Deep Brain Stimulation for Parkinson Disease

Updated: Nov 20, 2014
  • Author: Rajesh Pahwa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Overview

Overview

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 20 years, DBS reemerged as one of the most effective treatments for advanced movement disorders. [1, 2]

Deep brain stimulation, 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; it can be adjusted as the disease progresses or adverse events occur; and bilateral procedures can be performed without a significant increase in adverse events.

Continued refinement of the knowledge of basal ganglia circuitry and PD pathophysiology has narrowed the focus of movement disorder surgery to 3 key gray matter structures: the thalamus, the globus pallidus, and the subthalamic nucleus. DBS is used to relieve both parkinsonian tremor and essential tremor.

A randomized, controlled trial in 255 patients with advanced PD found that bilateral DBS was more effective than best medical therapy in improving “on” time without troubling dyskinesias, motor function, and quality of life at 6 months; however, DBS was associated with an increased risk of serious adverse events. [3]

In Australia, 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. [4]

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Mechanism of Action

Currently, no explanation clearly describes the mechanism of action of deep brain stimulation (DBS), though several hypotheses have been formulated.

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. [5]

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Advantages and Disadvantages

The main advantages of deep brain stimulation (DBS) are its reversibility and adjustability. Because the DBS lead is left in place, physicians have ongoing access to the target site, which allows them to adjust stimulation parameters 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.

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Procedure

The deep brain stimulation (DBS) system consists of a lead that is implanted into the targeted brain structure (thalamus, globus pallidus interna, or subthalamic nucleus [STN]). 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 chest cavity. The lead and the IPG are connected by an extension wire that is tunneled down the neck under the skin (see the image below).

The Medtronics, Inc, Activa Tremor control system The Medtronics, Inc, Activa Tremor control system consists of 3 components: (1) the stimulating lead, which is implanted to the desired target; (2) the extension cable, which is tunneled under the scalp and soft tissues of the neck to the anterior chest wall; and (3) the pulse generator, which is the programmable source of the electrical impulses.

DBS provides monopolar or bipolar electrical stimulation to the targeted brain area. Stimulation amplitude, frequency, and pulse width can be adjusted to control symptoms and eliminate 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.

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) l Implantation of the deep brain stimulation (DBS) lead.

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 on the morning of the procedure, and a targeting MRI is performed (see the second image below).

The stereotactic headframe is applied at the start The stereotactic headframe is applied at the start of surgery. The MRI-localizing box is attached to the frame only during the targeting MRI. The localizer defines the working volume of the frame and provides the reference coordinate system from which the target coordinates are derived.
Axial, fast spin-echo inversion recovery MRI at th Axial, fast spin-echo inversion recovery MRI at the level of the posterior commissure. The typical target for placing a thalamic stimulator is demonstrated (cross-hairs).

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.

Intraoperative physiological monitoring equipment. Intraoperative physiological monitoring equipment. The surgical team, consisting of a neurosurgeon, a neurologist, and a highly trained neurophysiologist (pictured), employs single-cell microelectrode recording to define the surgical target physiologically.
Insertion of an electrode during deep brain stimul Insertion of an electrode during deep brain stimulation for Parkinson's disease.

Magnetic resonance imaging (MRI) of the brain is performed immediately after the procedure (see the image below) to confirm proper electrode placement and to make sure that no hemorrhage has occurred. If the MRI result is acceptable, the patient is returned to the operating room, where the remainder of the device is implanted with the patient under general anesthesia.

Postoperative coronal MRI demonstrating desired pl Postoperative coronal MRI demonstrating desired placement of bilateral subthalamic nuclei-deep brain stimulation (STN-DBS) leads.

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).

The deep brain stimulating lead is equipped with 4 The deep brain stimulating lead is equipped with 4 electrode contacts, each of which may be used, alone or in combination, for therapeutic stimulation.

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).

Deep brain stimulation parameters can be adjusted Deep brain stimulation parameters can be adjusted at any time using a transcutaneous programmer.

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. [6] 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.

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Thalamic Stimulation

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. [7] In most patients, the very good results with stimulation seen at 1 year were maintained after more than 6 years. [8]

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.

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Pallidal Stimulation

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. [9] 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. [10]

A 2005 comparative study by Anderson et al showed no significant differences in the overall benefits of DBS at these 2 sites. [11] 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. [11, 12, 13]

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.

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Subthalamic Stimulation

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. [14, 15]

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.

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%. [16] “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. [14]

Whereas select 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 dopamimetic 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. [17] Positron emission tomography (PET) studies have correlated apathy after STN-DBS with local changes in glucose metabolism. [15]

Adverse events associated with STN-DBS can be classified into 3 main groups (see Complications):

  • Surgical complications
  • Hardware-related complications
  • Stimulation-related complications
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Pallidal Stimulation Versus Subthalamic Stimulation

No large controlled trials comparing deep brain stimulation (DBS) of the subthalamic nucleus (STN) with DBS of the globus pallidus pars interna (GPi) stimulation have been completed; however, a large well-designed study is currently under way.

Several small uncontrolled studies have compared STN-DBS with GPi-DBS. Most studies have shown greater improvement after STN-DBS than after GPi DBS, and antiparkinsonian medications are reduced only after STN-DBS. Accordingly, STN-DBS is currently the surgical procedure of choice for Parkinson disease.

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Complications

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. [16] 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.

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.

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.

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