Surgical movement disorders
Content
Surgical T reatment of Movement Disord ers Benzi M. Kluger, Kluger, MDa,*, Olga Klepitskaya, MDa, Michael S. Okun, MDb,c KEYWORDS Movement disorders Surgical treatment Deep brain stimulation Parkinson’s disease Dystonia Essential tremor
The The past past 2 to 3 deca decade des s have have been been ma mark rked ed by a resu resurg rgen ence ce in surg surgic ical al appr approa oach ches es for for the treatment of movement disorders, specifically the creation of neuroanatomical lesions and deep brain stimulation (DBS). This renewed interest has been spurred on by several factors including (1) improvements in our understanding of the neurophys physio iolo logy gy and and anat anatom omy y of move moveme ment nt disor disorde ders rs,, (2) (2) the the refi refine neme ment nt of DBS DBS as a surgic surgical al approac approach, h, (3) improv improveme ements nts in neuros neurosurg urgery ery and neuroim neuroimagi aging, ng, which which have enhanced our ability to localize brain structures, and (4) an increasing role for surgical interventions, especially in circumstances in which current pharmacologic treatments have reached their limits. Appropriate patient selection for surgery can result in a compelling treatment option for a variety of movement disorders, with the most common to date including Parkinson’s disease (PD), dystonia, and essential tremor. HISTORY
Surgical treatments for movement disorders can be traced to the late 1800s and early 1900s where applications applications included included lesions lesions placed in the motor cortex, 1 the corticospinal tracts, tracts,2 and the cerebral peduncles. 3 Early Early att attemp empts ts at therap therapy y were were focuse focused d mainly on treating hyperkinetic movement disorders, including tremor. Not surprisingly, these early treatments had an unacceptable rate of side effects, particularly of motor weakness. With the introduction of the stereotactic head frame technology in
This work was supported supported by an American Academy of Neurology Neurology Foundation Foundation Clinical Clinical Research Training Fellowship (B.M.K.), and the National Parkinson Foundation Center of Excellence, Gainesville, FL. a University of Colorado Denver and Health Sciences Center, Academic Office 1 mailstop B185, PO Box 6511, Aurora, CO 80045, USA b Department of Neurology, University of Florida, 100 S. Newell Dr, Room L3-100, PO Box 100236, Gainesville, FL 32610, USA c University of Florida Movement Disorders Center, McKnight Brain Institute, 100 S. Newell Dr. Room L3-100, PO Box 100236, Gainesville, FL, USA * Corresponding author. E-mail address: benzi.kluger@ucdenver [email protected] .edu (B.M. (B.M. Kluger). Neurol Clin 27 (2009) 633–677 doi:10.1016/j.ncl.2009.04.006 neurologic.theclinics.com 0733-8619/09 0733-8619/09/$ /$ – see front matter ª 2009 Elsevier Inc. All rights rights reserved. reserved.
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the late 1940s 1940s by Spiegel and colleagues, colleagues, 4 targeting very small subcortical structures became a more realistic possibility. possibility. However, there was still a paucity paucity of basic or clinical scientific evidence to know which nodes of this circuitry would be most appropriate for surgical interventions. A breakthrough in our understanding came in 1953, when when Cooper Cooper acciden accidentall tally y ligated ligated the anteri anterior or choroi choroidal dal artery artery during during a peduncu pedunculot lotomy omy,, and this dramatically improved his patient’s tremor. The ligation interrupted the main blood supply to many structures in the basal ganglia, including the globus pallidus, a finding confirmed by pathologic examination of some of Cooper’s 5 similar but later cases. cases. Althoug Although h this procedure procedure was abando abandoned ned as a result result of unacce unaccepta ptable ble side effects, and because of difficulty in reproducing Cooper’s success, it was followed by more refined surgical approaches that focused largely on many subcortical structures. In 1955, Hassler 6 reported that thalamotomy was more effective than pallidotomy for tremor. Cooper subsequently endorsed this surgical approach, adding that result results s of thalam thalamoto otomy my were were more more consis consisten tentt than than those those of pallido pallidotom tomy. y. In 1960, 1960, 7 Svennilson and colleagues reported that the clinical results of pallidotomy were location depend dependent ent,, with poster posterior ior lesion lesions s demons demonstra tratin ting g superi superior or results results to anteri anterior or lesions. lesions. Although Although this article demonstrate demonstrated d that posteroventral posteroventral pallidotomy pallidotomy improved improved all the cardinal motor signs of PD, this research did not influence general clinical practice, which continued to favor the thalamotomy. In 1963, a few authors published results suggesting that subthalamotomy may obtain tremor improvement similar to that with thalamotomy. 8 However, the fear of inducing hemiballism and subsequent reports showing clinical improvements in only a minority of patients with subthalamotomy led to thalamotomy being the procedure of choice. 9 The introduction of levodopa in 1967 for the treatment of PD provided a remarkable therapeutic benefit, which initially threatened to make all surgical approaches to PD obsolete. 10 The 1980s brought a renewed interest in surgical approaches for movement d isorisor11 ders, beginning with the use us e of thalamotomy for severe drug-resistant tremor. In 1992 1992 Laitin Laitinen en and collea colleague gues s 12 replica replicated ted Leksel Leksell’s l’s benefi benefits ts for poster posterov oventral entral pallidotpallidot13 omy in all cardinal PD motor signs, and in 1997, Gill and Heywood reported their resu result lts s of bilat bilater eral al subth subthal alam amot otom omy. y. This This rene renewe wed d inte intere rest st in surg surger ery y was was drive driven n larg largel ely y by an increased recognition of the limitations of long-term levodopa therapy. Equally important were advances made in our understanding of basal ganglia circuitry and physiology,14 including the emergence of animal models of basal ganglia disease. 