AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

Background

Surgical approaches to the treatment of Parkinson disease (PD) have developed primarily in response to the failure of medical therapies to provide long-term relief from the disabling motor symptoms of the disease. The introduction of levodopa (L-DOPA) in the mid-1960s, an event that revolutionized the medical management of PD, sets the focal point around which the history of movement disorder surgery may be examined.

Before the advent of L-DOPA therapy, a combination of factors, including the absence of effective medical therapies, the introduction of human stereotaxis, the large population of patients with postencephalitic parkinsonism, and a more permissive environment, promoted the development of neurosurgical approaches to PD and related disorders. Many of the surgeries for movement disorders performed today were introduced during this period.

With the advent of L-DOPA in the late 1960s and its remarkable effectiveness against most symptoms of PD, surgical treatments were abandoned except in rare situations when tremor was medically unresponsive. Over time, however, waning of the response to L-DOPA and unexplained side effects of long-term treatment became apparent.

The relative failure of L-DOPA to provide a lifelong cure for PD coincided with advances in stereotactic technique that resulted in a renaissance of the field of movement disorder surgery. Many factors contributed to this rebirth, including the following:

• Improved stereotactic frames adapted for use with CT scan and MRI ushered in the era of image-guided neurosurgery.
• Computers permitted human stereotactic atlases to be digitized and overlaid onto images of the patient's brain. This mathematical form-fitting enhanced targeting accuracy in the early CT scan/MRI era.
• Advances in the understanding of basal ganglia neurophysiology and circuitry provided a stronger rationale for some surgical approaches and revealed alternative sites that might be targeted.
• Refined microelectrode recording (MER) techniques permitted more detailed physiologic mapping of the basal ganglia in the operating room, providing more detailed knowledge of electrode location prior to neuroablation or insertion of an implanted deep brain-stimulating lead.
• The introduction of long-term deep brain stimulation (DBS) as an alternative to irreversible neuroablative procedures may enhance the safety of these procedures while maintaining therapeutic efficacy. Additionally, surgical targets that are lesioned at great peril may be treated effectively with DBS, broadening the surgical options for patients with PD.

Pathophysiology

The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective neurotoxin that destroys the dopaminergic cells of the substantia nigra pars compacta (the same cells that degenerate in PD), led to the development of primate models of PD. A more detailed model of the basal ganglia circuitry was produced by the seminal studies in MPTP-treated monkeys, which develop a parkinsonian syndrome. Although incomplete, this functional model has contributed significantly to the rebirth of movement disorders surgery. The basic structure of the circuit is demonstrated in Image 1 and described briefly in the following:

