Scott Cooper, MD, PhD

Implantation of a deep brain stimulator is the most common surgical procedure performed in the United States and industrialized world for the management of advanced movement disorders. These procedures are US Food and Drug Administration (FDA)–approved for the management of the symptoms of Parkinson disease (PD) and essential tremor. Deep brain stimulation (DBS) is also approved for managing primary generalized dystonia and torticollis under a humanitarian device exemption.

Deep brain stimulation has largely replaced ablative procedures such as thalamotomy and pallidotomy. While ablative procedures can be effective for the symptoms of movement disorders, they cause a permanent lesion in the targeted nuclei and are therefore not reversible. DBS is considered safer because it can be adjusted over time and the location of the leads can be revised.¹ On the other hand, regular maintenance of implanted hardware may be considered a disadvantage of DBS.

HARDWARE AND TARGETS

While ablative procedures do not require implantable hardware, DBS consists of permanently implanted neurostimulation systems. The battery-powered pulse generators typically last for several years but require multiple replacements during a lifetime. In addition, if other hardware components fail, surgical revision may be required to maintain treatment efficacy. Surgery involving implantation of hardware carries a higher risk of infection than does a nonimplantation procedure. If infections occur, removal of the hardware is often required, with reimplantation performed after the infection clears. In addition, the expense of DBS hardware may limit availability in some cases.

Three components

Permanently implanted DBS devices have three components: the DBS lead, which is inserted into the brain and extends to the outside of the skull; the implantable pulse generator, typically located in the infraclavicular area; and an extension cable that connects the two components (Figure 1). Patients may have unilateral or bilateral lead implantation and unilateral or bilateral implantation of pulse generators. A single generator may be connected to both brain leads. Patients also have the option of receiving either a nonrechargeable or a rechargeable pulse generator. The advantage of the latter is longer intervals between battery replacement surgery (up to 9 years). However, these require more maintenance by the patient, who needs to periodically recharge the generators at home using a wireless charging unit. The recharging procedure may be time consuming and difficult for patients who are challenged by new technologies. In our experience, most patients with PD and tremor prefer nonrechargeable pulse generators.

Target nuclei

Several nodes or nuclei can serve as targets for DBS. In patients with PD, the most common surgical target is the subthalamic nucleus (STN), either unilaterally or bilaterally.² The globus pallidus pars interna (GPi) is also a viable target and is preferred for some patients with PD. The most common target for managing essential tremor is the ventral intermediate nucleus (VIM) of the thalamus, which can also be the target of choice for patients with tremor-predominant PD. However, the GPi and STN are usually preferred over the VIM in patients with PD because stimulation of these targets can relieve symptoms other than tremor, such as rigidity and bradykinesia. Bilateral stimulation of the GPi is the most frequent approach in patients with generalized torsion dystonia and torticollis, although the STN and thalamic nuclei (off-label) are also considered options.

PATIENT SELECTION

Patients are evaluated in our center at Cleveland Clinic by a multidisciplinary team that includes a movement disorder neurologist, a subspecialized neurosurgeon, a movement disorder neuropsychologist, and a psychiatrist with special interest in the behavioral comorbidities of movement disorders.³ Neuroimaging is included in this assessment. We have also included physical therapy as part of the initial evaluation in order to gain insight into the patient’s limitations and develop rehabilitation strategies that may enhance the outcomes of surgery or provide alternatives should surgery not be indicated. This evaluation provides extensive data that are then reviewed by the team in a conference dedicated to discussing candidacy for DBS or options for managing the symptoms of advanced movement disorders. Behavioral and cognitive issues are assessed in detail and, in our experience, are the most common reasons for not recommending DBS.

An important part of the evaluation of patients with PD is a formal test with rating of the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS) with the patient off medications for 8 to 12 hours and then after a test dose of levodopa. At our center, this off/on test is videotaped so that the responsiveness of individual symptoms to levodopa can be reviewed later in conference.

Risk of cognitive decline

While DBS is considered safe and effective, there is a risk of cognitive decline in some patients. In most patients, long-term stimulation-related cognitive decline may be detected with formal measures but is not clinically significant and is outweighed by the motor and quality-of-life benefits of surgery. In some patients, long-term cognitive decline can be significant and can limit function. Cognitive neuropsychologic testing provides valuable information in this regard. Patients with preserved cognitive function seldom experience significant decline with DBS while those with substantial baseline impairment are thought to be at greater risk. Patients who meet criteria for dementia are usually not considered candidates for DBS, but exceptions exist. Transient perioperative cognitive difficulties are more common than persistent deficits, and typically resolve within a few weeks (see “Complications of deep brain stimulation”).

Benefits in Parkinson disease

Deep brain stimulation can address several symptoms of PD but with varying effects. Tremor, rigidity, and bradykinesia usually improve substantially. Gait has a more variable response, and balance is typically refractory. A general rule is that symptoms that improve with a single dose of levodopa should also improve with DBS. (Tremor, however, will most often respond to DBS even if refractory to medication.) Good candidates for surgery typically have a greater than 30% improvement in UPDRS motor score with levodopa challenge, but sometimes, improvement in the total score is less informative than evaluation of the effects of levodopa on particular symptoms. Treatment effects can be compared with the patient’s expectations for surgery in order to infer whether the goals for symptom improvement are realistic.

 

 

Treatment outcomes depend on etiology

After programming, DBS can provide PD symptom control similar to that of medication “on time,” but with fewer on-off fluctuations and less on-time dyskinesia. Good surgical candidates are patients who once responded well to dopaminergic medications but who, after several years with the disease, present with increased duration of “off time,” unpredictable duration of on time, and medication side effects such as on-time dyskinesia. Patients who do not respond well to levodopa even in subscores of the UPDRS may not be good candidates for DBS, and in some cases the diagnosis itself needs to be reviewed.

Deep brain stimulation can improve quality of life and alleviate symptoms of essential tremor. Tremor control is best for the upper extremities and tends to be better for distal tremors than for proximal ones. Patients who are good candidates for surgery often have severe tremors. A substantial improvement in these symptoms often has a dramatic, positive effect on work and quality of life. In some patients, surgery is considered for mild tremor if it seriously disrupts the patient’s lifestyle or occupation and cannot be well controlled with medications. Often, in these cases, tremor that appears relatively mild to the examiner is significantly limiting for the patient.

Very severe and proximal tremor is more refractory, though it may also improve. The changes can be well documented with objective measures. In these cases, however, residual tremor can still be moderate to severe and can be functionally limiting. Head or vocal tremors are typically refractory. They may be improved with bilateral implantation, but this cannot be accurately predicted. Patients who present with head-only or head-predominant tremor are thought to be less likely to benefit than those with limb tremor. Nonetheless, tremors of the head can severely impair quality of life. Because there are few other treatment options, some patients choose DBS with the understanding that the outcome is uncertain and the benefit may be limited.

Tremor resulting from multiple sclerosis or other causes can be medically refractory and disabling. In our experience, DBS can be an off-label option for managing secondary tremors and good outcomes have been observed. However, outcomes are much less predictable and tremor control less effective than in patients with essential tremor.

Patients with primary generalized dystonia can be considered candidates for DBS and may experience improved symptom control and quality of life.⁴ Patients with the DYT1 mutation are more likely to respond well to DBS, as are those with other forms of primary generalized dystonia. In contrast to that seen in patients with PD and tremor, symptomatic improvement is frequently not observed during intraoperative testing. Several months of stimulation and programming may be required before significant improvements are detected.⁵ Surgery can also be considered for off-label use in the treatment of patients with secondary dystonia—such as that following injury or associated with cerebral palsy—but outcomes are less predictable and usually more limited. A possible exception may be seen in cases of tardive dystonia, for which there is increasing evidence⁶ for the effectiveness of DBS. This remains an off-label use of DBS.

Realistic expectations

An important aspect of the multidisciplinary evaluation includes a discussion of the expectations for surgery, the risks, and the requirements for postoperative care. As discussed above, DBS is reversible and adjustable, so outcomes depend not only on accurate implantation of the hardware but also on postoperative programming. Also, monitoring and maintenance of the implanted hardware are required in these patients. It is important that patients and families appreciate the fact that specialized, long-term postoperative follow-up is as much a part of the treatment as is the implantation itself.

UNILATERAL VERSUS BILATERAL DBS

Most patients with generalized dystonia undergo bilateral DBS. However, patients with PD or essential tremor may receive bilateral, staged, or unilateral implants. Some patients with PD present with either near-complete predominance of symptoms on one side or with symptoms that affect mostly the dominant extremity. In these patients, unilateral implantation is often recommended because it has less risk than the bilateral approach and may be sufficient to address the most limiting symptoms.

As the disease advances, an additional surgery may be required to accomplish bilateral symptom control. Nevertheless, we do not routinely recommend preventive implantation because it is not known whether second-side symptoms will become severe enough to require it. This strategy allows for deferring surgical risk, which is in itself advantageous. In our experience, bilateral implantation is often recommended to PD patients who present with symptoms such as freezing of gait.

Patients who have essential tremor often present with bilateral symptoms. Although many patients will indicate that they need symptom relief on both upper extremities in order to perform activities of daily living, our practice is to recommend surgery on one side at first and to suggest the patient consider contralateral implantation after weeks or months. Bilateral implantation may carry a risk for dysarthria and the risk is thought to be reduced if bilateral procedures are staged. Although high rates of dysarthria have been reported following bilateral surgery for tremor, its occurrence has been infrequent in our experience with bilateral staged DBS. Benefits of treating tremor in the dominant extremity usually exceed those of treating nondominant tremor, so most patients prefer that the dominant side be the first one treated.

