Pallidal Interventions for Parkinson’s Disease

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CHAPTER 79 Pallidal Interventions for Parkinson’s Disease

The basal ganglia are a collection of subcortical nuclei involved in the focusing and scaling of movement. These nuclei participate in loop circuits involving the cortex and thalamus. A foundation of basal ganglia surgery for movement disorders is the “segregated circuit” hypothesis. This hypothesis holds that cortex–basal ganglia–thalamocortical loops that modulate different functions—somatic motor, limbic, associative, and oculomotor—involve anatomically distinct regions of each basal ganglion nucleus. This allows surgical intervention in the motor circuit without interfering with nonmotor functions. The motor part of the internal globus pallidus (GPi) is its posterior and lateral part, based on tract tracing in nonhuman primates and electrophysiology in humans and nonhuman primates.

The primary input structures of the basal ganglia are the striatum and the subthalamic nucleus (STN). The GPi is the primary output structure of the basal ganglia. The striatum and the GPi are connected by two major intrinsic basal ganglia pathways—a direct striatopallidal pathway and an indirect trisynaptic pathway from the striatum to the external globus pallidus (GPe), GPe to STN, and STN to GPi. The striatal cells originating in the direct pathway facilitate movement, and those originating in the indirect pathway suppress movement; thus, normal movement is thought to depend on an appropriate balance of direct and indirect pathway activity. The GPi is the final common terminus of both direct and indirect pathways. The posterior GPi sends a large GABAergic projection to the ventrolateral thalamus, with collaterals to the brainstem pedunculopontine nucleus. Because the GPi is a relatively small nucleus, a fairly focal intervention in the GPi has a major impact on basal ganglia output.

In the context of movement disorders such as Parkinson’s disease (PD), pallidal surgery refers to lesioning or chronic electrical stimulation (deep brain stimulation [DBS]) of the posterior GPi. Lesioning of the GPi, or pallidotomy, was first performed in patients with PD in the 1940s and 1950s, before any theoretical understanding of its function. The first modern study of pallidotomy for PD (performed in the era of computed tomography and magnetic resonance imaging) was that of Laitinen and colleagues ¹ in 1992. In the 1990s, chronic DBS emerged as a reversible, adjustable alternative to stereotactic lesioning and was used at all targets where lesioning was effective. GPi-DBS was first reported by Siegfried and Lippitz² in 1994. Several controlled studies have shown that either GPi-DBS or STN-DBS can modify all cardinal motor signs of PD.³ DBS is safer than pallidotomy for bilateral intervention. Currently, for patients undergoing DBS for PD, the STN is the more commonly selected target, based on evidence that STN-DBS allows a greater reduction in antiparkinsonian medications and a lower stimulation voltage than GPi-DBS. However, randomized studies comparing GPi and STN are showing comparable efficacy,⁴ and there may be subgroups of PD patients for whom GPi-DBS is preferred. At this time, GPi-DBS for PD is an “on-label” indication for the Medtronic Activa DBS system (Minneapolis, MN).

Mechanism of Action

In the parkinsonian state, neuronal discharge in the GPi and STN is abnormal in several ways: spontaneous firing rates are elevated, neurons that normally discharge independently develop abnormal synchrony, bursting discharge is increased, neurons show oscillations in both the theta to alpha (3 to 8 Hz) and low beta (8 to 20 Hz) ranges, and cells that normally respond to movement of a single joint show responses to multiple joints (loss of joint selectivity).⁵ Pallidotomy, when it covers the majority of the motor territory of the GPi, eliminates these abnormalities. Although it clearly does not restore normal function (presumably, it reduces GPi output to zero), it partially corrects the cortical metabolic abnormalities found in PD.⁶ Apparently, motor-controlling cortical areas in adults can function more normally without basal ganglia output than under the influence of the highly abnormal basal ganglia output characteristic of PD.

With regard to GPi-DBS, the mechanism of action is less clear. Originally conceived of as a “reversible lesion,” it now appears that DBS at the frequencies used in PD surgery (100 to 200 Hz) drives the efferent axons of the stimulated structure. The effect on neuronal cell bodies is not certain. GPi-DBS decreases the firing rates in one of its major efferent targets, the ventrolateral thalamus, consistent with activation of the GABAergic pallidothalamic projection.⁷ Thus, unlike pallidotomy, GPi-DBS does not suppress the abnormally increased GPi firing rates, although it probably does reduce bursting and oscillatory activity in the most detrimental (alpha to beta) frequency ranges.