15 In 1987, Benabid and colleagues 16 observed that high-frequency electrical stimulation to the ventral intermediate (VIM) nucleus of the thalamus, usually performed as part of neurosurgical localization, could be left in place and have dramatic chronic effect effects s in improvi improving ng tremor tremor.. This This observ observati ation on fueled fueled the furthe furtherr develo developmen pmentt of DBS DBS as a me mean ans s of trea treati ting ng basa basall gang gangli lia a diso disord rder ers. s. Alth Althou ough gh ther there e are are no adequ adequat atel ely y powe powere red d trial trials s publis publishe hed d to date date compa compari ring ng DBS DBS to lesi lesion on ther therap apy, y, DBS has virtually supplanted surgical lesions mainly due to its reversibility, flexibility in chan changi ging ng se sett ttin ings gs,, and and its its impro improve ved d tole tolera rabil bility ity in pati patien ents ts requi requirin ring g bilat bilater eral al surgic surgical al treatm treatment ent (eg, (eg, avoidin avoiding g speech speech and swallo swallowing wing problem problems). s). We focus focus on DBS in this this review, review, recogniz recognizing ing that that the effica efficacy cy and genera generall principl principles es of lesion lesion therapy are similar and that there may be cases in which ablative surgery may be advantageous.18 MECHANISM MECHANISMS S OF ACTION
Ablative brain lesions seem to achieve their functional improvement through the disruption of aberrant network activity. The pioneering work of Delong 14 and Albin and Young 17 in describing the direct and indirect pathways as well as the parallel
Surgical Treatment of Movement Disorders
circuitry of the basal ganglia circuitry has laid the foundation for identifying potential regions where surgical interventions may improve symptoms. PD is known to result in increased firing rates and changes in the pattern of a of activity ctivity of both the globus pal19 lidus lidus interna interna (GPi) (GPi) and subtha subthalam lamic ic nucleu nucleus s (STN). (STN). Thes These e patte pattern rns s have have been been confirmed in humans human s by physiologic recordings from PD patients undergoing DBS or ablati ablative ve surger surgery. y.20 Moreov Moreover, er, ablati ablative ve lesion lesions s within within the GPi and STN appear appear to somewhat normalize thi t his s abnormal physiologic activity and are associated with 15 functional improvements. Although DBS appears to produce an informational lesion (a term coined by Grill) that that ma may y mimic mimic ma many ny of the the effe effect cts s from from ablat ablativ ive e surg surger ery, y, the the phys physio iolo logi gic c me mech chan anis isms ms 21 are thought to be more complex. In simple terms, DBS is thought to work by inhibitinhibiting cells close to the stimulating stimulating electrode and by exciting passing passing fiber tracts, but this simplistic model does not consider many of the complex changes that may contribute to DBS effects. effects. There is currently currently evidence to support the existence existence of several several potential sites of action including the following: 1. Inhibition Inhibition of neuronal neuronal cell bodies in close proximity to the electrode. electrode. Evidence from primate recordings demonstrates a reduction in firing rates of cells adjacent to stimulation electrodes during therapeutic stimulation of both STN and GPi. 22 This reduction in firing rate may be due to a depolarization block through alterations of potassium or sodium channels and/or alterations in the balance of presynaptic excitatory and inhibitory afferents. 23 Depolarization blockade as a singular mechanism has fallen out of support of most experts in the field. 2. Stim Stimul ulat atio ion n of axon axons s in clos close e prox proxim imit ity y to the the elec electr trod ode. e. In fact fact,, stud studie ies s have have show shown n increased output from an inhibited nucleus, which is believed to be due to action potentials initiated via axonal stimulation. 24 This activity is time locked to the stimulator frequency. Computer models have further sug gested gested that the therapeutic 25 efficacy of STN is strongly linked to axonal activation. 3. Stimula Stimulation tion of fiber fiber tracts tracts passing passing throug through h the field of stimula stimulatio tion. n. DBS curren currents ts sufficient for axonal activation may spread beyond the anatomic target to adjacent fiber tracts. Several tracts important to basal ganglia functioning pass in close prox proxim imity ity to the the STN STN and and have have been been hypo hypoth thes esiz ized ed to cont contrib ribut ute e to the the clin clinic ical al effe effect ct of DBS, including cerebellothalamic fibers (tremor reduction), nigrostriatal tracts (incre (increase ase striata striatall dopami dopamine ne release release), ), and the zona zona incert incerta a (all (all cardin cardinal al motor motor symptoms).23 4. Alterations in neurotransmitter release and synthesis. As noted above, activation of the nigrostriatal tract may increase striatal dopamine release. Other microdialysis studies of STN DBS in rats have demonstrated modulatory effects on both glutamate and g-aminobutyr -aminobutyric ic acid release release within basal ganglia ganglia circuits. circuits. 