TECHNICAL OPTIONS

There are several technical options for implantation of DBS systems. Stereotactic procedures rely on co-registration of preoperative imaging with external and internal fiducials, or points of reference. Targeting of the intended structures is performed by combining direct and indirect methods. Direct methods rely on identification of the target structures with imaging, such as visualization of the STN and GPi on preoperative magnetic resonance imaging (MRI). Indirect targeting relies on cadaveric anatomic atlases and coordinate systems that infer the location of the intended structures in relation to anatomical points of reference.

Frame-based systems

In the most common approach to DBS surgery,⁷ stereotactic frames are placed over the patient’s head and secured with pins. The frame becomes the fixed point of reference for accurate stereotactic surgery and must remain in place for the duration of the procedure. Computed tomography or MRI is then performed with the frame in place, so that the images are co-registered with the fiducial points of the stereotactic frame. The targets are then selected for surgery and trajectories are chosen based on anatomic structures. The patient is positioned supine and the frame and head are secured to the operating table. The coordinates calculated by the clinical workstations are then set to the stereotactic frame and arc. The stereotactic arc (Figure 2) is attached to the base of the frame and the entry points of the leads—where the burr hole will be placed—are marked on the skin and then on the skull. Once the burr hole and opening of the meninges are completed, the targeting cannulae are inserted. The microelectrode system is then mounted for recording of the target area and subsequently for final lead implantation.

Frameless systems

The workflow and overall surgical procedure for implantation of DBS with frameless systems are similar to those of the frame-based procedure. However, instead of fixing the head to a rigid frame that prevents head motion, a lighter-weight, frameless system is fixed to the head and moves with it (Figure 3). First, metal screws and fiducials are fixed to the head under local anesthesia or sedation. Preoperative imaging is then acquired with the fiducials in place and the surgical plans are completed in the same fashion as for frame-based surgery. The patient is then placed supine on the operating table and the frameless system is attached to the head with the aid of image guidance, in the location determined by target and trajectory planning.

The key advantage of the frameless system over the frame-based system is greater mobility of the head. Another important advantage is easier access to the airway, should an emergency situation occur. In our practice, patients with experience of both frameless and frame-based systems did not report significantly less discomfort with the frameless system.

The frameless system also has disadvantages, including less secure fixation of the head, which can add risk to the procedure. In addition, because of its lightweight, plastic construction, it provides less robust support to the instrumentation entering the brain than do metallic head frames and, in some cases, there is less flexibility for adjusting targets if needed during surgery. In addition, frameless systems are nonreusable and represent a substantial additional cost.

 

 

Microelectrode recording

Physiologic verification of anatomic targets identified by imaging can be accomplished with microelectrode recording (MER). This technique involves placing fine, high-impedance electrodes through the target area, so that anatomic structures can be recognized by characteristic electrical activity of individual neurons or groups of neurons. The locations of the structures are identified and the lengths of the electrode trajectories through the different structures—as well as the gaps between these structures—are recorded. The distances are then compared with the anatomy and a best-fit model is created to infer the location of the trajectory in the target area. Additional MER penetrations are made in order to further delineate the anatomy. Once a location for implantation has been selected, the DBS lead is inserted into the target area.

Electrode implantation

Lead implantation is often performed under fluoroscopic guidance in order to ensure accuracy and stability. When implanted, the electrode may cause a microlesional effect, manifested by transient improvement in symptoms.

The DBS leads are then connected to external pulse generators and assessed for clinical benefits and side effects. Amplitude, pulse width, and frequency are adjusted to test the therapeutic window of stimulation (clinical improvement thresholds versus side effect thresholds). Some PD patients develop dyskinesia during test stimulation, which may be a positive indicator for lead location. If good effects and a therapeutic window are observed, the location of the lead is considered to be satisfactory and the procedure is completed.

Pulse generator implantation

During the final step of surgery, performed under general anesthesia, the pulse generator is implanted. The extension cable that connects the DBS lead to the implantable pulse generator is tunneled subcutaneously, connecting the DBS lead to the pulse generator in the chest.

Intraoperative, real-time MRI stereotaxis

Real-time intraoperative MRI has become available for DBS implantation with devices recently cleared for use by the FDA. The procedure, typically performed in a diagnostic MRI suite, uses MR images acquired during surgery to guide DBS lead implantation in the target area and to verify implantation accuracy.⁸

Implantation of a deep brain stimulator is the most common surgical procedure performed in the United States and industrialized world for the management of advanced movement disorders. These procedures are US Food and Drug Administration (FDA)–approved for the management of the symptoms of Parkinson disease (PD) and essential tremor. Deep brain stimulation (DBS) is also approved for managing primary generalized dystonia and torticollis under a humanitarian device exemption.

Deep brain stimulation has largely replaced ablative procedures such as thalamotomy and pallidotomy. While ablative procedures can be effective for the symptoms of movement disorders, they cause a permanent lesion in the targeted nuclei and are therefore not reversible. DBS is considered safer because it can be adjusted over time and the location of the leads can be revised.¹ On the other hand, regular maintenance of implanted hardware may be considered a disadvantage of DBS.

HARDWARE AND TARGETS

While ablative procedures do not require implantable hardware, DBS consists of permanently implanted neurostimulation systems. The battery-powered pulse generators typically last for several years but require multiple replacements during a lifetime. In addition, if other hardware components fail, surgical revision may be required to maintain treatment efficacy. Surgery involving implantation of hardware carries a higher risk of infection than does a nonimplantation procedure. If infections occur, removal of the hardware is often required, with reimplantation performed after the infection clears. In addition, the expense of DBS hardware may limit availability in some cases.

Three components

Permanently implanted DBS devices have three components: the DBS lead, which is inserted into the brain and extends to the outside of the skull; the implantable pulse generator, typically located in the infraclavicular area; and an extension cable that connects the two components (Figure 1). Patients may have unilateral or bilateral lead implantation and unilateral or bilateral implantation of pulse generators. A single generator may be connected to both brain leads. Patients also have the option of receiving either a nonrechargeable or a rechargeable pulse generator. The advantage of the latter is longer intervals between battery replacement surgery (up to 9 years). However, these require more maintenance by the patient, who needs to periodically recharge the generators at home using a wireless charging unit. The recharging procedure may be time consuming and difficult for patients who are challenged by new technologies. In our experience, most patients with PD and tremor prefer nonrechargeable pulse generators.

Target nuclei

Several nodes or nuclei can serve as targets for DBS. In patients with PD, the most common surgical target is the subthalamic nucleus (STN), either unilaterally or bilaterally.² The globus pallidus pars interna (GPi) is also a viable target and is preferred for some patients with PD. The most common target for managing essential tremor is the ventral intermediate nucleus (VIM) of the thalamus, which can also be the target of choice for patients with tremor-predominant PD. However, the GPi and STN are usually preferred over the VIM in patients with PD because stimulation of these targets can relieve symptoms other than tremor, such as rigidity and bradykinesia. Bilateral stimulation of the GPi is the most frequent approach in patients with generalized torsion dystonia and torticollis, although the STN and thalamic nuclei (off-label) are also considered options.

PATIENT SELECTION

Patients are evaluated in our center at Cleveland Clinic by a multidisciplinary team that includes a movement disorder neurologist, a subspecialized neurosurgeon, a movement disorder neuropsychologist, and a psychiatrist with special interest in the behavioral comorbidities of movement disorders.³ Neuroimaging is included in this assessment. We have also included physical therapy as part of the initial evaluation in order to gain insight into the patient’s limitations and develop rehabilitation strategies that may enhance the outcomes of surgery or provide alternatives should surgery not be indicated. This evaluation provides extensive data that are then reviewed by the team in a conference dedicated to discussing candidacy for DBS or options for managing the symptoms of advanced movement disorders. Behavioral and cognitive issues are assessed in detail and, in our experience, are the most common reasons for not recommending DBS.

An important part of the evaluation of patients with PD is a formal test with rating of the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS) with the patient off medications for 8 to 12 hours and then after a test dose of levodopa. At our center, this off/on test is videotaped so that the responsiveness of individual symptoms to levodopa can be reviewed later in conference.

Risk of cognitive decline

While DBS is considered safe and effective, there is a risk of cognitive decline in some patients. In most patients, long-term stimulation-related cognitive decline may be detected with formal measures but is not clinically significant and is outweighed by the motor and quality-of-life benefits of surgery. In some patients, long-term cognitive decline can be significant and can limit function. Cognitive neuropsychologic testing provides valuable information in this regard. Patients with preserved cognitive function seldom experience significant decline with DBS while those with substantial baseline impairment are thought to be at greater risk. Patients who meet criteria for dementia are usually not considered candidates for DBS, but exceptions exist. Transient perioperative cognitive difficulties are more common than persistent deficits, and typically resolve within a few weeks (see “Complications of deep brain stimulation”).

Benefits in Parkinson disease

Deep brain stimulation can address several symptoms of PD but with varying effects. Tremor, rigidity, and bradykinesia usually improve substantially. Gait has a more variable response, and balance is typically refractory. A general rule is that symptoms that improve with a single dose of levodopa should also improve with DBS. (Tremor, however, will most often respond to DBS even if refractory to medication.) Good candidates for surgery typically have a greater than 30% improvement in UPDRS motor score with levodopa challenge, but sometimes, improvement in the total score is less informative than evaluation of the effects of levodopa on particular symptoms. Treatment effects can be compared with the patient’s expectations for surgery in order to infer whether the goals for symptom improvement are realistic.