• The corpus striatum, composed of the caudate and putamen, is the largest nuclear complex of the basal ganglia.
• The striatum receives excitatory input from several areas of the cerebral cortex as well as inhibitory input from the dopaminergic cells of the substantia nigra pars compacta (SNc).
• These cortical and nigral inputs are received by the spiny projection neurons, which are of 2 types: those that project directly to the internal segment of the globus pallidus (GPi), the major output site of the basal ganglia, and those that project to the external segment of globus pallidus (GPe), establishing an antagonistic indirect pathway to GPi via the subthalamic nucleus (STN); for an illustration of the STN, see Image 2.
• The complementary actions of the direct and indirect pathways regulate the neuronal output from GPi, which provides tonic inhibitory input to the thalamic nuclei that project to the primary and supplementary motor areas.
  • The direct pathway inhibits GPi, resulting in a net disinhibition of the motor thalamus and facilitation of the thalamocortical projections.
  • The indirect pathway, through its serial connections via GPe and STN, provides excitatory input to the GPi, increasing inhibitory action on the thalamocortical projections.
• In PD, loss of dopaminergic input to the striatum leads to a functional reduction of direct pathway activity and a facilitation of the indirect pathway. These changes result in an increase in excitatory output to the GPi and a concomitant hyperinhibition of the motor thalamus. The excessive inhibitory outflow from GPi reduces the thalamic output to supplementary motor areas that are critical to the normal execution of movements.
• The MPTP-treated monkey is a good model for the negative symptoms of PD (ie, rigidity and bradykinesia) and supports both GPi and STN as rational targets for therapeutic lesions or DBS in patients with PD. In fact, positron emission tomography (PET) studies demonstrate reduced inhibitory afferent activity to the thalamus and "renormalization" of motor cortical activity in patients with PD who undergo therapeutic lesioning of the GPi (ie, pallidotomy), postoperative changes that are predicted by the model. However, this model does not explain some aspects of PD pathophysiology.
• Tremor: The means by which dopaminergic cell loss results in tremor and the fact that the tremor typically abates with voluntary activity remain unexplained. Tremor activity is detected consistently in the ventrolateral thalamic nucleus (VL) of patients with parkinsonian tremor or essential tremor (ET). VL continues to be the primary surgical target for treating medically refractory tremor, but whether the motor thalamus is the primary generator of tremor activity is unclear. Recent studies also implicate the STN-GP axis in the generation of tremor in patients with PD, and both pallidotomy and STN-DBS are effective treatments for medically refractory tremor.
• A valid physiological explanation for L-DOPA-induced dyskinesia (LID) is also lacking. LID is defined as hyperkinesis of the limbs or trunk in association with L-DOPA administration. Often, these are choreiform (twisting, turning) movements, but LID also can manifest as dystonia (involuntary patterned and sustained contractions).
• According to the model, hyperkinesis results from reduced GPi activity. The reduced inhibitory output from GPi releases VL thalamus, leading to hyperstimulation of the supplementary motor areas and excessive motor activity.
• This scenario is supported by the experimental observation that STN lesions, which reduce the excitatory output from STN to GPi, cause dyskinesias in primates that are indistinguishable from LID observed in MPTP-treated primates receiving L-DOPA. However, the following facts suggest that LID is a more complex phenomenon:
• • The model predicts that pallidotomy (ie, lesioning the GPi) should exacerbate LID by reducing GPi activity; in reality, the opposite is true. In fact, LID is the symptom that is improved most reliably by Pallidotomy in Surgical Procedures. Similarly, primary dystonia also responds to pallidotomy.
  • Pharmacodynamic factors related to the chronic exogenous dopaminergic stimulation play a fundamental role in LID. Rather than a simple reduction of GPi firing rate, sensitization of dopamine receptors likely causes aberrant neuronal firing patterns, with consequent disruption of the normal flow of information to the thalamus and the cortical motor areas.

Patient Education

For excellent patient education resources, visit eMedicine's Dementia Center. Also, see eMedicine's patient education article Parkinson Disease.

PREOPERATIVE EVALUATION

Section 3 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

Good surgical outcomes begin with careful patient selection and end with attentive, detail-oriented postoperative care. The authors believe that this level of care is best provided by a multidisciplinary team comprising a movement disorder neurologist, a neurosurgeon who is well-versed in stereotactic technique, a neurophysiologist, a psychiatrist, and a neuropsychologist. Additional support from neuroradiology and rehabilitation medicine is essential. At the authors' movement disorder center, patients are evaluated for surgery as follows:

• First, a neurologist with expertise in movement disorders evaluates the patient. Patient selection is particularly important for successful STN DBS because a number of factors concur to determine positive surgical outcome (Lang, 2002; Okun, 2004). These can be summarized as follows:
  1. A diagnosis of idiopathic PD
  2. Positive response to levodopa
  3. Absence of atypical parkinsonian features
  4. Advanced disease, virtually unmanageable with dopaminergic medications
  5. Relatively young age - However, advanced age (>75 y) is not an absolute contraindication to surgery. If a patient otherwise meets the selection criteria for a procedure and the quality of life is predicted to improve substantially, surgery should be offered.
  6. Normal cognition
  7. Absence of active psychiatric disease
  8. Good social support and access to programming
• Potential surgical candidates then are evaluated by the neurosurgeon, who determines whether the patient is indeed a surgical candidate and decides which procedure(s) would benefit the patient most (see Selection of the Proper Procedure). Close collaboration between the neurologist and the neurosurgeon aids the decision-making process, minimizing patient confusion and stress.
• If the neurologist and neurosurgeon agree that the patient is a good surgical candidate, further workup includes the following:
  • Brain MRI to rule out comorbid conditions and to assess the degree of brain atrophy; significant atrophy may increase the risk of perioperative hemorrhage
  • Detailed neuropsychological testing to rule out subtle cognitive impairment, which can be worsened by the surgical procedure
  • A psychiatrist with expertise in psychiatric complications of movement disorders may be consulted to rule out active psychiatric disease and screen relevant past psychiatric history that may pose a contraindication to surgery (eg, major depression, suicidality)
  • Fluorodopa PET scan in the unusual circumstance that an alternative diagnosis of multiple system atrophy cannot be ruled out clinically
  • Medical evaluation to determine the patient's general fitness for surgery

