Deep Brain Stimulation for Parkinson Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of neuronal dopamine production in the brain, causing motor and non-motor symptoms.

Deep brain stimulation (DBS) was first used in the 1970s for the treatment of chronic pain. Mixed results and poor electrode design caused a cessation of significant activity in this field in the 1980s, but over the ensuing 25 years, DBS has become a safe and effective treatment for advanced movement disorders, including PD when symptoms are no longer managed adequately with medications. ^{[1, 2]}  DBS is currently approved by the US Food and Drug Administration for PD and essential tremor, as well as a humanitarian device exception for dystonia and obsessive-compulsive disorder. DBS is used for patients with PD of at least 4 years' duration and 4 months of motor complications, and can improve tremor, rigidity, slowness of movement, and drug-induced dyskinesias.

DBS, a form of stereotactic surgery, has become the surgical procedure of choice for Parkinson disease (PD) because it does not involve destruction of brain tissue; it is reversible and can be adjusted as the disease progresses or adverse events occur. Bilateral DBS can be performed without a significant increase in adverse events.

Continued refinement of the knowledge of basal ganglia circuitry and PD pathophysiology of movement disorders has narrowed DBS surgery to 3 key gray matter structures: subthalamic nucleus (STN), pars interna of the globus pallidus (GPi), and intermediate thalamus (VIM) in the thalamus.

The STN and GPi are the preferred two targets for using DBS to treat PD, but VIM can also be utilized when tremor is the primary symptom. ^{[3, 4, 5]} There are evidences in the literature demonstrating the benefit of DBS for treatment of PD. Studies have showed that DBS plus best medical therapy is superior to best medical therapy alone for advanced PD in controlling motor symptoms and improving quality of life. ^{[6, 7, 8, 9]} Moreover, a meta-analysis of randomized controlled trials of DBS in 1184 patients with PD showed that DBS significantly improves patients' symptoms, functionality, and quality of life, in addition to the reduction of the required medication dose and its associated complications. ^[10] It has also been reported that the DBS benefits can be maintained for more than 10 years. ^[11]  The long-term outcomes of DBS of GPi and STN for patients with PD were reported in a multicenter randomized controlled trial. ^[12] The results showed motor function improved between baseline and 36 months for GPi (41.1 to 27.1) and STN (42.5 to 29.7). Health-related quality of life improved at 6 months on all subscales, but improvement diminished over time. It is concluded that the beneficial effect of DBS on motor function was stable and comparable by target over 36 months.

Guidelines have been developed to help neurologists and general physicians identify PD patients who may benefit from referral to a specialized DBS team; these teams assess the likely benefits and risks of DBS for each referred patient. ^[13]

Currently, the underlying mechanism of action of DBS for treatment of movement disorders is not clear, although different theories have been proposed.

DBS may function through local and network-wide electrical and neurochemical effects of stimulation, modulation of oscillatory activity, synaptic plasticity, neuroprotection, and neurogenesis. ^[14]  DBS acts through not only inhibition but also excitation of basal ganglia circuits. DBS may inhibit the neuronal networks in the target. On the other hand, it may also activate the efferent axons. It may suppress pathological rhythms and involve neuronal networks with widespread connections, resulting in beneficial effects. ^[15] High-frequency stimulation may create a global hyperpolarization of the cell membrane, resulting in a loss of excitability. Alternatively, stimulation may "jam" signal flow out of an abnormally functioning structure. Antidromic and orthodromic depolarization currents may modulate neuronal activity at sites distant from the stimulation target. Finally, stimulation-induced disruption of pathologic network activity may explain the effects of DBS on disorders of abnormal movement. ^[16] It has also been reported that DBS creates an informational lesion in the circuit ^[17] and may control neuronal network activity by involving neurochemistry modulation, such as upregulation of dopamine and gamma-aminovutyric acid (GABA) through glia, which is induced by stimulation. ^[18]

DBS is a minimally invasive surgical procedure. Importanly, it is effective for treatment of patients with PD. The main advantages of DBS are its reversibility and adjustability. DBS leads are placed in the target(s) and allow stimulation parameters to be adjusted in response to changes in the patient’s condition. If DBS induces unwanted adverse effects, the stimulator can be turned off, adjusted, or removed. If DBS proves clinically ineffective, the patient has not suffered an irreversible lesion to the brain.