 

 

Treatment outcomes depend on etiology

After programming, DBS can provide PD symptom control similar to that of medication “on time,” but with fewer on-off fluctuations and less on-time dyskinesia. Good surgical candidates are patients who once responded well to dopaminergic medications but who, after several years with the disease, present with increased duration of “off time,” unpredictable duration of on time, and medication side effects such as on-time dyskinesia. Patients who do not respond well to levodopa even in subscores of the UPDRS may not be good candidates for DBS, and in some cases the diagnosis itself needs to be reviewed.

Deep brain stimulation can improve quality of life and alleviate symptoms of essential tremor. Tremor control is best for the upper extremities and tends to be better for distal tremors than for proximal ones. Patients who are good candidates for surgery often have severe tremors. A substantial improvement in these symptoms often has a dramatic, positive effect on work and quality of life. In some patients, surgery is considered for mild tremor if it seriously disrupts the patient’s lifestyle or occupation and cannot be well controlled with medications. Often, in these cases, tremor that appears relatively mild to the examiner is significantly limiting for the patient.

Very severe and proximal tremor is more refractory, though it may also improve. The changes can be well documented with objective measures. In these cases, however, residual tremor can still be moderate to severe and can be functionally limiting. Head or vocal tremors are typically refractory. They may be improved with bilateral implantation, but this cannot be accurately predicted. Patients who present with head-only or head-predominant tremor are thought to be less likely to benefit than those with limb tremor. Nonetheless, tremors of the head can severely impair quality of life. Because there are few other treatment options, some patients choose DBS with the understanding that the outcome is uncertain and the benefit may be limited.

Tremor resulting from multiple sclerosis or other causes can be medically refractory and disabling. In our experience, DBS can be an off-label option for managing secondary tremors and good outcomes have been observed. However, outcomes are much less predictable and tremor control less effective than in patients with essential tremor.

Patients with primary generalized dystonia can be considered candidates for DBS and may experience improved symptom control and quality of life.⁴ Patients with the DYT1 mutation are more likely to respond well to DBS, as are those with other forms of primary generalized dystonia. In contrast to that seen in patients with PD and tremor, symptomatic improvement is frequently not observed during intraoperative testing. Several months of stimulation and programming may be required before significant improvements are detected.⁵ Surgery can also be considered for off-label use in the treatment of patients with secondary dystonia—such as that following injury or associated with cerebral palsy—but outcomes are less predictable and usually more limited. A possible exception may be seen in cases of tardive dystonia, for which there is increasing evidence⁶ for the effectiveness of DBS. This remains an off-label use of DBS.

Realistic expectations

An important aspect of the multidisciplinary evaluation includes a discussion of the expectations for surgery, the risks, and the requirements for postoperative care. As discussed above, DBS is reversible and adjustable, so outcomes depend not only on accurate implantation of the hardware but also on postoperative programming. Also, monitoring and maintenance of the implanted hardware are required in these patients. It is important that patients and families appreciate the fact that specialized, long-term postoperative follow-up is as much a part of the treatment as is the implantation itself.

UNILATERAL VERSUS BILATERAL DBS

Most patients with generalized dystonia undergo bilateral DBS. However, patients with PD or essential tremor may receive bilateral, staged, or unilateral implants. Some patients with PD present with either near-complete predominance of symptoms on one side or with symptoms that affect mostly the dominant extremity. In these patients, unilateral implantation is often recommended because it has less risk than the bilateral approach and may be sufficient to address the most limiting symptoms.

As the disease advances, an additional surgery may be required to accomplish bilateral symptom control. Nevertheless, we do not routinely recommend preventive implantation because it is not known whether second-side symptoms will become severe enough to require it. This strategy allows for deferring surgical risk, which is in itself advantageous. In our experience, bilateral implantation is often recommended to PD patients who present with symptoms such as freezing of gait.

Patients who have essential tremor often present with bilateral symptoms. Although many patients will indicate that they need symptom relief on both upper extremities in order to perform activities of daily living, our practice is to recommend surgery on one side at first and to suggest the patient consider contralateral implantation after weeks or months. Bilateral implantation may carry a risk for dysarthria and the risk is thought to be reduced if bilateral procedures are staged. Although high rates of dysarthria have been reported following bilateral surgery for tremor, its occurrence has been infrequent in our experience with bilateral staged DBS. Benefits of treating tremor in the dominant extremity usually exceed those of treating nondominant tremor, so most patients prefer that the dominant side be the first one treated.

TECHNICAL OPTIONS

There are several technical options for implantation of DBS systems. Stereotactic procedures rely on co-registration of preoperative imaging with external and internal fiducials, or points of reference. Targeting of the intended structures is performed by combining direct and indirect methods. Direct methods rely on identification of the target structures with imaging, such as visualization of the STN and GPi on preoperative magnetic resonance imaging (MRI). Indirect targeting relies on cadaveric anatomic atlases and coordinate systems that infer the location of the intended structures in relation to anatomical points of reference.

Frame-based systems

In the most common approach to DBS surgery,⁷ stereotactic frames are placed over the patient’s head and secured with pins. The frame becomes the fixed point of reference for accurate stereotactic surgery and must remain in place for the duration of the procedure. Computed tomography or MRI is then performed with the frame in place, so that the images are co-registered with the fiducial points of the stereotactic frame. The targets are then selected for surgery and trajectories are chosen based on anatomic structures. The patient is positioned supine and the frame and head are secured to the operating table. The coordinates calculated by the clinical workstations are then set to the stereotactic frame and arc. The stereotactic arc (Figure 2) is attached to the base of the frame and the entry points of the leads—where the burr hole will be placed—are marked on the skin and then on the skull. Once the burr hole and opening of the meninges are completed, the targeting cannulae are inserted. The microelectrode system is then mounted for recording of the target area and subsequently for final lead implantation.

Frameless systems

The workflow and overall surgical procedure for implantation of DBS with frameless systems are similar to those of the frame-based procedure. However, instead of fixing the head to a rigid frame that prevents head motion, a lighter-weight, frameless system is fixed to the head and moves with it (Figure 3). First, metal screws and fiducials are fixed to the head under local anesthesia or sedation. Preoperative imaging is then acquired with the fiducials in place and the surgical plans are completed in the same fashion as for frame-based surgery. The patient is then placed supine on the operating table and the frameless system is attached to the head with the aid of image guidance, in the location determined by target and trajectory planning.

The key advantage of the frameless system over the frame-based system is greater mobility of the head. Another important advantage is easier access to the airway, should an emergency situation occur. In our practice, patients with experience of both frameless and frame-based systems did not report significantly less discomfort with the frameless system.

The frameless system also has disadvantages, including less secure fixation of the head, which can add risk to the procedure. In addition, because of its lightweight, plastic construction, it provides less robust support to the instrumentation entering the brain than do metallic head frames and, in some cases, there is less flexibility for adjusting targets if needed during surgery. In addition, frameless systems are nonreusable and represent a substantial additional cost.

 

 

Microelectrode recording

Physiologic verification of anatomic targets identified by imaging can be accomplished with microelectrode recording (MER). This technique involves placing fine, high-impedance electrodes through the target area, so that anatomic structures can be recognized by characteristic electrical activity of individual neurons or groups of neurons. The locations of the structures are identified and the lengths of the electrode trajectories through the different structures—as well as the gaps between these structures—are recorded. The distances are then compared with the anatomy and a best-fit model is created to infer the location of the trajectory in the target area. Additional MER penetrations are made in order to further delineate the anatomy. Once a location for implantation has been selected, the DBS lead is inserted into the target area.

Electrode implantation

Lead implantation is often performed under fluoroscopic guidance in order to ensure accuracy and stability. When implanted, the electrode may cause a microlesional effect, manifested by transient improvement in symptoms.

The DBS leads are then connected to external pulse generators and assessed for clinical benefits and side effects. Amplitude, pulse width, and frequency are adjusted to test the therapeutic window of stimulation (clinical improvement thresholds versus side effect thresholds). Some PD patients develop dyskinesia during test stimulation, which may be a positive indicator for lead location. If good effects and a therapeutic window are observed, the location of the lead is considered to be satisfactory and the procedure is completed.

Pulse generator implantation

During the final step of surgery, performed under general anesthesia, the pulse generator is implanted. The extension cable that connects the DBS lead to the implantable pulse generator is tunneled subcutaneously, connecting the DBS lead to the pulse generator in the chest.

Intraoperative, real-time MRI stereotaxis

Real-time intraoperative MRI has become available for DBS implantation with devices recently cleared for use by the FDA. The procedure, typically performed in a diagnostic MRI suite, uses MR images acquired during surgery to guide DBS lead implantation in the target area and to verify implantation accuracy.⁸

Implantation of a deep brain stimulator is the most common surgical procedure performed in the United States and industrialized world for the management of advanced movement disorders. These procedures are US Food and Drug Administration (FDA)–approved for the management of the symptoms of Parkinson disease (PD) and essential tremor. Deep brain stimulation (DBS) is also approved for managing primary generalized dystonia and torticollis under a humanitarian device exemption.

Deep brain stimulation has largely replaced ablative procedures such as thalamotomy and pallidotomy. While ablative procedures can be effective for the symptoms of movement disorders, they cause a permanent lesion in the targeted nuclei and are therefore not reversible. DBS is considered safer because it can be adjusted over time and the location of the leads can be revised.¹ On the other hand, regular maintenance of implanted hardware may be considered a disadvantage of DBS.