SURGICAL TECHNIQUE

Section 4 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

During stereotactic surgery, imaging data are correlated to 3-dimensional space, permitting a target deep within the brain to be reached blindly and with minimal trauma. Frame-based techniques are dependent upon the application to the skull of a reference coordinate system, permitting any point within the brain to be described with Cartesian (ie, x, y, z) coordinates.

• Ventriculography, an important method for target localization before the development of CT scan and MR imaging, is used uncommonly now.
• CT-guided stereotaxis provides direct imaging of brain parenchyma without image distortion; however, its gray-white resolution is inferior to that of MRI and only axial imaging is possible.
• MRI provides superior target resolution and triplanar imaging; however, some smaller targets cannot always be visualized, and MRI is prone to image distortion. Although usually small, these distortions can affect targeting for functional neurosurgery.
• The possibility of targeting errors due to image distortion necessitates the use of some form of intraoperative neurophysiologic monitoring (see Image 3) to confirm the correct targeting during surgery for movement disorders. Intraoperative physiological monitoring can consist of any combination of the following:
• • Macroelectrode (>1 mm diameter) techniques include impedance measurements and direct stimulation of the target nucleus. These techniques may be used to confirm electrode location within the deep gray matter, assess the clinical effects of electrostimulation prior to permanently implanting a DBS lead (see Procedure in Deep Brain Stimulation), or estimate proximity to surrounding structures prior to lesioning.
  • Semimicroelectrodes (50-150 µm) detect field potentials of neuronal groups and can be used to determine the nature of the nucleus in which the electrode is placed (ie, sensory or motor).
  • Microelectrodes (1-25 µm) may be used to record individual neuronal field potentials or to stimulate discreet regions of the brain. While microelectrode techniques provide the most detailed information and the greatest targeting resolution, their routine use during movement disorder surgery is controversial. Detractors of the technique argue that the resolution provided by microelectrodes is not necessary to achieve good clinical results and that the methodology is difficult to perform, time consuming, and expensive; they also express speculative concern that the increased number of trajectories used with microelectrode technique may increase the risk of hemorrhage.
  • In the authors' opinion, microelectrode techniques have provided invaluable targeting data that may have prevented aberrant targeting in as many as 12% of pallidotomy cases. Moreover, the authors' hemorrhage rate and that reported in other series of microelectrode-guided functional neurosurgical procedures is no higher than that reported with macroelectrode techniques.

SURGICAL PROCEDURES

Section 5 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

Until recently, surgery for movement disorders involved predominantly destructive lesioning of abnormally hyperactive deep brain nuclei; however, the observation that high-frequency electrostimulation in the VL thalamus eliminates tremors in patients undergoing thalamotomy led to investigation of long-term DBS as a reversible alternative to lesioning procedures. 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: (1) the thalamus, (2) the globus pallidus, and (3) the subthalamic nucleus.

Neuroablative procedures

During neuroablation, a specific deep brain target is destroyed by thermocoagulation. A radiofrequency generator is used most commonly to heat the lesioning electrode tip to the prescribed temperature in a controlled fashion. The 2 most commonly performed neuroablative procedures are thalamotomy and pallidotomy, in which lesions are created in the VL thalamus and the GPi, respectively.