Additional advantages include the ability to intervene at targets that cannot or should not be treated with neuroablative lesion surgery and the provision of a unique opportunity to study human basal ganglia physiology.

The main disadvantage of DBS is the cost. Currently, the cost of the device is approximately $10,000 per unit. Additional disadvantages include an increased risk of infection due to the presence of implanted hardware and the cost of maintenance (eg, repair or replacement of fractured wires or repeated office visits for stimulation adjustments). Currently, battery exhaustion necessitates replacement of the entire pulse generator, the most expensive component of the system (costing about $8000), every few years.

The deep brain stimulation (DBS) system consists of a lead that is implanted into the targeted brain structure, such as STN, GPi, and VIM. The lead is connected to an implantable pulse generator (IPG), which is the power source of the system that is generally implanted in the subclavicular region of the upper chest. The lead and the IPG are connected by an extension wire that is tunneled down the neck under the skin (see the image below).

Implantation of the DBS system is performed in 2 stages as follows:

• During the first stage, the DBS lead is implanted stereotactically into the target nucleus (see the image below)

• During the second stage, the DBS lead is connected subcutaneously to an implantable pulse generator (IPG), which is inserted into a pocket beneath the skin of the chest wall, like a pacemaker

  Implantation of the deep brain stimulation (DBS) lead.

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In DBS for Parkinson disease (PD), as in most stereotactic movement disorder procedures, the first stage is performed with the patient awake to allow monitoring of neurologic status. The stereotactic headframe (see the first image below) is applied to the patient's head on the morning of the procedure, and a targeting MRI is performed (see the second image below).

A combination of microelectrode recording (MER) and macroelectrode stimulation is used to refine the desired target physiologically (see the images below). Once the DBS lead has been implanted, it is anchored to the skull with a burr hole cap.

After DBS electrode implantation, CT is performed to confirm no bleeding in the brain and MRI to confirm proper electrode placement. One or two weeks later, the patient will undergo the second stage of surgery – implantation of IPG under general anesthesia.

The electrode is thin (approximately 1.3 mm in diameter) and flexible, so that it moves atraumatically with the brain. The device can be programmed to deliver stimulation in monopolar or bipolar fashion, employing any of the 4 electrode contacts, alone or in combination (see the image below).

After proper patient selection and accurate lead location, competent programming of the implanted device is essential for optimizing DBS therapy. After approximately 2 weeks, therapeutic electrical parameters can be set by using a transcutaneous programmer (see the image below).

The primary goals of programming are to maximize symptom suppression and minimize adverse effects; minimizing battery drain is a secondary goal. These goals can be achieved by following a systematic, multistep approach. ^[19] The ability to deliver either monopolar or bipolar stimulation using any of the 4 electrode contacts (or combinations thereof) offers the treating physician a great deal of therapeutic flexibility, permitting customized stimulation for each patient. Moreover, stimulation parameters can be adjusted at any time if needed.

DBS provides monopolar or bipolar electrical stimulation to the targeted brain area. The amplitude, frequency, and pulse width of stimulation can be adjusted to control symptoms and minimize the adverse events. The patient can turn the stimulator on or off using an Access Review Therapy Controller or a handheld magnet. The usual stimulation parameters are an amplitude of 1–3 V, a frequency of 135–185 Hz, and a pulse width of 60–120 msec.

It has been suggested that DBS works by resetting abnormal firing patterns in the brain and thereby bringing about a reduction in parkinsonian symptoms. The response from DBS is only as good as the patient’s best “on” time, with the exception of tremor, which may show greater improvement than is seen with medication; however, after DBS, the amount of daily “on” time is significantly extended. DBS requires regular follow-up for adjustment of stimulation parameters to account for symptom changes due to disease progression and adverse effects.