HARDWARE AND TARGETS

While ablative procedures do not require implantable hardware, DBS consists of permanently implanted neurostimulation systems. The battery-powered pulse generators typically last for several years but require multiple replacements during a lifetime. In addition, if other hardware components fail, surgical revision may be required to maintain treatment efficacy. Surgery involving implantation of hardware carries a higher risk of infection than does a nonimplantation procedure. If infections occur, removal of the hardware is often required, with reimplantation performed after the infection clears. In addition, the expense of DBS hardware may limit availability in some cases.

Three components

Permanently implanted DBS devices have three components: the DBS lead, which is inserted into the brain and extends to the outside of the skull; the implantable pulse generator, typically located in the infraclavicular area; and an extension cable that connects the two components (Figure 1). Patients may have unilateral or bilateral lead implantation and unilateral or bilateral implantation of pulse generators. A single generator may be connected to both brain leads. Patients also have the option of receiving either a nonrechargeable or a rechargeable pulse generator. The advantage of the latter is longer intervals between battery replacement surgery (up to 9 years). However, these require more maintenance by the patient, who needs to periodically recharge the generators at home using a wireless charging unit. The recharging procedure may be time consuming and difficult for patients who are challenged by new technologies. In our experience, most patients with PD and tremor prefer nonrechargeable pulse generators.

Target nuclei

Several nodes or nuclei can serve as targets for DBS. In patients with PD, the most common surgical target is the subthalamic nucleus (STN), either unilaterally or bilaterally.² The globus pallidus pars interna (GPi) is also a viable target and is preferred for some patients with PD. The most common target for managing essential tremor is the ventral intermediate nucleus (VIM) of the thalamus, which can also be the target of choice for patients with tremor-predominant PD. However, the GPi and STN are usually preferred over the VIM in patients with PD because stimulation of these targets can relieve symptoms other than tremor, such as rigidity and bradykinesia. Bilateral stimulation of the GPi is the most frequent approach in patients with generalized torsion dystonia and torticollis, although the STN and thalamic nuclei (off-label) are also considered options.

PATIENT SELECTION

Patients are evaluated in our center at Cleveland Clinic by a multidisciplinary team that includes a movement disorder neurologist, a subspecialized neurosurgeon, a movement disorder neuropsychologist, and a psychiatrist with special interest in the behavioral comorbidities of movement disorders.³ Neuroimaging is included in this assessment. We have also included physical therapy as part of the initial evaluation in order to gain insight into the patient’s limitations and develop rehabilitation strategies that may enhance the outcomes of surgery or provide alternatives should surgery not be indicated. This evaluation provides extensive data that are then reviewed by the team in a conference dedicated to discussing candidacy for DBS or options for managing the symptoms of advanced movement disorders. Behavioral and cognitive issues are assessed in detail and, in our experience, are the most common reasons for not recommending DBS.

An important part of the evaluation of patients with PD is a formal test with rating of the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS) with the patient off medications for 8 to 12 hours and then after a test dose of levodopa. At our center, this off/on test is videotaped so that the responsiveness of individual symptoms to levodopa can be reviewed later in conference.

Risk of cognitive decline

While DBS is considered safe and effective, there is a risk of cognitive decline in some patients. In most patients, long-term stimulation-related cognitive decline may be detected with formal measures but is not clinically significant and is outweighed by the motor and quality-of-life benefits of surgery. In some patients, long-term cognitive decline can be significant and can limit function. Cognitive neuropsychologic testing provides valuable information in this regard. Patients with preserved cognitive function seldom experience significant decline with DBS while those with substantial baseline impairment are thought to be at greater risk. Patients who meet criteria for dementia are usually not considered candidates for DBS, but exceptions exist. Transient perioperative cognitive difficulties are more common than persistent deficits, and typically resolve within a few weeks (see “Complications of deep brain stimulation”).

Benefits in Parkinson disease

Deep brain stimulation can address several symptoms of PD but with varying effects. Tremor, rigidity, and bradykinesia usually improve substantially. Gait has a more variable response, and balance is typically refractory. A general rule is that symptoms that improve with a single dose of levodopa should also improve with DBS. (Tremor, however, will most often respond to DBS even if refractory to medication.) Good candidates for surgery typically have a greater than 30% improvement in UPDRS motor score with levodopa challenge, but sometimes, improvement in the total score is less informative than evaluation of the effects of levodopa on particular symptoms. Treatment effects can be compared with the patient’s expectations for surgery in order to infer whether the goals for symptom improvement are realistic.

 

 

Treatment outcomes depend on etiology

After programming, DBS can provide PD symptom control similar to that of medication “on time,” but with fewer on-off fluctuations and less on-time dyskinesia. Good surgical candidates are patients who once responded well to dopaminergic medications but who, after several years with the disease, present with increased duration of “off time,” unpredictable duration of on time, and medication side effects such as on-time dyskinesia. Patients who do not respond well to levodopa even in subscores of the UPDRS may not be good candidates for DBS, and in some cases the diagnosis itself needs to be reviewed.

Deep brain stimulation can improve quality of life and alleviate symptoms of essential tremor. Tremor control is best for the upper extremities and tends to be better for distal tremors than for proximal ones. Patients who are good candidates for surgery often have severe tremors. A substantial improvement in these symptoms often has a dramatic, positive effect on work and quality of life. In some patients, surgery is considered for mild tremor if it seriously disrupts the patient’s lifestyle or occupation and cannot be well controlled with medications. Often, in these cases, tremor that appears relatively mild to the examiner is significantly limiting for the patient.

Very severe and proximal tremor is more refractory, though it may also improve. The changes can be well documented with objective measures. In these cases, however, residual tremor can still be moderate to severe and can be functionally limiting. Head or vocal tremors are typically refractory. They may be improved with bilateral implantation, but this cannot be accurately predicted. Patients who present with head-only or head-predominant tremor are thought to be less likely to benefit than those with limb tremor. Nonetheless, tremors of the head can severely impair quality of life. Because there are few other treatment options, some patients choose DBS with the understanding that the outcome is uncertain and the benefit may be limited.

Tremor resulting from multiple sclerosis or other causes can be medically refractory and disabling. In our experience, DBS can be an off-label option for managing secondary tremors and good outcomes have been observed. However, outcomes are much less predictable and tremor control less effective than in patients with essential tremor.

Patients with primary generalized dystonia can be considered candidates for DBS and may experience improved symptom control and quality of life.⁴ Patients with the DYT1 mutation are more likely to respond well to DBS, as are those with other forms of primary generalized dystonia. In contrast to that seen in patients with PD and tremor, symptomatic improvement is frequently not observed during intraoperative testing. Several months of stimulation and programming may be required before significant improvements are detected.⁵ Surgery can also be considered for off-label use in the treatment of patients with secondary dystonia—such as that following injury or associated with cerebral palsy—but outcomes are less predictable and usually more limited. A possible exception may be seen in cases of tardive dystonia, for which there is increasing evidence⁶ for the effectiveness of DBS. This remains an off-label use of DBS.

Realistic expectations

An important aspect of the multidisciplinary evaluation includes a discussion of the expectations for surgery, the risks, and the requirements for postoperative care. As discussed above, DBS is reversible and adjustable, so outcomes depend not only on accurate implantation of the hardware but also on postoperative programming. Also, monitoring and maintenance of the implanted hardware are required in these patients. It is important that patients and families appreciate the fact that specialized, long-term postoperative follow-up is as much a part of the treatment as is the implantation itself.

UNILATERAL VERSUS BILATERAL DBS

Most patients with generalized dystonia undergo bilateral DBS. However, patients with PD or essential tremor may receive bilateral, staged, or unilateral implants. Some patients with PD present with either near-complete predominance of symptoms on one side or with symptoms that affect mostly the dominant extremity. In these patients, unilateral implantation is often recommended because it has less risk than the bilateral approach and may be sufficient to address the most limiting symptoms.

As the disease advances, an additional surgery may be required to accomplish bilateral symptom control. Nevertheless, we do not routinely recommend preventive implantation because it is not known whether second-side symptoms will become severe enough to require it. This strategy allows for deferring surgical risk, which is in itself advantageous. In our experience, bilateral implantation is often recommended to PD patients who present with symptoms such as freezing of gait.

Patients who have essential tremor often present with bilateral symptoms. Although many patients will indicate that they need symptom relief on both upper extremities in order to perform activities of daily living, our practice is to recommend surgery on one side at first and to suggest the patient consider contralateral implantation after weeks or months. Bilateral implantation may carry a risk for dysarthria and the risk is thought to be reduced if bilateral procedures are staged. Although high rates of dysarthria have been reported following bilateral surgery for tremor, its occurrence has been infrequent in our experience with bilateral staged DBS. Benefits of treating tremor in the dominant extremity usually exceed those of treating nondominant tremor, so most patients prefer that the dominant side be the first one treated.

TECHNICAL OPTIONS

There are several technical options for implantation of DBS systems. Stereotactic procedures rely on co-registration of preoperative imaging with external and internal fiducials, or points of reference. Targeting of the intended structures is performed by combining direct and indirect methods. Direct methods rely on identification of the target structures with imaging, such as visualization of the STN and GPi on preoperative magnetic resonance imaging (MRI). Indirect targeting relies on cadaveric anatomic atlases and coordinate systems that infer the location of the intended structures in relation to anatomical points of reference.