Ventrolateral thalamotomy

VL thalamotomy was the most frequently performed procedure for movement disorders in the pre-levodopa era because tremor responds best to thalamotomy and can be monitored more easily in the operating room than gait abnormalities, rigidity, and akinesia.

Physiological rationale: VL thalamus receives afferent innervation from 2 primary sources: the GPi via the ansa lenticularis and thalamic fasciculus and the contralateral cerebellum via the superior cerebellar peduncle. These cerebellar fibers synapse primarily in the ventral intermediate (VIM) and ventral oral posterior (VOP) nuclei, the most posterior segments of the VL. Oscillating excitatory input from the cerebellum may be responsible for the tremor observed in PD, as cellular activity synchronous with the frequency of PD tremor can be recorded in VL. These data support the clinical observation that lesions placed within VL (and specifically within VIM/VOP) arrest parkinsonian and essential tremors.

Indication: Thalamotomy is indicated in patients with PD who are disabled by medically refractory tremor. The anticipated benefit of tremor reduction or elimination must be considered carefully. Rest tremor alone is rarely disabling, and bradykinesia and rigidity can reduce dexterity irrespective of tremor.

Target and results: VIM almost unanimously is considered the best target for tremor suppression, with excellent short-term and long-term results in 80-90% of patients with PD. Rigidity and akinesia are improved less significantly. When these symptoms are prominent, other targets, including GPi and STN, are preferred.

Morbidity and mortality: The reported morbidity rate for thalamotomy ranges from 9-23%. The predominant complication is speech impairment with dysarthria and hypophonia. The risk of speech abnormalities is 30% for unilateral thalamotomy and greater than 60% following bilateral lesions. Other complications include memory loss, contralateral hemiparesis, and, more rarely, hemineglect, dystonia, hemiballismus, athetosis, and dyspraxia. Preoperative memory and language evaluation can predict patients who are at greatest risk for postoperative cognitive and language dysfunction. In the largest series, the mortality rate for thalamotomy ranges from 0.5-1%. Death results almost exclusively from intraparenchymal hemorrhage.

Pallidotomy

Svenillson and Leksell described ventral posterior pallidotomy in the 1960s; however, their report was largely overlooked. In 1992, Laitinen et al reported improved tremor, rigidity, akinesia, and LID in 38 patients treated with pallidotomy, prompting a reappraisal of the procedure performed with more modern techniques.

Rationale: The negative symptoms of PD (ie, rigidity, bradykinesia) are caused, in part, by excessive inhibitory output from the GPi to the VL thalamus (see Pathophysiology in Introduction). Lesioning of the sensorimotor region of the GPi, which lies ventral and posterior in the nucleus, decreases this hyperinhibition of motor thalamus.

Indications: Pallidotomy improves the symptoms of PD, including rigidity, bradykinesia, and gait abnormalities, as well as the long-term complications of L-DOPA therapy (ie, dyskinesia and off-state dystonia). Tremor improvement is less consistent than with thalamotomy.

Targets and results: The original pallidotomy target was in the medial and anterodorsal part of the nucleus. This so-called "medial pallidotomy" effectively relieved rigidity but inconsistently improved tremor. Leksell subsequently moved the target to the posteroventral and lateral GPi, resulting in sustained improvement in as many as 96% of patients.

Morbidity and mortality: The most serious and frequent (3.6%) adverse effect of pallidotomy is a scotoma in the contralateral lower-central visual field. This complication occurs when the GPi lesion extends into the optic tract, which lies immediately below the GPi. The risk of visual field deficit is reduced greatly by accurate delineation of the ventral GPi border by MER. Less frequent complications (<5%) include injury to the internal capsule, facial paresis, and intracerebral hemorrhage (1-2%). As with bilateral thalamotomy, abnormalities of speech, swallowing, and cognition can be observed after bilateral pallidotomy.

Subthalamotomy

Hyperactivity of the excitatory STN projections to the GPi is a crucial physiologic feature of PD. Although lesioning the STN usually has been avoided out of concern of producing hemiballismus, recent results obtained by experimental lesions of the STN in animals and humans suggest that subthalamotomy may be performed safely and may reverse parkinsonism dramatically.

