS system. Hardware infections commonly manifest with erythema and drainage. DBS patients should report any symptoms of possible infection immediately so that timely measures can be taken to prevent serious complications.32

Behavioral Changes: As noted previously, behavioral changes may occur in some patients following DBS, which prompted the recommendation that psychological assessments be performed as a determinant of DBS candidacy. Even in those without presurgical behavioral issues, depression, anxiety, hypomania, apathy, personality changes, and aggression can occur.39 Impulse control disorders (analogous to those associated with dopamine agonist use) may also manifest after DBS implantation, and may include pathologic gambling, hypersexuality, punding (i.e., repetitive, purposeless behavior), and spending.40-42 Awareness and monitoring for possible behavioral changes are crucial during long-term management, particularly in light of findings of increased suicide following DBS surgery.32,43

In addition, and in relation to, the potential complications of DBS outlined above, a number of additional risks and complications have been associated with DBS surgery. TABLE 4 provides a summary of key points about the risks and complications of DBS as outlined by the National Parkinson Foundation in Parkinson Disease: Guide to Deep Brain Stimulation Therapy.26

tbl4

Discussion

While this article has discussed DBS in terms of the treatment of advanced PD, DBS is also FDA approved for the treatment of tremor, dystonia, and obsessive-compulsive disorder (OCD).44,45 Additionally, DBS is being studied in conditions such as treatment-resistant depression, epilepsy, and Tourette's syndrome.45 As the use of DBS for advanced PD and other neuropsychiatric conditions increases, the likelihood that pharmacists will encounter patients who have undergone, or are considering undergoing, DBS surgery also increases. In light of the efficacy and safety considerations surrounding DBS surgery for the treatment of PD, patient education is key when discussing the potential role of DBS in the management of their symptoms (TABLE 5).

tbl5

While DBS is not a pharmacologic treatment, pharmacists can play an important role in the care of PD patients who are considering or who have undergone DBS surgery. It is important that people with PD understand that DBS is not a cure for their disease and that they must have realistic expectations about the benefit they may gain from the surgery. DBS treatment may improve tremor, rigidity, bradykinesia, and dyskinesia, but PD patients must be aware that other symptoms such as balance problems, speech difficulties, and cognition will generally not improve (and may actually worsen) following DBS surgery. Realistic expectations are important since symptoms that are typically not responsive to dopamine often prompt patients to seek additional treatment.32 DBS patients will continue to require medications to adequately manage their PD symptoms, and pharmacists (both inpatient and ambulatory) can play an invaluable role in providing support to these patients and answering their questions as they undergo the process of titrating their PD medications while their DBS settings are optimized.

Pharmacists can also play a very important role as patient advocates during the perisurgical period for PD patients undergoing DBS surgery in order to facilitate the timely and accurate administration of PD medications in the inpatient setting.46 (See TABLE 6 for patient resources.) Ultimately, PD is a complex condition to manage, and pharmacists are in a unique position to make a significant impacts on the quality of care that people with Parkinson's receive.

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