Frame-based systems

In the most common approach to DBS surgery,⁷ stereotactic frames are placed over the patient’s head and secured with pins. The frame becomes the fixed point of reference for accurate stereotactic surgery and must remain in place for the duration of the procedure. Computed tomography or MRI is then performed with the frame in place, so that the images are co-registered with the fiducial points of the stereotactic frame. The targets are then selected for surgery and trajectories are chosen based on anatomic structures. The patient is positioned supine and the frame and head are secured to the operating table. The coordinates calculated by the clinical workstations are then set to the stereotactic frame and arc. The stereotactic arc (Figure 2) is attached to the base of the frame and the entry points of the leads—where the burr hole will be placed—are marked on the skin and then on the skull. Once the burr hole and opening of the meninges are completed, the targeting cannulae are inserted. The microelectrode system is then mounted for recording of the target area and subsequently for final lead implantation.

Frameless systems

The workflow and overall surgical procedure for implantation of DBS with frameless systems are similar to those of the frame-based procedure. However, instead of fixing the head to a rigid frame that prevents head motion, a lighter-weight, frameless system is fixed to the head and moves with it (Figure 3). First, metal screws and fiducials are fixed to the head under local anesthesia or sedation. Preoperative imaging is then acquired with the fiducials in place and the surgical plans are completed in the same fashion as for frame-based surgery. The patient is then placed supine on the operating table and the frameless system is attached to the head with the aid of image guidance, in the location determined by target and trajectory planning.

The key advantage of the frameless system over the frame-based system is greater mobility of the head. Another important advantage is easier access to the airway, should an emergency situation occur. In our practice, patients with experience of both frameless and frame-based systems did not report significantly less discomfort with the frameless system.

The frameless system also has disadvantages, including less secure fixation of the head, which can add risk to the procedure. In addition, because of its lightweight, plastic construction, it provides less robust support to the instrumentation entering the brain than do metallic head frames and, in some cases, there is less flexibility for adjusting targets if needed during surgery. In addition, frameless systems are nonreusable and represent a substantial additional cost.

 

 

Microelectrode recording

Physiologic verification of anatomic targets identified by imaging can be accomplished with microelectrode recording (MER). This technique involves placing fine, high-impedance electrodes through the target area, so that anatomic structures can be recognized by characteristic electrical activity of individual neurons or groups of neurons. The locations of the structures are identified and the lengths of the electrode trajectories through the different structures—as well as the gaps between these structures—are recorded. The distances are then compared with the anatomy and a best-fit model is created to infer the location of the trajectory in the target area. Additional MER penetrations are made in order to further delineate the anatomy. Once a location for implantation has been selected, the DBS lead is inserted into the target area.

Electrode implantation

Lead implantation is often performed under fluoroscopic guidance in order to ensure accuracy and stability. When implanted, the electrode may cause a microlesional effect, manifested by transient improvement in symptoms.

The DBS leads are then connected to external pulse generators and assessed for clinical benefits and side effects. Amplitude, pulse width, and frequency are adjusted to test the therapeutic window of stimulation (clinical improvement thresholds versus side effect thresholds). Some PD patients develop dyskinesia during test stimulation, which may be a positive indicator for lead location. If good effects and a therapeutic window are observed, the location of the lead is considered to be satisfactory and the procedure is completed.

Pulse generator implantation

During the final step of surgery, performed under general anesthesia, the pulse generator is implanted. The extension cable that connects the DBS lead to the implantable pulse generator is tunneled subcutaneously, connecting the DBS lead to the pulse generator in the chest.

Intraoperative, real-time MRI stereotaxis

Real-time intraoperative MRI has become available for DBS implantation with devices recently cleared for use by the FDA. The procedure, typically performed in a diagnostic MRI suite, uses MR images acquired during surgery to guide DBS lead implantation in the target area and to verify implantation accuracy.⁸

Over the last decade, several studies have demonstrated that deep brain stimulation (DBS) is among the most effective approaches for the treatment of patients with advanced movement disorders, including chorea, levodopa-induced dyskinesia, tremor, and dystonia.¹ The goal of DBS is to restore function or relieve pain by stimulating neuronal activity through surgically implanted electrodes. DBS produces marked and persistent reductions in abnormal movements in patients with common hyperkinetic disorders, with a generally low incidence of serious adverse events in pediatric patients and adults.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Tremor is a rhythmic, involuntary, oscillatory movement of a body part. Tremors may be subdivided into several categories on the basis of clinical signs and symptoms, including rest, postural, and kinetic.² Essential tremor is the most common tremor disorder, affecting an estimated 5% of the population over the age of 60 years.³ Tremor is also commonly associated with other neurologic conditions, including multiple sclerosis, Parkinson disease, and severe head trauma.³ Hand, head, and vocal tremor are the most common clinical manifestations of essential tremor, and may significantly interfere with normal function.⁴ For example, the effect of essential tremor on a simple hand-drawing task is illustrated in Figure 1, which demonstrates the marked tremor-related impairment in a patient’s ability to draw a spiral shape and the resulting improvement in hand coordination after the application of DBS.

Improvement with thalamic DBS

The ventral intermediate nucleus (VIM) of the thalamus is the most common target for DBS treatment of essential tremor. Several studies have demonstrated significant long-term improvement in tremor following thalamic DBS.³ Most studies enrolled 20 to 30 patients, who were followed for 1 to 5 years after device implantation. On average, these studies reported an improvement in overall tremor of approximately 50% from baseline with thalamic DBS.

Patient selection and stimulation parameters

Symptoms targeted for DBS treatment include unilateral and sometimes bilateral limb tremor. Some evidence exists for effectiveness in axial and vocal tremor as well. Factors to consider in patient selection for DBS surgery include tremor severity, degree of refractoriness to medication, and type of tremor. In addition, individual patient characteristics should be considered, including age, comorbid conditions, surgical risk, patient preference, social and employment factors, and social support.

Reprinted with permission from Journal of Clinical Neurophysiology (Cooper SE, et al. A model predicting optimal parameters for deep brain stimulation in essential tremor. J Clin Neurophysiol 2008; 2:26–273). Copyright © 2008 by the ACNS.

Research is ongoing to define the stimulation parameters that are most important for ensuring symptom control in patients undergoing DBS for tremor. Studies that have modeled tremor response to DBS across a range of stimulation parameters have found that suppression of tremor is most closely associated with stimulation voltage and frequency, with pulse width producing less of an effect.⁵ Figure 2 shows tremor power (measured in decibel units) associated with different combinations of frequency and pulse width applied to the VIM in nine patients with essential tremor.⁵ The observations from this study suggest that stimulation programming is complex even for essential tremor, a condition for which programming is generally among the simplest to perform.

DEEP BRAIN STIMULATION FOR DYSTONIA

Dystonia is characterized by involuntary twisting muscle contractions causing abnormal postures sometimes accompanied by jerky or repetitive involuntary movements. It may be classified according to the body part affected as generalized, segmental, or focal; in some cases it may be classified as multifocal dystonia or hemidystonia. Dystonia is also classified as primary or secondary, according to etiology. Primary dystonias are those not caused by any other identifiable condition and not associated with other neurologic abnormalities. These include idiopathic and some genetic dystonias, such as the DYT1 torsinA gene mutation. DBS of the globus pallidus internus (GPi) or subthalamic nucleus (STN) was approved by the US Food and Drug Administration under a humanitarian device exemption in 2003 for the treatment of primary generalized dystonia (PGD) in patients aged 7 years and older; GPi is the more common target).¹

Evidence of efficacy

Several clinical studies have demonstrated the efficacy of DBS for patients with disabling PGD that is unresponsive to pharmacotherapy.

Long-term efficacy. Isaias and colleagues examined long-term safety and efficacy of DBS in 30 consecutive patients with PGD who were followed for at least 3 years after pallidal DBS surgery.⁶ DBS was delivered bilaterally in 28 patients and unilaterally in 2 patients. Clinical rating scales of motor function improved by a mean of 82.5% after 2 years, and dystonia-related disability improved by a mean of 75.2%. Improvement in motor function from baseline was noted for all 30 subjects. In five patients who were followed for 7 years, improvement in motor function remained greater than 80% at the last follow-up visit. Transient regressions were noted for patients with hardware failures or whose batteries had reached the end of life. Stimulation-related adverse events were reported for three patients and included speech difficulties and, in one patient, transient blepharospasm.

Vidailhet and colleagues examined the efficacy of bilateral pallidal stimulation in 22 patients with PGD who were followed prospectively for 3 years.⁷ Mean improvement from baseline in motor function on a dystonia rating scale was 51% after 1 year and 58% after 3 years (P = .03). Significant improvement was noted for individual ratings of upper and lower limb function scores. Health-related quality of life was also significantly improved at 3-year follow-up (P = .05). Serious adverse events were reported for three patients, including two lead fractures and one infection.

Results from double-blind trial. Kupsch and colleagues performed a randomized, double-blind clinical trial comparing pallidal DBS versus device implantation and sham stimulation in 40 patients with primary segmental or generalized dystonia.⁸ After 3 months, the mean change from baseline in severity of dystonia was 15.8% for patients who received DBS versus 1.4% with sham stimulation (P < .001). At the conclusion of the double-blind treatment phase, patients entered an open-label extension phase in which all patients received DBS for another 3 months. The initial benefit of treatment was sustained across the entire 6-month study period for patients initially randomized to DBS, whereas patients who were initially randomized to sham stimulation exhibited improved motor function during the open-label extension phase. Ratings of disability and quality of life also improved for patients receiving DBS at the end of the 6-month study. Adverse events included dysarthria (five patients), serious infections (four patients), and lead dislodgement (one patient).