26 5. Alterations Alterations in network dynamics. dynamics. DBS may interrupt interrupt pathologic neural neural output by providing stimulation greater than a neuron’s spontaneous activity and thus preemptin empting g intrins intrinsic ic firing. firing. This This has been been referr referred ed to as an ‘‘infor ‘informat mation ional al lesion lesion,’ ,’’’ because it replaces irregular pathologic activity with regular but ‘‘informationally’’ neutra neutrall output output..21 Functi Functiona onall imagin imaging g studies studies have have demonst demonstrat rated ed change changes s in multiple nodes of the motor circuitry, including the motor cortex, supplementary motor area (SMA) and cerebellum with symptom improvement following DBS. 6. Chronic Chronic network changes. changes. As discussed discussed in the section on dystonia, many clinical clinical improvements take days to weeks, suggesting that they are dependent on neuroplastic changes. Consistent with this concept, studies have demonstrated longterm term change changes s in synapt synaptic ic plastic plasticity ity follow following ing DBS.27 There is also preli pr eliminary minary evidence to suggest that DBS may confer some neuroprotective effects. 28
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These mechanisms are not mutually exclusive, and it appears likely that the therapeutic effects of DBS are the result of multiple mechanisms. 26 Moreover, there is evidence that the me m echanisms of DBS may not be b e identical across disease disease states, states, 29 subcortical targets, 30 or stimulation parameters. 31 SELECTION SELECTION OF SURGICAL SURGICAL CANDIDATES CANDIDATES
The evolution of DBS therapy has resulted in the acceptance that selection of appropriate patients is critically important to the therapeutic benefit. In fact, only a small subs subset et of patie patient nts s (10% (10%–2 –20% 0%)) ma may y be appr appropr opria iate te at any any one one time time.. 32 Currently, patients with PD, dystonia, and essential tremor (ET) may be considered surgical cand ca ndida idate tes s afte afterr they they have have faile failed d me medic dical al ma mana nage geme ment nt (DBS (DBS is Food Food and and Drug Drug Admin Admin-istration approved for these indications in the United States). Patients must be motivated vated and have have the resour resources ces availab available le to partici participate pate in the extens extensive ive follow follow-up -up required to program and monitor the DBS device. In addition, potential candidates must have an acceptable risk benefit ratio favoring surgery. All indications (PD, ET, and dystonia) for DBS carry risks, especially with comorbidities such as age, cognitive dysfunction, frailty, psychiatric disease, cerebral atrophy, blood thinners, and especially hypertension. hypertension. Among dystonia dystonia patients, patients, primary and/or tardive dystonia dystonia seems to have the best response, whereas patients with other forms of secondary dystonia, including structural changes or neurometabolic diseases, tend to have less-predictable responses responses to DBS.33 Howeve However, r, an increa increasin sing g number number of succes successes ses may be seen in these secondary dystonias with appropriate selection of target and stimulus parameters.34 In PD, patients and clinicians should be aware that DBS will potentially benefit only symptoms that are levodopa responsive. 35 DBS can improve ‘‘on’’ time, reduce reduce on-off on-off fluctu fluctuatio ations, ns, and decrea decrease se dyskin dyskinesi esias as but, with the except exception ion of tremor, tremor, does not provide motor benefits that exceed the patient’s patient’s best ‘‘on’’ ‘on’’ medicamedication state (with the current available targets of STN or GPi). It is thus critical for potential PD DBS candidates to have the Unified Parkinson disease rating scale (UPDRS) completed in both the practically defined ‘‘on’’ and ‘‘off’’ states. In general, clinics should follow the Core Assessment Program for Surgical Intervention Therapies in PD criteria, which include a minimal disease duration of 5 years, a diagnosis of idiopathic pathic PD, screen screening ing for depres depressio sion n and cognit cognitive ive decline decline,, and assess assessmen mentt for 35 minimal motor improvement of 30% based on UPDRS scores. One exception to this 30% rule is medically refractory tremor in PD, which may occur in 20% or more patients. There is currently insufficient evidence to support the use of ‘‘early’’ DBS in any movement disorder, although considerations are being explored in research arenas, including effects on quality of life (QOL), decreased surgical mortality (vs delayed operations ), operations ), cost savings, and the possibility that DBS may have a diseasemodifying effect. 36 Caution is required in how we define ‘‘early’’ disease, particularly in patie patient nts s witho without ut sign signifi ifica cant nt disab disabili ility ty,, pati patien ents ts who who have have not not rece receiv ived ed adequ adequat ate e tria trials ls of stan standa dard rd me medic dicat atio ions ns,, and and in patie patient nts s with with shor shortt disea disease se dura duratio tion n who who ma may y not not have have a definitive definitive diagnosis. diagnosis. Although potential surgical candidates may be identified by general neurologists, the decision to proceed through surgery is in the best circumstances made by an experienced experienced multidisciplina multidisciplinary/inte ry/interdiscipl rdisciplinary inary team typically typically including including a movement movement disorders neurologist, neurosurgeon, psychiatrist, neuropsychologist, and, in some circums circumstan tances ces,, a social social worker worker,, speech speech therap therapist, ist, occupa occupation tional al therap therapist, ist, and/or and/or physic physical al therap therapists ists ( Fig. Each member member of the multidi multidisci sciplin plinary ary tea team m should should F ig. 1 ).37 Each have a specific role in this evaluation and should contribute to a discussion by the team regarding the diagnosis, scale changes, expectations of benefit, risk, financial
Surgical Treatment of Movement Disorders
Fig.1. Multidisciplinary team.