DEEP BRAIN STIMULATION

Section 6 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

Introduction

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 last 15 years, DBS has reemerged as one of the most effective treatments for advanced movement disorders.

Mechanism of action

Currently, no explanation clearly describes the mechanism of action of DBS, although 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 pathological network activity has been proposed to explain DBS effects on abnormal movement disorders (McIntyre, 2004).

Advantages

The main advantages of DBS are reversibility and adjustability. Because the DBS lead is left in place, physicians have ongoing access to the target site, allowing them to adjust stimulation parameters in response to changes in the patient's condition. If stimulation induces unwanted adverse effects, the stimulator can be turned off, adjusted, or removed. In the event that 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 lesioned and the provision of a unique opportunity to study human basal ganglia physiology.

Disadvantages

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 (ie, repair/replacement of fractured wires, repeated office visits for stimulation adjustments). Currently, battery exhaustion necessitates replacement of the entire pulse generator, the most expensive component of the system (cost is approximately $8,000) every few years.

Procedure

DBS implantation is performed in 2 stages. During the first stage, the DBS lead is implanted stereotactically into the target nucleus. 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 (see Image 4). As with most stereotactic movement disorder procedures, the first stage is performed with the patient awake to allow monitoring of neurologic status. The stereotactic headframe (see Image 5) is applied on the morning of surgery and a targeting MRI is performed (see Image 6). A combination of MER and macroelectrode stimulation is used to refine the desired target physiologically. The DBS lead is implanted (see Image 7) and anchored to the skull with a burr hole cap.

A brain MRI is obtained immediately postoperatively to confirm proper electrode placement and to make sure that no hemorrhage has occurred (see Image 8). If the MRI is acceptable, the patient is returned to the operating room, where the remainder of the device is implanted under general anesthesia.

The electrode is thin (approximately 1.3 mm in diameter) and flexible, so that it atraumatically moves 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 Image 9). Thus, a great deal of therapeutic flexibility is provided, permitting customized stimulation for each patient.

Following proper patient selection and accurate lead location, competent programming of the implanted device is essential to optimized DBS therapy. After approximately 2 weeks, therapeutic electrical parameters can be set using a transcutaneous programmer (see Image 10). The primary goals of DBS programming are to maximize symptom suppression and minimize adverse effects. Minimizing battery drain is a significant secondary goal. In order to achieve these goals, a systematic, multistep approach is recommended (Krack, 2002). Stimulation can be delivered in monopolar or bipolar fashion, using any of 4 electrode contacts, alone or in combination. Thus, a great deal of therapeutic flexibility is provided, permitting customized stimulation for each patient. Moreover, stimulation parameters can be adjusted at any time if needed.

Thalamic DBS

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.

The Multicentre European study of thalamic stimulation in parkinsonian and essential tremor reported rates of significant improvement between 85% for PD tremor and 89% for ET at 12 months (Limousin, 1999). In most patients, the very good results with stimulation seen at 1 year were maintained after more than 6 years (Sydow, 2003). As with thalamotomy, thalamic DBS uncommonly provides 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.

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.

Pallidal DBS

Siegfrid and Lippitz introduced bilateral pallidal (ie, GPi) stimulation in 1994, reporting improvements in rigidity, akinesia, and LID in 4 patients. Twelve years later, GPi DBS has received much less attention than the comparable procedure in the STN, although the best overall target for PD remains controversial (Okun, 2005). Recently, a comparative study by Anderson et al (2005) showed no significant differences in the overall benefits of DBS at these 2 sites.

Benefits ranging from 37-39% in the "off-medicine" Unified Parkinson Disease Rating Scale (UPDRS), a widely accepted rating scale of PD signs, motor subscore at 1 year have been reported (Burchiel, 1999; DBS Study group, 2001; Anderson, 2005). Dyskinesia improves dramatically and GPi DBS has also been effective in decreasing off time and 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 in the pallidum is more challenging than in the thalamus. Higher stimulation voltages may exacerbate freezing, nullifying the therapeutic effects of L-DOPA. Moreover, stimulation in different regions of the pallidum 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 DBS

While select patients with PD derive significant benefit from neuroablation or stimulation at VIM and/or 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 subthalamic nucleus.