Traditional DBS surgery is performed while patients stay awake. With improvement in high-resolution brain imaging, interventional MRI-guided DBS lead implantation (asleep DBS) has been developed, in which anatomic verification of target can be performed intraoperatively. ^[20] Moreover, study has shown that microelectrode recording (MER) and intraoperative MRI are both effective to ensure adequate electrode placement in DBS surgery. ^[21] Other advances include the mini-frame, robot (Rosa)-assisted stereotactic systems for DBS surgery, and rechargeable pulse generators. Currently, directional DBS with new electrode designs that have the capability to steer stimulation current for better and specific targeting, and closed loop DBS systems are under development.

The multicenter European study of thalamic stimulation in parkinsonian and essential tremor reported rates of significant improvement of 85% for Parkinson disease (PD) tremor and 89% for essential tremor (ET) at 12 months. ^[22] In most patients, the very good results with stimulation seen at 1 year were maintained after more than 6 years. ^[23]

Like thalamotomy, thalamic deep brain stimulation (DBS) often does not provide significant functional improvement for patients with PD, because their rest tremor is not usually a source of functional disability. In fact, nowadays, thalamic DBS is rarely—if ever—offered to patients with PD.

Thalamic DBS initially was used contralateral to previous thalamotomies to reduce the risk associated with bilateral thalamotomy. However, the results were so encouraging that thalamic DBS has become not only an accepted alternative to thalamotomy, but it is currently the procedure of choice for patients who require unilateral or bilateral procedures for medically refractory tremor. A decade of experience in Europe and the United States indicates that thalamic DBS is equivalent to thalamotomy for tremor suppression.

Because the lesion is eliminated, hemorrhage rates and cognitive adverse effects may prove less frequent than with thalamotomy. Side effects related to stimulation, including paresthesia, dysarthria, and gait disorders, are relatively common though reversible by setting adjustments. Device-related complications, including end of battery life, skin erosion, or infection can be observed and resolved in most cases.

The promising results initially achieved in the thalamus prompted the application of DBS to other key targets for the treatment of PD.

Thalamic stimulation involves implantation of a DBS lead in the ventral intermediate (VIM) nucleus of the thalamus. It provides significant control of Parkinson disease tremor but does not affect the other symptoms of Parkinson disease such as rigidity, bradykinesia, dyskinesia, or motor fluctuations.

Studies of thalamic DBS have demonstrated good initial and long-term tremor control up to 7 years after implantation; however, long-term studies have shown a significant worsening in other parkinsonian symptoms such as bradykinesia and rigidity and worsening of gait leading to major disability.

Candidates for thalamic DBS are patients with disabling medication-resistant tremor who have minimal rigidity or bradykinesia. They should not have significant cognitive impairment, mood or behavioral disturbances, or other factors that may increase the risk of surgery.

Siegfrid and Lippitz introduced bilateral pallidal stimulation (ie, stimulation of the globus pallidus pars interna [GPi]) in 1994, reporting improvements in rigidity, akinesia, and levodopa-induced dyskinesia (LID) in 4 patients. ^[24] Subsequently, deep brain stimulation (DBS) in the GPi received much less attention than the comparable procedure in the subthalamic nucleus (STN), though the best overall target for Parkinson disease (PD) remains controversial. ^[25]

A 2005 comparative study by Anderson et al showed no significant differences in the overall benefits of DBS at these 2 sites. ^[26] Long-term studies up to 4 years after pallidal DBS have continued to show significant improvements in the cardinal features of PD and dyskinesia as compared with status for surgery.

Through the implantation of a DBS lead in the GPi, pallidal stimulation significantly controls all the cardinal symptoms of PD (tremor, rigidity, bradykinesia), as well as dyskinesia. Candidates for pallidal DBS include levodopa-responsive patients with medication-resistant disabling motor fluctuations or levodopa-induced dyskinesia without significant cognitive impairment, behavioral issues, or mood problems.