Indications

Indications for pallidal surgery in PD are as follows:

• Clear diagnosis of idiopathic PD, determined by a movement disorder neurologist

• Documented improvement in symptoms with levodopa-carbidopa (Sinemet)

• Presence of complications of medical therapy (motor fluctuations and levodopa-induced dyskinesias) despite optimal medical management by a movement disorder neurologist

Contraindications to pallidal surgery in PD are as follows:

• Significant cognitive impairment (<24/30 on the Folstein Mini Mental Status Exam or <124 on the Mattis Dementia Rating Scale)

• Presence of prominent non–levodopa-responsive symptoms such as postural instability, hypophonia, and “on-medication” freezing of gait

• Coagulopathy, untreated hypertension, severe diabetes, or another medical condition that increases the risk of stereotactic surgery

In addition to the indications listed, good candidates for pallidal lesioning include patients with asymmetric symptoms (because pallidotomy can be safely performed on only one side) and patients who will have difficulty complying with the follow-up required for the management of deep brain stimulators. For patients requiring bilateral surgery and who can comply with follow-up appointments, bilateral DBS is generally preferred. The exact indications for GPi-DBS versus STN-DBS have not been well defined.⁴^,⁸ There is no evidence that either pallidotomy or GPi-DBS is neuroprotective against ongoing brain degeneration in PD; thus, they should not be performed early in the disease when symptoms are well managed medically.

Results

Outcomes for surgical therapy in PD are described in terms of standard rating scales of parkinsonian motor signs and symptoms, the most prevalent of which is the Unified Parkinson’s Disease Rating Scale (UPDRS). In a randomized trial of pallidotomy with a medical control arm and blinded evaluations, unilateral pallidotomy produced a 32% decrease (improvement) in the total UPDRS score at 1 year, which was significant compared with a 5% increase in the control group.⁹ A European study produced similar results at 6-month follow-up.¹⁰

Unilateral pallidal stimulation produced similar results to unilateral pallidotomy in a randomized study.¹¹ Unilateral GPi-DBS has also been compared with unilateral STN-DBS, and both procedures produced similar improvements in contralateral bradykinesia¹² and manual dexterity.¹³ The only published randomized comparison of bilateral GPi-DBS and bilateral STN-DBS showed a 38% improvement in motor UPDRS in the GPi group not taking medication, compared with 48% in the STN group. However, cognitive and behavioral complications were observed only in the STN group.⁴ A large study (300 patients) is in progress comparing bilateral pallidal DBS (and bilateral STN-DBS) with a medical control arm.

Complications

The most serious intraoperative or early postoperative complication of DBS or pallidotomy is intracerebral hemorrhage. In the series reported by Binder and colleagues,¹⁴ the risk of symptomatic hemorrhage from DBS surgery on a per patient basis was 2.1%, which is consistent with other large series. Early postoperative complications include mental status changes and hardware infection. In the report by Sillay and coworkers,¹⁵ the incidence of perioperative (within 6 months) device infection requiring a return to the operating room for partial or complete hardware removal was 4.5% per patient. Long-term hardware-related complications include skin erosion, lead fracture, pulse generator migration, and lead twisting. The incidence of lead fracture and other hardware complications increases with longer postoperative follow-up time and may be as high as 8.4% per electrode-year.¹⁶

Long-term stimulation-related complications include induced dysarthria and worsening of bradykinesia or akinesia with certain programming configurations. These symptoms can be minimized by altering the stimulation parameters. Long-term cognitive and mood sequelae are a serious consideration with STN-DBS, but it is not clear whether GPi surgery is associated with similar risks.

The risk of hemorrhagic stroke is probably similar for pallidotomy and pallidal DBS. Lesioning surgery does not entail any hardware-related complications and has a much lower rate of infection owing to the absence of an indwelling device. Lesioning, however, carries certain risks that are not present with DBS surgery. It is possible to create inadvertent thermal lesions in critical structures surrounding the intended target, such as the corticobulbar tract (CBT), cortisospinal tract (CST), or optic tract (OT). Bilateral lesioning of the GPi carries a high risk of permanent speech or cognitive dysfunction, even when lesions are correctly placed.¹⁷^,¹⁸ Delayed ischemic subcortical infarction appears to be more common following pallidotomy than after GPi-DBS.¹⁹^,²⁰ This may relate to thermal damage to neighboring perforating vessels at the time of radiofrequency lesioning.

Surgical Technique

The optimal methods for movement disorder surgery are far from standardized and continue to evolve.