Response with DYT1mutation. Coubes and colleagues examined the long-term efficacy and safety of bilateral DBS in 31 children and adults with PGD.⁹ PGD is associated with autosomal DYT1 mutations in approximately 30% of cases, and these authors examined the effects of treatment in patients with and without the DYT1 mutation. After 2 years of treatment, mean scores on a dystonia clinical rating scale decreased by 79% from baseline, and mean disability ratings decreased by 65%. The improvement in clinical dystonia rating scale scores was significantly greater for children than adults after 2 years (84.7% vs 70.1%; P = .04). In children, functional improvement was greater after 2 years in the subset of patients with DYT1 mutations than in the subset of patients without (76.1% vs 44.5%; P = .03), whereas in adults, DYT1 mutation status did not significantly influence response to treatment. One case of unilateral infection was noted, which required removal of the implant with successful reimplantation 6 months later. No other adverse events were reported.

 

 

Patient selection

Appropriate patients for DBS include those with an unequivocal diagnosis of dystonia and significant disability. Etiology and type of dystonia should also be considered. Patients with secondary dystonia (eg, due to structural brain lesions or heredodegenerative disorders) generally do not respond to DBS as well as patients with primary dystonias. A possible exception is tardive dystonia, which is caused by past exposure to dopamine receptor–blocking drugs. Although it is a secondary dystonia, tardive dystonia may respond well to DBS. Data on this point remain limited. Moreover, with tardive dystonia (as well as Sydenham chorea and poststroke hemiballismus), there may be spontaneous remission. DBS in these conditions should therefore be considered when enough time has elapsed that the likelihood of spontaneous remission is low.¹

Not all dystonic symptoms have been shown to respond equally to DBS. Evidence of effectiveness is stronger and more consistent for limb and axial dystonia than for dystonic impairment of speech and swallowing. Phasic dystonia (jerky or rhythmic movements) appears to respond better than fixed postures. A critical point is that fixed postures not caused by electrically active muscle contraction will not respond to DBS. For example, bony deformity of the spine, joint disease, or tendon shortening cannot be expected to improve with DBS. The situation is complicated, since such conditions may develop as secondary consequences of dystonia. The potential for their development may warrant earlier rather than later DBS surgery in childhood-onset PGD.¹⁰

UNRESOLVED ISSUES IN DBS FOR DYSTONIA

How aggressively should other therapies be tried before starting DBS?

Pharmacologic options include a range of oral, intramuscular, and intrathecal agents. Injection of botulinum toxin to denervate affected muscles is a mainstay of treatment for focal or segmental dystonia, but often fails to improve symptoms because of the involvement of a large number of muscles, complexity of the movement pattern, or the development of neutralizing antibodies.⁸ With the exception of levodopa-responsive PGD, other pharmacologic therapy for PGD is generally of limited effectiveness for controlling symptoms of dystonia.⁹ Oral or intrathecal baclofen may improve symptoms, but often produces unacceptable sedation.

How important is intraoperative microelectrophysiology?

Although contemporary imaging techniques are important in the correct placement of stimulating electrodes, the available techniques do not always provide sufficient resolution to delineate the STN or GPi. The accuracy of electrode placement may also be influenced by distortions caused by lack of homogeneity among magnetic resonance images, brain shift, and signal deflections from cannulae or electrodes.¹⁴ These errors may result in significant deviation of electrode placement from the intended target. Microelectrode recording and micro-stimulation may be used to map the target region and refine the surgical target. It is widely, but not universally, held that this strategy contributes to superior accuracy and outcomes; it ordinarily requires an awake procedure, which is not always feasible in patients with severe dystonia or in pediatric patients.¹¹

How should be programming (stimulator adjustment) be performed?

Research continues to refine our understanding of how electrical parameters such as voltage, frequency, and pulse width affect clinical outcomes in patients undergoing DBS for dystonia. Some programming approaches, such as long pulse width and high frequency, that were once generally accepted are now widely questioned. Another major unresolved question is: “How long should it take to see the results of stimulation?” In the clinical studies described above, continued improvement was generally observed over months or even years, and, in most patients, stimulators are incrementally adjusted over an extended period. However, some patients may experience much more rapid onset of benefit.

Long-term DBS management of dystonia

Unlike DBS for Parkinson disease or even essential tremor, DBS for dystonia is performed in young patients. This creates special challenges in pediatric patients, who can be expected to grow and develop after device implantation. As a result, children may require additional surgeries to reposition devices.

In addition, the most widely used devices require repeated battery replacement surgeries, although newer rechargeable devices are becoming available.

Finally, there is a nontrivial incidence of hardware-related complications when devices are used continuously for many years. Although individual dystonia patients vary in the acuity of their response to the cessation of stimulation,⁶ deterioration can be acute and dramatic. In long-term studies of bilateral pallidal stimulation described above, hardware failures were the most commonly reported adverse events, including unilateral or bilateral lead fracture.^7,9 These appear to be more frequent in patients with dystonia than in other movement disorders.

SUMMARY AND CONCLUSIONS

Deep brain stimulation produces marked and long-lasting improvement in motor function and disability in patients with hyperkinetic disorders. In patients with essential tremor, stimulation usually targets the VIM of the thalamus. Reduction in tremor is most closely related to stimulation frequency and voltage, whereas pulse width has little effect on treatment outcome. In patients with dystonia, stimulation typically targets the GPi or STN. Long-term prospective clinical trials demonstrated significant reductions in motor severity rating scale scores. Selecting patients for DBS requires careful consideration of a range of factors, including the specific clinical presentation, treatment history, and social support. Areas of current investigation include optimal stimulation programming, intraoperative mapping, and the long-term efficacy and safety of stimulation.

Over the last decade, several studies have demonstrated that deep brain stimulation (DBS) is among the most effective approaches for the treatment of patients with advanced movement disorders, including chorea, levodopa-induced dyskinesia, tremor, and dystonia.¹ The goal of DBS is to restore function or relieve pain by stimulating neuronal activity through surgically implanted electrodes. DBS produces marked and persistent reductions in abnormal movements in patients with common hyperkinetic disorders, with a generally low incidence of serious adverse events in pediatric patients and adults.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Tremor is a rhythmic, involuntary, oscillatory movement of a body part. Tremors may be subdivided into several categories on the basis of clinical signs and symptoms, including rest, postural, and kinetic.² Essential tremor is the most common tremor disorder, affecting an estimated 5% of the population over the age of 60 years.³ Tremor is also commonly associated with other neurologic conditions, including multiple sclerosis, Parkinson disease, and severe head trauma.³ Hand, head, and vocal tremor are the most common clinical manifestations of essential tremor, and may significantly interfere with normal function.⁴ For example, the effect of essential tremor on a simple hand-drawing task is illustrated in Figure 1, which demonstrates the marked tremor-related impairment in a patient’s ability to draw a spiral shape and the resulting improvement in hand coordination after the application of DBS.

Improvement with thalamic DBS

The ventral intermediate nucleus (VIM) of the thalamus is the most common target for DBS treatment of essential tremor. Several studies have demonstrated significant long-term improvement in tremor following thalamic DBS.³ Most studies enrolled 20 to 30 patients, who were followed for 1 to 5 years after device implantation. On average, these studies reported an improvement in overall tremor of approximately 50% from baseline with thalamic DBS.

Patient selection and stimulation parameters

Symptoms targeted for DBS treatment include unilateral and sometimes bilateral limb tremor. Some evidence exists for effectiveness in axial and vocal tremor as well. Factors to consider in patient selection for DBS surgery include tremor severity, degree of refractoriness to medication, and type of tremor. In addition, individual patient characteristics should be considered, including age, comorbid conditions, surgical risk, patient preference, social and employment factors, and social support.

Reprinted with permission from Journal of Clinical Neurophysiology (Cooper SE, et al. A model predicting optimal parameters for deep brain stimulation in essential tremor. J Clin Neurophysiol 2008; 2:26–273). Copyright © 2008 by the ACNS.

Research is ongoing to define the stimulation parameters that are most important for ensuring symptom control in patients undergoing DBS for tremor. Studies that have modeled tremor response to DBS across a range of stimulation parameters have found that suppression of tremor is most closely associated with stimulation voltage and frequency, with pulse width producing less of an effect.⁵ Figure 2 shows tremor power (measured in decibel units) associated with different combinations of frequency and pulse width applied to the VIM in nine patients with essential tremor.⁵ The observations from this study suggest that stimulation programming is complex even for essential tremor, a condition for which programming is generally among the simplest to perform.

DEEP BRAIN STIMULATION FOR DYSTONIA

Dystonia is characterized by involuntary twisting muscle contractions causing abnormal postures sometimes accompanied by jerky or repetitive involuntary movements. It may be classified according to the body part affected as generalized, segmental, or focal; in some cases it may be classified as multifocal dystonia or hemidystonia. Dystonia is also classified as primary or secondary, according to etiology. Primary dystonias are those not caused by any other identifiable condition and not associated with other neurologic abnormalities. These include idiopathic and some genetic dystonias, such as the DYT1 torsinA gene mutation. DBS of the globus pallidus internus (GPi) or subthalamic nucleus (STN) was approved by the US Food and Drug Administration under a humanitarian device exemption in 2003 for the treatment of primary generalized dystonia (PGD) in patients aged 7 years and older; GPi is the more common target).¹

Evidence of efficacy

Several clinical studies have demonstrated the efficacy of DBS for patients with disabling PGD that is unresponsive to pharmacotherapy.