Benefits ranging from 37% to 39% on the “off-medicine” Unified Parkinson Disease Rating Scale (UPDRS), a widely accepted rating scale of PD signs, have been reported. ^{[26, 27, 28]}

Dyskinesia has been shown to improve dramatically, and GPi-DBS has also been effective in improving motor fluctuations. The effect on tremor is less dramatic, and significant medication reduction is usually not achieved with GPi-DBS. On the other hand, cognitive and behavioral adverse effects seem to be less frequent.

Stimulator programming is more challenging in the globus pallidus than in the thalamus. Higher stimulation voltages may exacerbate freezing, nullifying the therapeutic effects of levodopa. Moreover, stimulation in different regions of the globus pallidus may have strikingly different effects. Dorsal GPi stimulation has been reported to improve akinesia and rigidity but may result in abnormal involuntary movements (ie, dyskinesias). In contrast, ventral GPi stimulation can exacerbate akinesia and gait abnormalities but improves rigidity and LID.

Subthalamic stimulation involves implantation of a deep brain stimulation (DBS) lead into the subthalamic nucleus (STN). Currently, it is the surgical procedure most commonly used to treat Parkinson disease (PD). STN-DBS controls all of the cardinal symptoms of PD, as well as motor fluctuations and dyskinesia. STN-DBS also often results in significant reductions in antiparkinsonian medications. On average, dyskinesia and antiparkinsonian medication use are reduced by 50–80%.

Candidates for STN-DBS include levodopa-responsive patients with medication-resistant disabling motor fluctuations or levodopa-induced dyskinesia (LID) without significant cognitive impairment, behavioral issues, or mood problems. Unilateral or bilateral STN stimulation is indicated in patients with advanced idiopathic PD who are still responsive to levodopa but suffer from severe fluctuations in medication response, tremor, rigidity, or akinesia in the “off” state (ie, when medications are not working) and LID in the “on” state. ^{[29, 30]}

Multiple studies have examined the effects of STN-DBS and documented significant improvements in the motor symptoms of tremor, rigidity, and bradykinesia, as well as activities of daily living. Long-term follow-up reports have shown that significant improvements in motor function and activities of daily living are maintained for up to 5 years after surgery. According to one study, STN-DBS also can increase the sleep quality of PD patients, as measured by the Parkinson's disease sleep scale (PDSS). However, the study did not show improvements in the Epworth Sleepiness Scale (ESS). ^[31]

A meta-analysis found that on average, doses of levodopa equivalents were reduced by 55.9% after STN-DBS; dyskinesia was reduced by 69.1%; daily “off” periods were reduced by 68.2%; and quality of life was improved by 34.5%. ^[32] “On” time is also significantly increased, from 27% of the day at baseline to 74% at 3 months. Improvement is usually stable, at least up to 5 years.

Bilateral STN stimulation may produce dramatic beneficial effects on midline symptoms such as gait, posture, and balance. A 1-year study of unilateral STN-DBS in 37 patients found significant bilateral benefit; these researchers suggested unilateral stimulation followed by a later contralateral procedure, if necessary, especially in patients with prominent asymmetry. ^[29]

Selected patients with PD derive significant benefit from neuroablation or stimulation at the ventral intermediate (VIM) nucleus or the globus pallidus pars interna (GPi), in most instances akinesia (ie, freezing) and gait abnormalities are not improved significantly. Unfortunately, these symptoms are commonly the most disabling features of advancing PD. Consequently, a great deal of attention has been paid to a new procedure—bilateral electrostimulation of the STN.

The substantial decrease in dosage and frequency of antiparkinsonian drugs that is possible after STN-DBS can have an additive effect to LID. In some cases, patients may experience severe dyskinesias necessitating the reduction of dopaminertic medications. Whereas some groups significantly decrease drug dosages immediately after surgery, the authors prefer to act more conservatively; many patients do not tolerate immediate dosage reductions and may experience significant mood abnormalities—in particular, apathy and depression.