Stereotactic Localization

Figure 79-1 shows the intended active contact location for GPi-DBS within the posterior motor territory of the nucleus. Leads are placed so that the active contact is 3 to 4 mm from the border between the GPi and the internal capsule; this allows the stimulation-induced electrical effect to spread throughout most of the motor territory of the GPi without spreading to the internal capsule. For pallidotomy, the lesion includes the point shown but should extend to the border of the internal capsule posteromedially, the border of the GPe dorsolaterally, and the base of the pallidum inferiorly. Including the GPe in the lesion reduces the efficacy of pallidotomy.²¹

FIGURE 79-1 Typical active contact location for deep brain stimulation of the globus pallidus interna (GPi; dot) with respect to axial plane anatomy drawn from the Schaltenbrand and Wahren ²⁶ atlas of the human brain. The axial plane selected passes through the intercommissural line. AC, anterior commissure; GPe, globus pallidus externa; PC, posterior commissure; 3rd V, third ventricle.

(Modified from Starr PA. Placement of deep brain stimulators into the subthalamic nucleus or globus pallidus internus: technical approach. Stereotact Funct Neurosurg. 2002;79:118-145.)

A variety of techniques can be used for movement disorder surgery, including frame-based approaches, frameless neuronavigation-guided approaches, and frameless approaches with guidance by real-time interventional magnetic resonance imaging (MRI). The frame-based approach is most commonly used for pallidal interventions and is described here. A stereotactic head frame is placed with its axes orthogonal to standard anatomic planes of the brain. The eyes and mouth should remain unencumbered by the frame to allow visual field examination and airway access. Proper frame alignment ensures that the preoperative images, as well as maps made from intraoperative physiologic exploration, are interpretable in terms of familiar anatomy corresponding to standard brain atlases.

Magnetic Resonance Imaging Pulse Sequences

Two magnetic resonance image sets are obtained. For targeting by reference to the midcommissural point, a gadolinium-enhanced volumetric three-dimensional gradient echo (3D-GRE) image covering the whole brain in 1.5-mm axial slices is obtained. For targeting based on direct visualization of the target nucleus, a limited set of two-dimensional images passing through the target region is acquired, optimized for the best resolution of nuclear boundaries: axial T2-weighted fast spin echo (T2-FSE) images or axial inversion recovery fast spin echo (IR-FSE) images. Contiguous (zero interspace) image sets are used. Both sets of images are imported into a stereotactic surgical planning software package (Framelink, Medtronic-Sofamor-Danek, Minneapolis, MN). The two image sets are then computationally fused and reformatted to produce images orthogonal to the anterior commissure (AC)–posterior commissure (PC) line and midsagittal planes, and fiducial markers are registered.

Target Selection

Stereotactic coordinates for the initial anatomic target are first determined indirectly on reformatted 3D-GRE images. Typical coordinates are as follows: anteroposterior (AP) = +2 mm and vertical = −5 mm with respect to the midcommissural point, and lateral = 17.5 mm from the third ventricular wall. The lateral and vertical coordinates are then adjusted with respect to the individual nuclear anatomy on T2-FSE images or IR-FSE images, as shown in Figure 79-2. The target for the DBS lead tip or the inferiormost extent of a pallidotomy lesion is at the base of the GPi immediately superior to the lateral border of the OT. The active DBS contact, or the center of a pallidotomy lesion, is generally on the axial plane passing through the commissures. The active contact is 1 to 2 mm medial to the external accessory lamina, which forms the boundary between the GPi and GPe (see Fig. 79-2), and 3 to 4 mm from the internal capsule. Individual variation in the lateral position of the GPi is significant.

FIGURE 79-2 Stereotactic targeting of the GPi. A, Axial T2-weighted fast spin echo image at the level of the anterior commissure (AC) and posterior commissure (PC), used to determine the anteroposterior (AP) and lateral coordinates. The AP coordinate is 2 mm anterior to the midcommissural point. The lateral coordinate is adjusted to be 2 mm medial to the external accessory lamina (lateral border of the internal pallidum), indicated by the arrow. B, Coronal three-dimensional gradient echo (3D-GRE) image with the coordinate passing 2 mm anterior to the midpoint of the AC-PC line, through the posterior mamillary bodies. The vertical coordinate of the initial anatomic target point is determined from the dorsal border of the optic tract (arrow). C and D, Planning the entry point and trajectory using 3D-GRE imaging, which is computationally reformatted into “navigation” views that are coplanar (C) or perpendicular (D) to the planned electrode trajectory (arrow).