issues, QOL, target choice, staged versus simultaneous implantation if bilateral devices may be required, and the ability of the patient to meet the schedule of follow-up appointments. The neurologist must ensure that patients have been correctly diagnosed and that they present with symptoms likely to respond to DBS. They must have exhausted medical options and their symptoms carefully quantified with appropriate disease-specific scales (eg, on/off UPDRS for PD, tremor rating scale [TRS] for ET, and Burke-Fahn-Marsden dystonia rating scale [BFMDRS]). In the case of PD, it is recommended that the patient have at least 5 years of symptoms as it is frequently difficult to distinguish levodopa-responsive parkinsonian syndromes that may be manifesting in early stages. The Florida Surgical Questionnaire for Parkinson’s Disease (FLASQ-PD) was developed as a screening questionnaire to aid in the identification of surgical candidates with PD ( Box 1 ).37 It is important that the neurologist appropriately educates the patient, because unrealistic expectations regarding the benefits and convenience of DBS are a frequent cause of patient’s perception of DBS failure. As discussed later, significant nonmotor complications, including mood, cognition, and speech, may occur following DBS and may be in part preventable through the appropriate screening of high-risk patients. 38 There is some evidence that younger patients (younger than 70 years) may have less risk of cognitive complications; however, this is not an absolute rule, and many older patients have excellent outcomes following DBS. STIMULATOR PLACEMENT AND PROGRAMMING
The accurate localization of DBS targets requires a combination of high-quality neuroimaging, stereotactic localization (frameless or frame-based), and physiologic recordings. The superior resolution of subcortical structures evident on magnetic resonance imaging (MRI) has resulted in its use as the primary imaging modality at most centers. Many centers fuse computed tomography with MRI images to save time on the day of surgery (by performing the MRI the day before) and postoperatively to localize lead
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Box1 FLASQ-PD
A. Diagnosis of idiopathic Parkinson’s disease Diagnosis 1: Is Bradykinesia present? Yes/No (Please circle response) Diagnosis 2: (check if present): —Rigidity (Stiffness in arms, leg, or neck) —4–6 Hz resting tremor —Postural instability not caused by primary visual, vestibular, cerebellar, proprioceptive dysfunction Does your patient have at least 2 of the above? Yes/No (Please circle response) Diagnosis 3: (check if present): —Unilateral onset —Rest tremor —Progressive disorder —Persistent asymmetry affecting side of onset most —Excellent response (70%–100%) to levodopa —Severe levodopa-induced dyskinesia —Levodopa response for 5 y or more —Clinical course of 5 y or more Does your patient have at least 3 of the above? Yes/No (Please circle response) (‘‘Yes’’ answers to all 3 questions above suggest the diagnosis of idiopathic PD) B. Findings suggestive of Parkinsonism due to a process other than idiopathic PD Primitive reflexes 1- RED FLAG—presence of a grasp, snout, root, suck, or Myerson’s sign N/A—not done/unknown Presence of supranuclear gaze palsy 1- RED FLAG—supranuclear gaze palsy present N/A—not done/unknown Presence of ideomotor apraxia 1- RED FLAG—ideomotor apraxia present N/A—not done/unknown Presence of autonomic dysfunction 1- RED FLAG—presence of new severe orthostatic hypotension not due to medications, erectile dysfunction, or other autonomic disturbance within the first year or 2 of disease onset N/A—not done/unknown Presence of a wide-based gait 1- RED FLAG—wide-based gait present N/A—not done/unknown Presence of more than mild dementia
Surgical Treatment of Movement Disorders
1- RED FLAG—frequently disoriented or severe cognitive difficulties, severe memory problems, or anomia N/A—not done, not known Presence of severe psychosis 1- RED FLAG—presence of severe psychosis, refractory to medications N/A—not done, not known History of unresponsiveness to levodopa 1- RED FLAG—Parkinsonism is clearly not responsive to levodopa, patient is dopamine naı¨ve, or patient has not had a trial of levodopa N/A—not done, not known (Any of the ‘‘FLAGs’’ above may be contraindications to surgery)