By acting on the gating mechanism involved in response initiation, STN-DBS may produce improvement in motor function at the price of increasing certain types of impulsive behavior. ^[33] Positron emission tomography (PET) studies have correlated apathy after STN-DBS with local changes in glucose metabolism. ^[30]

Adverse events associated with STN-DBS can be classified into 3 main groups, including surgical, hardware, and stimulation-related (see Complications), which are better recognized and managed currently.

As mentioned, there are two main anatomic targets for using DBS to treat PD – the STN and the GPi. There have been several large randomized studies comparing STN and GPi DBS in PD. It is suggested that both STN DBS and GPi DBS overall equally and successfully improve motor symptom, and are similar in cost-effectiveness. ^{[34, 35, 36, 37, 38, 39]}  However, although no differences were observed in the on phase between STN DBS and GPi DBS, significant differences were seen in the off phase; STN DBS was more effective in terms of motor function improvement in the off phase. ^[40] There are different opinions in terms of effects of STN DBS and GPi DBS on quality of life. Some authors have found no significant difference between the STN and GPi targets. ^[34] However, others agree with that greater improvements in quality-of-life measures are achieved in patients with GPi DBS. ^[40]

GPi DBS can be used for patients with more axial symptoms, gait issues, dyskinesias, depression, and word fluency problems. ^[41] STN DBS is often favored in reducing medication post surgery, and for patients with greater tremor. ^[41]  STN-DBS has also demonstrated an improvement in the quality of sleep for patients. ^[42]

The stimulation settings in patients with GPi DBS are significantly higher in amplitude and pulse width as compared to STN DBS due to the large size of GPi. ^{[41, 42, 43]} Therefore, GPi DBS requires more frequent battery changes. On the other hand, the neurostimulator battery lasts longer for patients with STN DBS due to low stimulation parameters. The small size of STN make it easier to spread DBS stimulation to neighboring circuits in the limbic or associative areas of the STN, causing greater deterioration of cognitive and psychiatric parameters in patients with STN DBS. ^{[41, 42]}

Pedunculopontine nucleus DBS (PPN DBS) is a promising approach to treat patients with PD, particularly medication-refractory gait freezing and falls. ^[44] However, PPN DBS is still under the phase of investigation. The clinical data showed that gait freezing and falls can be improved by PPN DBS. ^[44] However, it is unclear whether PPN DBS can improve quality of life in patients with PD. Moreover, a collaborative effort is required to confirm whether PPN DBS is a reliable therapy for PD or not. ^[44]

Surgical

Surgical complications of deep brain stimulation (DBS) are comparable to those of other neurosurgical procedures. Serious adverse events occur in 1–2% of patients. Brain hemorrhages can result in permanent neurologic sequelae (eg, aphasia, hemiparesis, and coma) or death. Intracranial hemorrhage occurs in 3.9% of patients. ^[32] Infection occurs in about 3-5% of patients and may require explantation of the device until the infection is resolved. Seizures are rarely described; postoperative confusion is relatively frequent but usually transient. The risk of surgical complicatoins may be similar between STN DBS and GPi DBS. However, GPi DBS may have a high risk of infection due to more frequent battery replacement.

Hardware-related

Hardware-related complications include malfunction of the implantable pulse generator (IPG), breakage or displacement of the lead, skin erosion, superficial infections, and device fractures. These complications can occur in up to 25% of patients and generally require additional surgery. Misplacement of the lead may occur in approximately 10% of patients and require additional surgery to correct lead placement. Systematic review of hardware-related complications showed that the most common hardware-related complications were infections (5.12% of patients), followed by lead migration (1.6%), lead fracture (1.46%), IPG malfunctions (1.06%), and skin erosions without infections (0.48%). ^[45]

Although not considered a complication per se, replacement of the device’s battery generally is required every 3–5 years, and this process necessitates additional outpatient surgery.

Stimulation-related

Stimulation-related complications include muscle pulling, paresthesias, eyelid apraxia, hypophonia, worsened postural instability, visual disturbances, mood changes, and pain. Hemiballismus can occur with higher stimulation voltages, but it is controlled successfully by reducing the voltage, decreasing the dose of levodopa, or both. In general, all stimulation-related complications can be addressed with electrical parameter changes.