(Modified from Starr PA. Placement of deep brain stimulators into the subthalamic nucleus or globus pallidus internus: technical approach. Stereotact Funct Neurosurg. 2002;79:118-145.)

Entry Point and Trajectory Determination

A typical trajectory is 60 degrees from the AC-PC line in the sagittal projection, and 0 degrees lateral from the vertical in the coronal projection (e.g., a parasagittal approach). This standard trajectory is visualized on volumetric MRI using “navigation” views. If the trajectory will pass through the ventricle, I adjust the arc angle to a more lateral trajectory that avoids the ventricle. If the trajectory will pass through any sulci, I adjust the arc or ring angles (usually no more than 5 degrees) to avoid these and decrease the risk of damaging a cortical vessel. Figure 79-2 shows satisfactory trajectories to the GPi in navigation views.

Patient Positioning and Surgical Exposure

To provide access to the side of the body contralateral to implantation during microelectrode recording (MER) and test stimulation, the patient is placed in a semisitting position with the implantation side toward the anesthesiologist. The head frame is fixed to the Mayfield headrest in a neutral position. The patient’s head is draped so that the face and eyes are visible and accessible on the nonsterile side of the drape. Intravenous sedation (propofol) is used for the opening and closing. The typical trajectory places the bur hole just anterior to the coronal suture. I use a 14- to 15-mm bur hole to allow for several parallel microelectrode trajectories and provide space for a bur hole–mounted lead-anchoring device. Immediately after opening the dura and placing the guide tube for the microelectrode below the pial surface, I fill the hole with fibrin glue or a commercial equivalent. This technique reduces the risk of air emboli, prevents continued air entry, and dampens pulsation artifact in the MER.

Microelectrode Recording and Microstimulation

The theoretical maximal accuracy of a stereotactic system is rarely achieved owing to a variety of factors, such as intraoperative brain shift, that can affect the accuracy of probe placement. MER is a technique with high spatial resolution that can provide physiologic confirmation of accurate targeting. I record single-unit, extracellular action potentials using high-impedance (0.6 to 1.0 Mohm at 1000 Hz) tungsten or platinum-iridium microelectrodes. A micropositioner system (FHC positioner, Frederick Haer, Bowdoinham, ME; Elekta micropositioner, Elekta Inc., Atlanta, GA) is used to advance microelectrodes and DBS electrodes in a controlled manner and to measure their exact depths. Micropositioner systems may have an X-Y stage that permits continuous movements in the AP and mediolateral dimensions, or they may have multiple discrete channels separated by 2 to 3 mm through which instruments are passed. For MER in the pallidal region, I place the microelectrode guide tube 30 mm above the anatomic target. After completing MER, I change the guide tube on the micropositioner to a larger one that accommodates the DBS lead. The DBS guide tube length is adjusted so that it extends 10 to 15 mm above the final target.

Action potential discharge patterns encountered in the region of the GPi are shown in Figure 79-3. The microelectrode usually encounters the striatum (caudate or putamen) and then the GPe before the GPi. The majority of striatal neurons have very low (0 to 10 Hz) spontaneous discharge rates. In PD, GPe neurons have spontaneous discharge rates of 30 to 60 Hz and typically discharge in “bursting” or “pausing” patterns; GPi neurons are faster, with spontaneous discharge rates of 60 to 100 Hz. Cells with regular discharge rates of 20 to 40 Hz, known as “border” cells, are typically found in the white matter laminae surrounding the GPe and GPi. The OT is identified by light-evoked fiber activity below the inferior margin of the GPi.

FIGURE 79-3 Microelectrode recordings of spontaneous neuronal activity from the region of the globus pallidus interna (GPi). Each trace represents a 1-second recording in a patient with Parkinson’s disease. GPe, globus pallidus externa.

(Modified from Starr PA. Placement of deep brain stimulators into the subthalamic nucleus or globus pallidus internus: technical approach. Stereotact Funct Neurosurg. 2002;79:118-145.)

Cells in the GPi that are responsive to joint movements usually respond to the movement of one or several joints in a restricted region on the contralateral side of the body. The motor territory of the GPi is somatotopically organized, with leg representations more dorsal and more medial than arm representations.²²^–²⁴ Thus, noting the distribution of neuronal receptive fields helps determine the mediolateral coordinate of an electrode track. In patients with tremor, cells with discharges grouped at the tremor frequency are often recorded. Microstimulation can be used to localize both the CBT-CST and the OT. The CBT-CST in the internal capsule is identified by evoking muscle contractions (usually of the tongue, face, or hand) at low current thresholds (e.g., 10 µA at 300 Hz, 200 µsec pulse width). The OT is identified when the patient reports visual phenomena (focal scintillating scotomata) at low current thresholds.