positions. There is, however, even under the best circumstances, a chance for clinically significant errors from stereotactic targeting, frame shift, brain shift, or misinterpretation of microelectrode recordings (MER). Suboptimal lead placement by even a few millimeters may result in an unacceptable outcome. It should be noted that most DBS targets, including the thalamus (VIM), STN and GPi, have a somatotopic and functional organization that includes sensorimotor, cognitive (associative), and limbic regions. In fact, nonmotor regions have been estimated to make up roughly one-third of each target. 39 To ensure the accurate placement of DBS leads (or lesions) into the sensorimotor region of the intended target structure, most institutions will perform clinical examinations in the conscious patient and MER to ensure that they are within the correct region of their target site. Macrostimulation, which follows MER, involves delivering test stimulation with the actual DBS electrode. Macrostimulation may identify target areas on the basis of acute symptom improvement, and it may also clarify mislocalization on the basis of common side effects usually seen with the stimulation of nearby structures. Examples may include reports of phosphenes with stimulation in the region of the optic tract or muscle twitches or pulling with stimulation of the internal capsule. Some centers rely primarily on macrostimulation and do not routinely perform MER. MER involves the passage of a small micrometer-size recording tip (usually platinum iridium or tungsten) into the target region. As the microelectrode passes through various brain structures, the neurologist or physiologist can identify the relevant brain structures, including white matter and deep brain nuclei, on the basis of their unique firing rates and patterns of activity. These data may be supplemented by passive and active movements of the limbs and facilitate the identification of inhibition or driving activity that may define sensorimotor territories. Oscillatory activity may also be identified and correlated to a patient’s tremor. Although MER and macrostimulation data may aid the accuracy of DBS placement, there also may be some risk to using multiple passes through cerebral structures to generate a 3-dimensional representation that guides localization. 40,41 These risks may include a slightly higher rate of hemorrhage (especially in patients with uncontrolled hypertension) and cognitive or mood side effects, most prominently postoperative confusion, particularly when operations are performed in a simultaneous bilateral, as opposed to staged, procedure. Although there are 3 general tec hniques used for MER (target verification, multiple pass mapping, and Ben-Gunn), 41 these techniques have not been compared with regard to their risks or efficacy. Similarly,
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Table1 Deep brain stimulation complications Summary of Adverse Events Event
No. of Patients (%)
Intraoperative Vasovagal response
8 (2.5)
Syncope
4 (1.2)
Severe cough
3 (0.9)
IVH
2 (0.6)
ICH
2 (0.6)
Arrhythmia (junctional rhythm)
1 (0.3)
Confusion
1 (0.3)
Extreme anxiety
1 (0.3)
Laceration of soft palate
1 (0.3)
TIA
1 (0.3)
Perioperative (within 2 wk) Headache
48 (15.0)
Confusion
16 (5.0)
Hallucination
9 (2.8)
Nausea/vomiting
5 (1.6)
Seizure
4 (1.2)
Dysarthria
3 (0.9)
Dyskinesia
2 (0.6)
Hypertension
2 (0.6)
Paranoia
2 (0.6)
Paresthesia
2 (0.6)
Sore throat
2 (0.6)
TIA
2 (0.6)
Urinary retention
2 (0.6)
Angina
1 (0.3)
Arrhythmia (right bundle branch block)
1 (0.3)
Deep vein thrombosis
1 (0.3)
Depression
1 (0.3)
Dizziness
1 (0.3)
Insomnia
1 (0.3)
Pulmonary edema
1 (0.3)
SDH (evacuated)
1 (0.3)
Long-term (2 wk) Infection
14 (4.4)
Cognitive dysfunction
13 (4.0)
Dysarthria
13 (4.0)
Worsening gait
12 (3.8)
Agitation
5 (1.6)
Paresthesia
4 (1.2)
Depression
3 (0.9)
Headache