Long-term efficacy. Isaias and colleagues examined long-term safety and efficacy of DBS in 30 consecutive patients with PGD who were followed for at least 3 years after pallidal DBS surgery.⁶ DBS was delivered bilaterally in 28 patients and unilaterally in 2 patients. Clinical rating scales of motor function improved by a mean of 82.5% after 2 years, and dystonia-related disability improved by a mean of 75.2%. Improvement in motor function from baseline was noted for all 30 subjects. In five patients who were followed for 7 years, improvement in motor function remained greater than 80% at the last follow-up visit. Transient regressions were noted for patients with hardware failures or whose batteries had reached the end of life. Stimulation-related adverse events were reported for three patients and included speech difficulties and, in one patient, transient blepharospasm.

Vidailhet and colleagues examined the efficacy of bilateral pallidal stimulation in 22 patients with PGD who were followed prospectively for 3 years.⁷ Mean improvement from baseline in motor function on a dystonia rating scale was 51% after 1 year and 58% after 3 years (P = .03). Significant improvement was noted for individual ratings of upper and lower limb function scores. Health-related quality of life was also significantly improved at 3-year follow-up (P = .05). Serious adverse events were reported for three patients, including two lead fractures and one infection.

Results from double-blind trial. Kupsch and colleagues performed a randomized, double-blind clinical trial comparing pallidal DBS versus device implantation and sham stimulation in 40 patients with primary segmental or generalized dystonia.⁸ After 3 months, the mean change from baseline in severity of dystonia was 15.8% for patients who received DBS versus 1.4% with sham stimulation (P < .001). At the conclusion of the double-blind treatment phase, patients entered an open-label extension phase in which all patients received DBS for another 3 months. The initial benefit of treatment was sustained across the entire 6-month study period for patients initially randomized to DBS, whereas patients who were initially randomized to sham stimulation exhibited improved motor function during the open-label extension phase. Ratings of disability and quality of life also improved for patients receiving DBS at the end of the 6-month study. Adverse events included dysarthria (five patients), serious infections (four patients), and lead dislodgement (one patient).

Response with DYT1mutation. Coubes and colleagues examined the long-term efficacy and safety of bilateral DBS in 31 children and adults with PGD.⁹ PGD is associated with autosomal DYT1 mutations in approximately 30% of cases, and these authors examined the effects of treatment in patients with and without the DYT1 mutation. After 2 years of treatment, mean scores on a dystonia clinical rating scale decreased by 79% from baseline, and mean disability ratings decreased by 65%. The improvement in clinical dystonia rating scale scores was significantly greater for children than adults after 2 years (84.7% vs 70.1%; P = .04). In children, functional improvement was greater after 2 years in the subset of patients with DYT1 mutations than in the subset of patients without (76.1% vs 44.5%; P = .03), whereas in adults, DYT1 mutation status did not significantly influence response to treatment. One case of unilateral infection was noted, which required removal of the implant with successful reimplantation 6 months later. No other adverse events were reported.

 

 

Patient selection

Appropriate patients for DBS include those with an unequivocal diagnosis of dystonia and significant disability. Etiology and type of dystonia should also be considered. Patients with secondary dystonia (eg, due to structural brain lesions or heredodegenerative disorders) generally do not respond to DBS as well as patients with primary dystonias. A possible exception is tardive dystonia, which is caused by past exposure to dopamine receptor–blocking drugs. Although it is a secondary dystonia, tardive dystonia may respond well to DBS. Data on this point remain limited. Moreover, with tardive dystonia (as well as Sydenham chorea and poststroke hemiballismus), there may be spontaneous remission. DBS in these conditions should therefore be considered when enough time has elapsed that the likelihood of spontaneous remission is low.¹

Not all dystonic symptoms have been shown to respond equally to DBS. Evidence of effectiveness is stronger and more consistent for limb and axial dystonia than for dystonic impairment of speech and swallowing. Phasic dystonia (jerky or rhythmic movements) appears to respond better than fixed postures. A critical point is that fixed postures not caused by electrically active muscle contraction will not respond to DBS. For example, bony deformity of the spine, joint disease, or tendon shortening cannot be expected to improve with DBS. The situation is complicated, since such conditions may develop as secondary consequences of dystonia. The potential for their development may warrant earlier rather than later DBS surgery in childhood-onset PGD.¹⁰

UNRESOLVED ISSUES IN DBS FOR DYSTONIA

How aggressively should other therapies be tried before starting DBS?

Pharmacologic options include a range of oral, intramuscular, and intrathecal agents. Injection of botulinum toxin to denervate affected muscles is a mainstay of treatment for focal or segmental dystonia, but often fails to improve symptoms because of the involvement of a large number of muscles, complexity of the movement pattern, or the development of neutralizing antibodies.⁸ With the exception of levodopa-responsive PGD, other pharmacologic therapy for PGD is generally of limited effectiveness for controlling symptoms of dystonia.⁹ Oral or intrathecal baclofen may improve symptoms, but often produces unacceptable sedation.

How important is intraoperative microelectrophysiology?

Although contemporary imaging techniques are important in the correct placement of stimulating electrodes, the available techniques do not always provide sufficient resolution to delineate the STN or GPi. The accuracy of electrode placement may also be influenced by distortions caused by lack of homogeneity among magnetic resonance images, brain shift, and signal deflections from cannulae or electrodes.¹⁴ These errors may result in significant deviation of electrode placement from the intended target. Microelectrode recording and micro-stimulation may be used to map the target region and refine the surgical target. It is widely, but not universally, held that this strategy contributes to superior accuracy and outcomes; it ordinarily requires an awake procedure, which is not always feasible in patients with severe dystonia or in pediatric patients.¹¹

How should be programming (stimulator adjustment) be performed?

Research continues to refine our understanding of how electrical parameters such as voltage, frequency, and pulse width affect clinical outcomes in patients undergoing DBS for dystonia. Some programming approaches, such as long pulse width and high frequency, that were once generally accepted are now widely questioned. Another major unresolved question is: “How long should it take to see the results of stimulation?” In the clinical studies described above, continued improvement was generally observed over months or even years, and, in most patients, stimulators are incrementally adjusted over an extended period. However, some patients may experience much more rapid onset of benefit.

Long-term DBS management of dystonia

Unlike DBS for Parkinson disease or even essential tremor, DBS for dystonia is performed in young patients. This creates special challenges in pediatric patients, who can be expected to grow and develop after device implantation. As a result, children may require additional surgeries to reposition devices.

In addition, the most widely used devices require repeated battery replacement surgeries, although newer rechargeable devices are becoming available.

Finally, there is a nontrivial incidence of hardware-related complications when devices are used continuously for many years. Although individual dystonia patients vary in the acuity of their response to the cessation of stimulation,⁶ deterioration can be acute and dramatic. In long-term studies of bilateral pallidal stimulation described above, hardware failures were the most commonly reported adverse events, including unilateral or bilateral lead fracture.^7,9 These appear to be more frequent in patients with dystonia than in other movement disorders.

SUMMARY AND CONCLUSIONS

Deep brain stimulation produces marked and long-lasting improvement in motor function and disability in patients with hyperkinetic disorders. In patients with essential tremor, stimulation usually targets the VIM of the thalamus. Reduction in tremor is most closely related to stimulation frequency and voltage, whereas pulse width has little effect on treatment outcome. In patients with dystonia, stimulation typically targets the GPi or STN. Long-term prospective clinical trials demonstrated significant reductions in motor severity rating scale scores. Selecting patients for DBS requires careful consideration of a range of factors, including the specific clinical presentation, treatment history, and social support. Areas of current investigation include optimal stimulation programming, intraoperative mapping, and the long-term efficacy and safety of stimulation.

Over the last decade, several studies have demonstrated that deep brain stimulation (DBS) is among the most effective approaches for the treatment of patients with advanced movement disorders, including chorea, levodopa-induced dyskinesia, tremor, and dystonia.¹ The goal of DBS is to restore function or relieve pain by stimulating neuronal activity through surgically implanted electrodes. DBS produces marked and persistent reductions in abnormal movements in patients with common hyperkinetic disorders, with a generally low incidence of serious adverse events in pediatric patients and adults.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Tremor is a rhythmic, involuntary, oscillatory movement of a body part. Tremors may be subdivided into several categories on the basis of clinical signs and symptoms, including rest, postural, and kinetic.² Essential tremor is the most common tremor disorder, affecting an estimated 5% of the population over the age of 60 years.³ Tremor is also commonly associated with other neurologic conditions, including multiple sclerosis, Parkinson disease, and severe head trauma.³ Hand, head, and vocal tremor are the most common clinical manifestations of essential tremor, and may significantly interfere with normal function.⁴ For example, the effect of essential tremor on a simple hand-drawing task is illustrated in Figure 1, which demonstrates the marked tremor-related impairment in a patient’s ability to draw a spiral shape and the resulting improvement in hand coordination after the application of DBS.

Improvement with thalamic DBS

The ventral intermediate nucleus (VIM) of the thalamus is the most common target for DBS treatment of essential tremor. Several studies have demonstrated significant long-term improvement in tremor following thalamic DBS.³ Most studies enrolled 20 to 30 patients, who were followed for 1 to 5 years after device implantation. On average, these studies reported an improvement in overall tremor of approximately 50% from baseline with thalamic DBS.

Patient selection and stimulation parameters

Symptoms targeted for DBS treatment include unilateral and sometimes bilateral limb tremor. Some evidence exists for effectiveness in axial and vocal tremor as well. Factors to consider in patient selection for DBS surgery include tremor severity, degree of refractoriness to medication, and type of tremor. In addition, individual patient characteristics should be considered, including age, comorbid conditions, surgical risk, patient preference, social and employment factors, and social support.