Lead Placement and Test Stimulation

I use the Medtronic model 3387 DBS leads. These quadripolar leads have four platinum-iridium contacts that are 1.5 mm long and separated by 3 mm, center to center (also available is the model 3389 lead, with contacts separated by 2 mm, center to center). It is important to avoid placements that are too close (0 to 2 mm) to the internal capsule; in this situation, it would be impossible to use the DBS system at adequate voltages for symptomatic relief owing to stimulation-induced adverse motor effects. I place the end of the distal contact (contact 0) 1 mm superior to the OT.

Before internalizing the lead, I perform a final check on its location by testing it intraoperatively with the extracranial end attached to the Medtronic model 3625 handheld pulse generator. Test stimulation is performed at the following settings: contacts 0−, 3+; 185 Hz; 90 µsec pulse width. Voltage thresholds for activating the OT and the CBT-CST indicate the proximity of the probe to inferior and posteromedial borders, respectively. It should be possible to elicit dysarthria or tonic facial contraction at high voltages, typically 6 to 12 V (other parameters are as noted earlier); if this occurs below 3 V, the lead is too close to the CBT and should be moved anterolaterally. Many patients also report transient visual phenomena (flashes) at 6 to 12 V.

Symptoms other than tremor may not respond immediately to acute intraoperative test stimulation. Thus, failure to improve bradykinesia with brief test stimulation does not necessarily imply an incorrect lead placement. Motor symptoms may be partially or completely suppressed by simple placement of the DBS lead, even before test stimulation. This “microlesion” effect, when observed, provides evidence that the probe is within or has passed through the motor territory of the GPi. Unless an intentional permanent lesion is made, this effect is temporary.

Following satisfactory test stimulation, the lead is anchored to the skull using a commercial bur hole–mounted lead-anchoring device (Stimlock, Medtronic Inc., Minneapolis, MN). When beginning a DBS program or introducing a new methodology, it is wise to use intraoperative lateral fluoroscopy during final lead positioning and anchoring to confirm correct lead depth with respect to the frame arc center. A temporary protective cap is placed over the lead, and it is positioned under the parietal scalp posterior to the pinna of the ear.

Placement of the Lead Extender and Pulse Generator

After removal of the head frame and induction of general endotracheal anesthesia, the patient is moved to a supine position with the head turned away from the side of the implant, similar to the positioning for a ventriculoperitoneal shunt procedure. A 2-cm incision is made over the temporary protective cap. A 5-cm infraclavicular incision is made, and a pocket is dissected bluntly over the pectoralis fascia to hold the pulse generator. The lead extender is tunneled between the two incisions and attached proximally to the DBS lead, taking care to place the Silastic insulating sheath over the connector, and distally to the pulse generator.

The connector on the lead extender is positioned under the galea in the region of the parieto-occipital junction, 2 to 4 cm posterior to the pinna. If it is placed in the neck, constant mobility at the lead-connector junction may cause lead fracture. After attaching the distal connector to the pulse generator, the generator is placed in its pocket so that the engraved letters on the case face superficially. The skin is closed with a subcuticular closure and Steri-Strips for the pectoral incision and running nylon for the scalp incisions.

Internal Globus Pallidus Lesioning Technique

For pallidotomy, the localization techniques are identical to those for GPi-DBS. After MER localization, lesioning is planned based on the MER map to correspond to the total mapped motor area. MER mapping for lesioning is more extensive than for DBS because localization with absolute certainty is imperative. Lesioning is performed with a 3-mm cylindrical radiofrequency electrode (Radionics, Burlington, MA) at multiple depths and along multiple (two to three) trajectories of the lesioning probe, at 70°C to 85°C for 1 minute each.²²

Postoperative Management

Magnetic Resonance Imaging

Medtronic has issued specific guidelines for the use of MRI in the presence of an implanted Activa DBS system. I routinely obtain 1.5-tesla MRI postoperatively and have had no adverse events in more than 1000 examinations.²⁵ Postoperative imaging of the DBS lead is important for documentation of its exact location (Fig. 79-4).

FIGURE 79-4 GPi electrode location on postoperative magnetic resonance image at the axial level of the anterior and posterior commissures.

(Modified from Starr PA. Placement of deep brain stimulators into the subthalamic nucleus or globus pallidus internus: technical approach. Stereotact Funct Neurosurg. 2002;79:118-145.)