Rationale

Hyperactivity of the excitatory pathway from STN to GPi is considered a key pathophysiological hallmark of PD, a fact that is supported by the observation that lesioning the STN in primates with MPTP reverses their parkinsonism.

Indications

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, and/or akinesia in the off state (ie, when medications are not working) and LID in the on state.

Results

DBS of the subthalamic nucleus, like that of the GPi, improves all the cardinal motor symptoms of PD. As already noted, STN DBS is generally performed more commonly than GPi DBS. Studies of STN DBS have consistently reported remarkable improvement, ranging from 45–to-70% in the off-medicine motor subscore of the UPDRS. Improvement is usually stable at least up to 5 years, with continued efficacy and a 54% benefit in the "off" motor score in one study. "On" time is also significantly increased from 27% of the day at baseline to 74% at 3 months. Bilateral STN stimulation may produce dramatic beneficial effects on midline symptoms such as gait, posture, and balance.

Dosage and frequency of antiparkinsonian drugs can be substantially decreased with STN DBS, which can have an additive effect to LID. In some cases, patients may experience severe dyskinesias necessitating the reduction of dopamimetic medications. While some groups significantly decrease drugs immediately after surgery, the authors prefer to act more conservatively, as many patients do not tolerate this and may experience significant mood abnormalities, in particular apathy and depression.

Complications

Adverse events of STN DBS can be classified into 3 main groups:

• Surgical complications, mainly including brain hemorrhages, which can result in permanent neurologic sequelae, including aphasia, hemiparesis, coma, and death. Seizures have been rarely described, while postoperative confusion can be relatively frequent but is usually transient in nature.
• Hardware-related complications, including superficial infections, wire breaks or dislocations, and battery end-of-life requiring replacement
• Stimulation-related complications, including muscle pulling, paresthesias, eyelid apraxia, hypophonia, and worsened postural instability. Hemiballismus can occur with higher stimulation voltages, but it is controlled successfully by reducing the voltage and/or decreasing the dose of L-DOPA. In general, all stimulation-related complications can be addressed with electrical parameter changes.

Is subthalamic nucleus stimulation neuroprotective?

STN stimulation has been hypothesized to be neuroprotective, slowing down the progression of PD. The STN provides excitatory (glutamatergic) output to the GPi, the substantia nigra pars reticulata (SNr), the pedunculopontine nucleus, and the dopaminergic neurons in the SNc. Therefore, STN hyperactivity caused by loss of dopaminergic input to the striatum (see Pathophysiology in Introduction) may, in turn, produce excitotoxic damage to the dopaminergic neurons to which they project, resulting in further neuronal loss in the SNc. Thus, pharmacologic or surgical therapies that reduce STN neuronal hyperactivity may be neuroprotective to the dopaminergic neurons of the SNc, possibly slowing or halting the progression of PD. Further studies are required to evaluate this hypothesis.

SELECTION OF THE PROPER PROCEDURE

Section 7 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

Presently, surgery is reserved for patients with medically refractory PD with disabling problems. Currently, the authors' center adopts the following surgical recommendations for patients with medically refractory PD:

• Unilateral pallidotomy is offered to patients with asymmetric PD who develop fluctuations in their response to L-DOPA, including disabling dyskinesias and off-state dystonia. Bilateral pallidotomy is avoided, although investigations are underway to evaluate contralateral GPi DBS in patients who have undergone a successful pallidotomy and are experiencing disease progression in the untreated side.
• Thalamotomy or thalamic DBS is offered to the minority of patients with PD who suffer from predominant and disabling tremor. More commonly, this procedure is performed on patients with disabling ET. Thalamic DBS is preferred, particularly in young patients with PD who are disabled solely by tremor early in the course of their disease, because it gives the option of removing the stimulator if more effective therapies are developed or if symptom progression necessitates DBS at another target such as STN.
• Bilateral STN DBS is offered to patients with advanced PD with (1) bilateral LID, (2) significant gait disturbances and axial symptoms, or (3) medically refractory rigidity and akinesia.
• Prior to surgery, the patient should be informed that these procedures do not cure PD and that progression is expected.