Reprinted with permission from Journal of Clinical Neurophysiology (Cooper SE, et al. A model predicting optimal parameters for deep brain stimulation in essential tremor. J Clin Neurophysiol 2008; 2:26–273). Copyright © 2008 by the ACNS.

Research is ongoing to define the stimulation parameters that are most important for ensuring symptom control in patients undergoing DBS for tremor. Studies that have modeled tremor response to DBS across a range of stimulation parameters have found that suppression of tremor is most closely associated with stimulation voltage and frequency, with pulse width producing less of an effect.⁵ Figure 2 shows tremor power (measured in decibel units) associated with different combinations of frequency and pulse width applied to the VIM in nine patients with essential tremor.⁵ The observations from this study suggest that stimulation programming is complex even for essential tremor, a condition for which programming is generally among the simplest to perform.

DEEP BRAIN STIMULATION FOR DYSTONIA

Dystonia is characterized by involuntary twisting muscle contractions causing abnormal postures sometimes accompanied by jerky or repetitive involuntary movements. It may be classified according to the body part affected as generalized, segmental, or focal; in some cases it may be classified as multifocal dystonia or hemidystonia. Dystonia is also classified as primary or secondary, according to etiology. Primary dystonias are those not caused by any other identifiable condition and not associated with other neurologic abnormalities. These include idiopathic and some genetic dystonias, such as the DYT1 torsinA gene mutation. DBS of the globus pallidus internus (GPi) or subthalamic nucleus (STN) was approved by the US Food and Drug Administration under a humanitarian device exemption in 2003 for the treatment of primary generalized dystonia (PGD) in patients aged 7 years and older; GPi is the more common target).¹

Evidence of efficacy

Several clinical studies have demonstrated the efficacy of DBS for patients with disabling PGD that is unresponsive to pharmacotherapy.

Long-term efficacy. Isaias and colleagues examined long-term safety and efficacy of DBS in 30 consecutive patients with PGD who were followed for at least 3 years after pallidal DBS surgery.⁶ DBS was delivered bilaterally in 28 patients and unilaterally in 2 patients. Clinical rating scales of motor function improved by a mean of 82.5% after 2 years, and dystonia-related disability improved by a mean of 75.2%. Improvement in motor function from baseline was noted for all 30 subjects. In five patients who were followed for 7 years, improvement in motor function remained greater than 80% at the last follow-up visit. Transient regressions were noted for patients with hardware failures or whose batteries had reached the end of life. Stimulation-related adverse events were reported for three patients and included speech difficulties and, in one patient, transient blepharospasm.

Vidailhet and colleagues examined the efficacy of bilateral pallidal stimulation in 22 patients with PGD who were followed prospectively for 3 years.⁷ Mean improvement from baseline in motor function on a dystonia rating scale was 51% after 1 year and 58% after 3 years (P = .03). Significant improvement was noted for individual ratings of upper and lower limb function scores. Health-related quality of life was also significantly improved at 3-year follow-up (P = .05). Serious adverse events were reported for three patients, including two lead fractures and one infection.

Results from double-blind trial. Kupsch and colleagues performed a randomized, double-blind clinical trial comparing pallidal DBS versus device implantation and sham stimulation in 40 patients with primary segmental or generalized dystonia.⁸ After 3 months, the mean change from baseline in severity of dystonia was 15.8% for patients who received DBS versus 1.4% with sham stimulation (P < .001). At the conclusion of the double-blind treatment phase, patients entered an open-label extension phase in which all patients received DBS for another 3 months. The initial benefit of treatment was sustained across the entire 6-month study period for patients initially randomized to DBS, whereas patients who were initially randomized to sham stimulation exhibited improved motor function during the open-label extension phase. Ratings of disability and quality of life also improved for patients receiving DBS at the end of the 6-month study. Adverse events included dysarthria (five patients), serious infections (four patients), and lead dislodgement (one patient).

Response with DYT1mutation. Coubes and colleagues examined the long-term efficacy and safety of bilateral DBS in 31 children and adults with PGD.⁹ PGD is associated with autosomal DYT1 mutations in approximately 30% of cases, and these authors examined the effects of treatment in patients with and without the DYT1 mutation. After 2 years of treatment, mean scores on a dystonia clinical rating scale decreased by 79% from baseline, and mean disability ratings decreased by 65%. The improvement in clinical dystonia rating scale scores was significantly greater for children than adults after 2 years (84.7% vs 70.1%; P = .04). In children, functional improvement was greater after 2 years in the subset of patients with DYT1 mutations than in the subset of patients without (76.1% vs 44.5%; P = .03), whereas in adults, DYT1 mutation status did not significantly influence response to treatment. One case of unilateral infection was noted, which required removal of the implant with successful reimplantation 6 months later. No other adverse events were reported.

 

 

Patient selection

Appropriate patients for DBS include those with an unequivocal diagnosis of dystonia and significant disability. Etiology and type of dystonia should also be considered. Patients with secondary dystonia (eg, due to structural brain lesions or heredodegenerative disorders) generally do not respond to DBS as well as patients with primary dystonias. A possible exception is tardive dystonia, which is caused by past exposure to dopamine receptor–blocking drugs. Although it is a secondary dystonia, tardive dystonia may respond well to DBS. Data on this point remain limited. Moreover, with tardive dystonia (as well as Sydenham chorea and poststroke hemiballismus), there may be spontaneous remission. DBS in these conditions should therefore be considered when enough time has elapsed that the likelihood of spontaneous remission is low.¹

Not all dystonic symptoms have been shown to respond equally to DBS. Evidence of effectiveness is stronger and more consistent for limb and axial dystonia than for dystonic impairment of speech and swallowing. Phasic dystonia (jerky or rhythmic movements) appears to respond better than fixed postures. A critical point is that fixed postures not caused by electrically active muscle contraction will not respond to DBS. For example, bony deformity of the spine, joint disease, or tendon shortening cannot be expected to improve with DBS. The situation is complicated, since such conditions may develop as secondary consequences of dystonia. The potential for their development may warrant earlier rather than later DBS surgery in childhood-onset PGD.¹⁰

UNRESOLVED ISSUES IN DBS FOR DYSTONIA

How aggressively should other therapies be tried before starting DBS?

Pharmacologic options include a range of oral, intramuscular, and intrathecal agents. Injection of botulinum toxin to denervate affected muscles is a mainstay of treatment for focal or segmental dystonia, but often fails to improve symptoms because of the involvement of a large number of muscles, complexity of the movement pattern, or the development of neutralizing antibodies.⁸ With the exception of levodopa-responsive PGD, other pharmacologic therapy for PGD is generally of limited effectiveness for controlling symptoms of dystonia.⁹ Oral or intrathecal baclofen may improve symptoms, but often produces unacceptable sedation.

How important is intraoperative microelectrophysiology?

Although contemporary imaging techniques are important in the correct placement of stimulating electrodes, the available techniques do not always provide sufficient resolution to delineate the STN or GPi. The accuracy of electrode placement may also be influenced by distortions caused by lack of homogeneity among magnetic resonance images, brain shift, and signal deflections from cannulae or electrodes.¹⁴ These errors may result in significant deviation of electrode placement from the intended target. Microelectrode recording and micro-stimulation may be used to map the target region and refine the surgical target. It is widely, but not universally, held that this strategy contributes to superior accuracy and outcomes; it ordinarily requires an awake procedure, which is not always feasible in patients with severe dystonia or in pediatric patients.¹¹

How should be programming (stimulator adjustment) be performed?

Research continues to refine our understanding of how electrical parameters such as voltage, frequency, and pulse width affect clinical outcomes in patients undergoing DBS for dystonia. Some programming approaches, such as long pulse width and high frequency, that were once generally accepted are now widely questioned. Another major unresolved question is: “How long should it take to see the results of stimulation?” In the clinical studies described above, continued improvement was generally observed over months or even years, and, in most patients, stimulators are incrementally adjusted over an extended period. However, some patients may experience much more rapid onset of benefit.

Long-term DBS management of dystonia

Unlike DBS for Parkinson disease or even essential tremor, DBS for dystonia is performed in young patients. This creates special challenges in pediatric patients, who can be expected to grow and develop after device implantation. As a result, children may require additional surgeries to reposition devices.

In addition, the most widely used devices require repeated battery replacement surgeries, although newer rechargeable devices are becoming available.

Finally, there is a nontrivial incidence of hardware-related complications when devices are used continuously for many years. Although individual dystonia patients vary in the acuity of their response to the cessation of stimulation,⁶ deterioration can be acute and dramatic. In long-term studies of bilateral pallidal stimulation described above, hardware failures were the most commonly reported adverse events, including unilateral or bilateral lead fracture.^7,9 These appear to be more frequent in patients with dystonia than in other movement disorders.

SUMMARY AND CONCLUSIONS

Deep brain stimulation produces marked and long-lasting improvement in motor function and disability in patients with hyperkinetic disorders. In patients with essential tremor, stimulation usually targets the VIM of the thalamus. Reduction in tremor is most closely related to stimulation frequency and voltage, whereas pulse width has little effect on treatment outcome. In patients with dystonia, stimulation typically targets the GPi or STN. Long-term prospective clinical trials demonstrated significant reductions in motor severity rating scale scores. Selecting patients for DBS requires careful consideration of a range of factors, including the specific clinical presentation, treatment history, and social support. Areas of current investigation include optimal stimulation programming, intraoperative mapping, and the long-term efficacy and safety of stimulation.