2 (0.6) (continued on next page)
Surgical Treatment of Movement Disorders
Table1 (continued ) Summary of Adverse Events Event
No. of Patients (%)
Psychogenic tremor
2 (0.6)
Urinary incontinence
2 (0.6)
Blepharospasm
1 (0.3)
Emotional lability
1 (0.3)
Insomnia
1 (0.3)
Metallic taste
1 (0.3)
Suicide
1 (0.3)
Data from Kenney C, Simpson R, Hunter C, et al. Short-term and long-term safety of deep brain
stimulation in the treatment of movement disorders. J Neurosurg 2007;106:621–5.
more research is needed to determine if staged or simultaneous procedures have distinct advantages and in which populations they should be applied. SURGICAL AND DBS COMPLICATIONS
DBS complications may be divided into risks associated with the surgical procedure and chronic complications of therapy that may or may not be device related. The most serious complications associated with DBS surgery are cerebrovascular accidents (including transient ischemic events) (0.9%), intracranial hemorrhage (1.2%), seizure (1.2%), device infection (4.4%), lead fracture (3.8%), and device movement or misplacement (3.2%),42 and the risks vary from study to study depending on many factors. Many centers do not prospectively assess adverse events, and this may lead to under-reporting. 43 These risks may be somewhat attenuated by appropriate screening and treatment of comorbid conditions, including hypertension, which increases hemorrhage risk during MER; diabetes, which increases the risk of infection; psychiatric disease, which increases the risk of depression and suicide; cognitive deficits, which increase the risk of postoperative confusion; and obesity or other significant cardiopulmonary diseases, which may increase the general risk of surgery.44,45 Complications of DBS may also occur following the acute operative period. These complications may occur from problems in triage, screening, inadequate patient counseling/unreasonable patient expectations, operative procedure (including DBS misplacement), medication adjustments, or device programming difficulties. In a series of patients seeking further management after suboptimal DBS outcomes, the most common reasons for poor DBS outcome/DBS failure included inadequate screening (no movement disorder neurologist or documented neuropsychological testing) (66%), inappropriate or missed diagnosis (22%), suboptimally placed electrodes (46%), inadequate programming follow-up (17%) or suboptimal DBS parameters (37%), and suboptimal medication management (73%). 38 Of the patients seen in this series, two-thirds had good outcomes (51%) or modest improvement (15%) after receiving appropriate interventions. Chronic side effects may occur in patients even when the device has been appropriately placed, and lead settings may be optimized for the greatest symptomatic benefit. Side effects may be stimulation related and may be reversible with a simple change in settings. However, some side effects may be due to microlesional effects of the DBS placement and thus not amenable to changes in
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K l u g e r e t a l
Table 2 Summary of STN and GPi DBS outcomes for PD
Author, Year
N
Type
Target
Duration (mo)
Krack et al., 1997101
27
Prosp NC
STN
1–12
NA
Ghika et al., 1998102
6
Prosp NC
GPi
24
Krack et al., 1998103
8
Retrosp NC
STN
5
UPDRS III Motor
LE
NA
22/17 22.7%
63/28 55.6%
N/A
N/A
20/8 60.0%
31/10 67.7%
38/28 26.3%
66/33 50.0%
1080/960 11.1%
3.5/2.5 28.6%
6
7.9/4.6 41.8%
33.3/9.1 72.7%
4.0/1.4 65.0%
6
13.6/ 10.6 22.0%
27.8/ 15.0 46.0
57.5/ 17.1 70.3% 53.6/ 32.5 39.4%
1156/681 41.1%
GPi
18.2/ 14.7 19.2% 23.2/ 26.5 14.0%
865/1110 28.3%
4.8/1.2 75.0%
N/A
26.0% 40.0%
N/A
27.0% 41.0%
UPDRS II ADL
Kumar et al., 1998104
8 6
Prosp NC Prosp NC
GPi STN
3 3
Kumar et al., 1998105
7
Prosp DB
STN
6
10.5/ 12.4 18.1%
28.1/ 19.7 29.9%
30.1/ 17.7 41.2%
Limousin et al., 1998106
20
Prosp NC
STN
12
N/A
60.0%
10.0%
LID
Unchanged 30.0%
Comments
Decreased speech fluency; Dysarthria Improvement of executive function (marginal) Decreased off time from 40% to 10%
60.0% 41.0%
55.7/ 19.4 65.2%
40.0%
1.8/0.3 83.3%
60.0%
1224/615 49.8%