OTHER SURGICAL OPTIONS

Section 8 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

Cell transplantation is an option.

• Autologous adrenal transplants showed no consistent efficacy and have been abandoned.
• Allogenic human fetal cell transplants
  • Clinical results: More than 300 patients with PD around the world have received fetal neural transplants.
  • A recent double-blind study compared 20 patients with advanced PD who received a putaminal transplant of human embryonic dopamine neurons with 20 comparable patients receiving "sham" surgery (Freed, 2001). Results 1 year after surgery showed the following:
    • Subjective global rating scores (primary outcome) were not significantly different in transplanted and nontransplanted patients.
    • In younger patients (60 years or younger), those who underwent transplantation demonstrated significantly greater improvement when assessed in the morning before receiving medication (UPDRS P=0.01; Schwab and England P=0.006). No significant differences were noted in older patients.
    • PET scans demonstrated an increase in 18F-fluorodopa uptake in 17 of the 20 patients in the transplantation group, a finding presumably consistent with fiber outgrowth from the transplanted neurons. This was confirmed in 2 postmortem cases.
    • Of patients who ultimately underwent transplantation and were monitored for up to 3 years after surgery, 15% developed dyskinesia or dystonia despite substantial reduction or withdrawal of dopaminergic medications.
  • Issues related to cell transplantation include (1) donor age and tissue storage, (2) solid vs suspension graft, (3) number and source of donors, (4) distribution of grafted tissue, (5) site of implantation, (6) unilateral vs bilateral transplantation, (7) immunologic issues, (8) patient selection, and (9) assessment methods.
• Xenogenic fetal transplant: Preliminary results are pending (porcine).
• Genetically engineered cells: Research is ongoing.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

Media file 1:  Schematic diagram of the basal ganglia circuitry. Inhibitory (red arrows) and excitatory (green arrows) projections between the motor cortex, the putamen, the globus pallidus pars externa (GPe) and globus pallidus pars interna (GPi), the subthalamic nucleus (STN), the substantia nigra pars reticulata (SNr) and substantia nigra pars compacta (SNc), and the ventrolateral thalamus (VL) are represented. D1 and D2 indicate the direct (regulated by dopamine D1 receptors) and indirect (regulated by dopamine D2 receptors) pathways, respectively.
	View Full Size Image
Media type:  Photo

Media file 2:  Sagittal section, 12 mm lateral of the midline, demonstrating the subthalamic nucleus (STN; lavender). STN is one of the preferred surgical targets for deep brain stimulation to treat symptoms of advanced Parkinson disease.
	View Full Size Image
Media type:  Photo

Media file 3:  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.
	View Full Size Image
Media type:  Photo

Media file 4:  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.
	View Full Size Image
Media type:  Photo

Media file 5:  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.
	View Full Size Image
Media type:  Photo

Media file 6:  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).
	View Full Size Image
Media type:  MRI

Media file 7:  Implantation of the deep brain stimulation (DBS) lead.
	View Full Size Image
Media type:  Photo

Media file 8:  Postoperative coronal MRI demonstrating desired placement of bilateral subthalamic nuclei-deep brain stimulation (STN-DBS) leads.
	View Full Size Image
Media type:  MRI

Media file 9:  The deep brain stimulating lead is equipped with 4 electrode contacts, each of which may be used, alone or in combination, for therapeutic stimulation.
	View Full Size Image
Media type:  Photo

Media file 10:  Deep brain stimulation parameters can be adjusted at any time using a transcutaneous programmer.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Preoperative Evaluation
• Surgical Technique
• Surgical Procedures
• Deep Brain Stimulation
• Selection Of The Proper Procedure
• Other Surgical Options
• Multimedia
• References