11.0/7.7 30.0%
S&E off 29.0/73.2 (152.4%) Off time 2.2/0.6 (72.7%) FBA 39.6/37.4 (5.6%)
Volkmann et al., 1998107
9
Prosp NC
GPi
3
Ardouin et al., 1999108
26
Prosp
STN
3
Burchiel et al., 1999109
6
Prosp DBl
STN
12
N/A
78.0%
N/A
4
Prosp DBl
GPi
12
N/A
63.0%
Limousin et al., 1999110
73
Prosp NC
Th
12
N/A
Moro et al., 1999111
7
Prosp NC
STN
16
Pinter et al., 1999112
9
Prosp NC
STN
9
12.6/4.8 61.9%
20.6/8.4 59.2%
33.9/ 19.4 42.8%
54.1/ 23.9 55.8%
767/675 12.0% NS
2.6/0.4 84.6%
Weight gain ADL improved Decrease in verbal fluency S&E off 52.2/83.9 (60.7%) Stable results in 6, 9 and 12 mo
44.0%
51.0%
N/A
N/A
39.0%
Unchanged
11.6/3.8 67.2% 9.5/5.0 47.4%
13.85/ 9.24 33.3%
N/A
37.0/ 25.7 30.5%
649/610 (LD)
2.0/1.5 25.0%
S&E 72.35/82.77 (14.4%)
15.3/ 14.3 6.5%
36.1/ 17.3 52.1%
29.3/ 30.7 -4.8%
67.6/ 39.3 41.9%
1507/521 65.4%
Reduced
Sleep improved Weight gain 13% Neuropsychological testing unchanged
3
11.6/9.1 21.6%
29.6/ 12.6 57.4%
24.1/ 18.8 22.0%
60.0/ 27.8 53.7%
527/133 74.8%
2.9/0.5 82.8%
STN
12
11.6/9.3 19.8%
29.6/ 12.8 56.8%
24.1/ 18.8 22.0%
60.0/ 27.1 53.8%
527/211 60.0%
S&E off 47.5/82.5 (73.7%) Off time decreased 8.8/ 1.0 (88.6%) S&E off 47.5/80.0 0. (68.4%)
55.4/ 19.8 64.3%
N/A
Bejjani et al., 2000113
12
Prosp NC
STN
6
N/A
N/A
78.0%
64.0%
70.0%
83.0%
Motor fluctuations 88.0%
Houeto et al., 2000114
23
Prosp NC
STN
6
11/2 81.8%
30/10 66.7%
N/A
N/A
1340/820 38.8%
7.0/1.6 77.1%
Fluctuation 4.5/1.0 (77.8%) (continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 4 3
6 4 4
K l u g e r e t a l
Table 2 (continued ) Author, Year
N
Type
Target
Duration (mo)
Jahanshahi et al., 2000115
7
NC (on/off)
STN
2–26
6
UPDRS II ADL
UPDRS III Motor
LE
LID
Comments
62.7/25.1 60.0%
GPi
Improves some aspects of executive functioning
54.2/27.2 49.8%
Molinuevo et al., 2000116
15
Prosp NC
STN
6
N/A
26.7/7.5 71.9%
N/A
49.6/16.9 65.9%
1338/262 80.4%
Pillon, 2000117
48
NC
STN
12
N/A
N/A
N/A
55.4/18.1 67.3%
1110/348 68.6%
15
STN
6
N/A
N/A
N/A
8
GPi
12
N/A
N/A
N/A
5
GPi
6
N/A
N/A
N/A
56.1/19.4 65.4% 55.4/37.1 33.0% 41.6/27.0 35.1%
1063/465 56.3% 744/873 17.3% 850/735 13.5%
Alegret, 2001118
15
Prosp
STN
3
N/A
29.9/10.9 63.6%
N/A
53.6/23.2 56.7%
57.9%
Capus, 2001119
7
Prosp NC
STN
6
N/A
N/A
20.3%
50.6%
40.7%
80.6%
Off time 89.7% S&E 38.7/84 (117.1%) H&Y 3.8/1.9 (50.0%) Improved psychomotor speed and working memory
S&E 27.5/72.5 (-163.6%) H&Y 4.2/2.3 (45.2%) Moderate deterioration of verbal memory 73.5%
Motor fluctuations improvement 57.2% PDQ38 improvement 49.9%
DBS/PD study group, 2001120
96
Prosp DBl Crossover
STN
6
11.2/10.2 8.9%
28.4/16.0 43.7%
23.6/17.8 24.6%
54.0/25.7 52.4%
1218/764 37.3%
1.9/0.8 57.9%
38
Same
GPi
6
12.7/8.8 30.7%
17.9/17.9 0.0%
24.1/16.5 31.5%
50.8/33.9 33.3%
1090/1120 -2.8%
2.1/0.7 66.7%
9
Prosp NC
STN
3
Prosp NC
STN
12
31.55/13.78 56.3% 31.2/14.3 54.2%
22.44/13.44 40.1% 21.6/17.2 20.4%
62.9/32.6 48.2% 65.0/40.5 37.7%
NA
6
8.66/7.67 11.4% 9.2/7.5 18.5%
5.33/2.22 58.4% 4.33/0.5 88.5%
Slight impairment in executive function The same subjects as those in the previous group
Faist et al., 2001122
8
Prosp NC
STN
15
N/A
N/A
N/A
49.8/7.4 85.1%
N/A
N/A
Improves walking velocity Stride length S&E off 43.7/88.7 (103.0%)
Lopiano et al., 2001123
16
Prosp NC
STN
3
8.8/7.7 12.5%
28.3/9.1 67.8%
20.3/14.8 27.1%
59.8/25.9 56.7%
1162/321 72.4%
3.5/1.1 68.6%
Off time 2.0/0.3 (85%)
Lopiano et al., 2001124
20
Prosp NC
STN
12
N/A
N/A
19.8/16.8 5.0%
58/25.1 56.7%
954/228 76.1%
Volkmann et al., 2001125
16
Prosp NC
STN
12
GPi
12
28.8/12.6 56.3% 21.0/12.1 42.4%
15.1/16.4 -8.6% 30.2/16.7 44.7%
56.4/22.4 60.3% 52.5/16.7 68.2%
2.73%
11
13.7/11.0 19.7% 12.1/5.8 52.1%
2.0/0.4 80.0%
2.4/0.4 83.3% 836/605 27.6%
6
GPi
6
N/A
N/A
Unchanged
36%
N/A
60%
6 6 6
GPi GPi GPi
12 24 36
N/A N/A N/A
N/A N/A N/A
Unchanged Unchanged Unchanged
26% 38% 32%
N/A N/A 1415/1225 13.4%
30% 20% 40%
Dujardin et al., 2001121
Durif et al., 2002126
NA
Off time 49/19% (percentage of waking hours) Off time 37/24% (percentage of waking hours)
Neuropsychological assessment stable
Off time decreased by 50% 25% 40% 10% (continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 4 5
6 4 6
K l u g e r e t a l