• Alterman RL, Sterio D, Beric A, Kelly PJ. Microelectrode recording during posteroventral pallidotomy: impact on target selection and complications. Neurosurgery. Feb 1999;44(2):315-21; discussion 321-3. [Medline].
• Anderson VC, Burchiel KJ, Hogarth P, et al. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol. Apr 2005;62(4):554-60. [Medline].
• Bejjani B, Damier P, Arnulf I, et al. Pallidal stimulation for Parkinson''s disease. Two targets?. Neurology. Dec 1997;49(6):1564-9. [Medline].
• Burchiel KJ, Anderson VC, Favre J, Hammerstad JP. Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson's disease: results of a randomized, blinded pilot study. Neurosurgery. Dec 1999;45(6):1375-82; discussion 1382-4. [Medline].
• Deep Brain Stimulation Study Group. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson''s disease. N Engl J Med. Sep 27 2001;345(13):956-63. [Medline].
• Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson''s disease. N Engl J Med. Mar 8 2001;344(10):710-9. [Medline].
• Krack P, Fraix V, Mendes A, et al. Postoperative management of subthalamic nucleus stimulation for Parkinson's disease. Mov Disord. 2002;17 Suppl 3:S188-97. [Medline].
• Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med. Nov 13 2003;349(20):1925-34. [Medline].
• Laitinen LV, Bergenheim AT, Hariz MI. Leksell''s posteroventral pallidotomy in the treatment of Parkinson''s disease. J Neurosurg. Jan 1992;76(1):53-61. [Medline].
• Lang AE, Lozano AM. Parkinson''s disease. Second of two parts. N Engl J Med. Oct 15 1998;339(16):1130-43. [Medline].
• Lang AE, Widner H. Deep brain stimulation for Parkinson's disease: patient selection and evaluation. Mov Disord. 2002;17 Suppl 3:S94-101. [Medline].
• Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson''s disease. N Engl J Med. Oct 15 1998;339(16):1105-11. [Medline].
• Limousin P, Speelman JD, Gielen F, Janssens M. Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. J Neurol Neurosurg Psychiatry. Mar 1999;66(3):289-96. [Medline].
• McIntyre CC, Savasta M, Kerkerian-Le Goff L, Vitek JL. Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both. Clin Neurophysiol. Jun 2004;115(6):1239-48. [Medline].
• Obeso JA, Linazasoro G, Gorospe A, et al. Complications associated with chronic levodopa therapy in Parkinson's disease. Complications associated with chronic levodopa therapy in Parkinson's disease. In: Olanow CW, Obeso JA, eds. Beyond the Decade of the Brain. Vol 2. 1997:11-31.
• Okun MS, Fernandez HH, Pedraza O, et al. Development and initial validation of a screening tool for Parkinson disease surgical candidates. Neurology. Jul 13 2004;63(1):161-3. [Medline].
• Okun MS, Tagliati M, Pourfar M, et al. Management of referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers. Arch Neurol. Aug 2005;62(8):1250-5. [Medline].
• Rodriguez MC, Obeso JA, Olanow CW. Subthalamic nucleus-mediated excitotoxicity in Parkinson''s disease: a target for neuroprotection. Ann Neurol. Sep 1998;44(3 Suppl 1):S175-88. [Medline].
• Siegfrid J, Lippitz B. Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery. 1994;35:1126-1129. [Medline].
• Svennilson E, Torvik A, Lowe R, Leksell L. Treatment of parkinsonism by stereotatic thermolesions in the pallidal region. A clinical evaluation of 81 cases. Acta Psychiatr Scand. 1960;35:358-77. [Medline].
• Sydow O, Thobois S, Alesch F, Speelman JD. Multicentre European study of thalamic stimulation in essential tremor: a six year follow up. J Neurol Neurosurg Psychiatry. Oct 2003;74(10):1387-91. [Medline].
• Tasker RR. Thalamotomy. Neurosurg Clin N Am. 1990;1:841-64. [Medline].
• Walter BL, Vitek JL. Surgical treatment for Parkinson's disease. Lancet Neurol. Dec 2004;3(12):719-28. [Medline].

Article Last Updated: Aug 7, 2006