Table 2 (continued ) Author, Year
N
Type
Figueiras-Mendez 22 Prosp NC et al., 2002127
Duration Target (mo)
STN
UPDRS III Motor
LE
LID
Comments
1–12
16/9 43.8%
30/16 46.7%
24/10 58.3%
2 13/18 91.6%
32.0%
NA
11/5 54.6%
22/7 68.2%
23/12 47.8%
44/14 68.2%
N/A
28.1/0 100.0%
Off time 31/0% (percentage of waking hours) PDQ 39 38.4/22.3 (24.3%) Nonsurgical 41.3/42.7 (3.4%)
9.6/5.8 39.6%
BDI 10.5/8.5 (19.0%) PDQ 90.3/129 (42.9%)
Just and Ostergaard, 2002128
11 Prosp NC STN Nonsurgical
6
Lagrange et al., 2002129
60 Prosp NC
12
Loher et al., 2002130
10 Prosp NC
GPi
Martinez-Martin et al., 2002131
17 Prosp NC
11.3/11.4 29.6/23.4 0.1% 21.0%
53.7/24.3 20.3/18.8 54.7% 7.4%
1010/522 48.3%
12
37.6/24.9 34.9/22.9 33.8% 34.4%
34.7/24.9 63.4/37.5 28.2% 40.8%
1235.5/1300.6 9.8/5.0 48.9% 5.3%
STN
6
N/A
29.53/8.29 N/A 71.9%
Ostergaard et al., 26 Prosp NC 2002132
STN
12
9.3/6.8 26.9%
25.2/8.5 66.3%
23.5/10.7 51.3/18.3 54.5% 64.3%
1197/964 19.5%
Romito et al., 2002133
STN
24–36
N/A
31.6/10 68.4%
N/A
1505.9/491.7 67.4%
22 Prosp
STN
UPDRS II ADL
55.7/20.76 1400/509 62.7% 63.6%
60.2/29.9 50.3%
S&E Off 28.8/45.0 (56.3%) On 51.0/60.0 (17.6%)
N/A
Off time 1.8/0.3 (83.3%) PDQL 40.89/20.18 (50.6%)
2.1/0.3 85.7%
Weight increase 75/8 kg S&E off 49/84 (71.4%) Off periods 1.8/0.3 (83.3%) Hypophonia Dysarthria Improved sleep S&E off med 24.5/80.0 (226.5%)
Simuni et al., 2002134
12 Prosp NC
Thobois et al., 2002135
18 Prosp NC
STN
12
N/A
N/A
19.3/19.8 43.5/23.0 2.6% 47.1%
1946/875 55.0%
4.2/1.5 64.3%
1045/360 35.5% same
76.0%
STN
6
5.3/8.1 52.8% 5.3/7.5 41.5%
26.9/12.7 52.8% 26.9/10.7 60.2%
17.9/15.2 15.1% 17.9/13 27.4%
44.9/20.2 55.0% 44.9/17 62.1%
Off time 1.6/1.0 (37.5%) S&E off 39.6/77.5 (95.7%)
14 Prosp NC
STN
12
Vesper et al., 2002136
38 Prosp NC
STN
12
N/A
N/A
27.7/17.4 48.3/24.9 37.2% 48.4%
900/580 35.5%
3.2/0.9 71.9%
Off time 14.5/6 (58.6%)
Vingerhoets et al., 2002137
20 Prosp NC
STN
21
N/A
21.0/13.3 37%
N/A
48.8/26.9 44.8%
1135/230 79.7%
4.8/0.4 92%
50% of patients discontinued medications
Voges et al., 2002138
15 Prosp NC
STN
6–12
N/A
NA
N/A
55.3/22.7 58.9%
909/374 58.9%
NA
S&E off 42/77 (83.3%)
Welter et al., 2002139
41 Prosp NC
STN
6
10.4/6.6 36.5%
29/11.1 61.7%
14.7/10.6 51.4/18.5 27.9% 64.0%
1459/480 67.1%
2.1/0.2 90.5%
Chen et al., 2003140
7
Prosp NC
STN
6
N/A
N/A
39.0/19.1 65.7/32.8 51.0% 50.0%
N/A
Improved S&E off 22.9/70.0 (205.7%)
Daniele et al., 2003141
20 Prosp NC
STN
12
9
STN
18
10.1/6.2 38.6% 12.4/5.4 56.5%
31.8/8.8 72.3% 33.1/7.4 77.6%
24.0/22.1 7.9% 25.0/17.3 30.8%
58.8/30.9 47.5% 60.8/27.0 55.6%
1395/500 64.2% 1185/535 54.8%
Funkiewiez et al., 50 Prosp NC 2003142
STN
12
N/A
N/A
N/A
N/A
N/A
12/4 67%
BDI 13.9/11.5 (17.3%) MDRS 136.8/136.7 (0.1%) FS 40.8/39.5 (3.2%)
Herzog et al., 2003143
48 Prosp NC
STN
6
N/A
STN
12
N/A
STN
24
N/A
44.2/21.7 50.9% 43.9/18.7 57.4% 44.9/19.2 57.2%
1425/730 48.8% 42.4%
20
18.7/14.7 21.4% 18.1/12.4 31.5% 19.3/12.4 35.8%
2.6/1.9 26.9% 2.5/0.3 87.0% 2.4/0.3 85.0%
Temporary psychiatric adverse events
32
22.6/10.7 52.6% 21.6/10.7 49.2% 23.4/13.2 43.2%
67.8%
91.0%
PDQ 83.2/54.3 (34.7%) 87.7/49.7 (43.3%)
(continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 4 7
6 4 8
K l u g e r e t a l Table 2 (continued ) Author, Year
N
Type
Target
Duration (mo)
Kleiner-Fisman et al., 2003144
25
Prosp NC
STN
12
Krack et al., 2003145
49
Prosp NC
STN
60 (5 y)
Pahwa et al., 2003146
33
UPDRS II ADL
19
STN
12
STN
24
LE
12.1/10.5 13.2%
25.8/17.4 32.6%
22.8/19.4 14.9%
50.1/24.6 50.9%
7.3/14.0 91.8%
30.4/15.6 48.7%
14.3/21.1 47.6%
N/A
21.1/14.3 32.2%
11.6/12.8 10.3%
Prosp NC
UPDRS III Motor
LID
Comments
38.0%
46.4%
55.7/25.8 53.7%
1409/518 63.2%
4.0/1.4 65.0%
DRS 136/131 (3.7%) BDI 15.5/14.9 (3.9%) FBA 40.4/37.3 (7.7%)
N/A
43.8/26.5 39.5%
10.4/5.8 44.2%
18/4%
21.1/15.3 27.5%
26.2/24.1 8.0%
41.3/29.8 27.8%
12.4/5.3 57.3%
19/11%
Off time 44/20% (percentage of waking hours) Off time 43/17% (percentage of waking hours)
Varma et al., 2003147
7
Prosp NC
STN
6
15/14 6.7%
38/25
34.2%
61%
2067/1055 49.0%
44%
Volkmann et al., 2004148
9
Prosp NC
Gpi
36
11.3/7.1 37.2% 8.8/10.3 17.1%
20.9/15.5 25.8% 19.5/19.8 1.5%
30.8/13.9 54.9% 22.2/18.7 15.8%
52.8/26.8 49.2% 49.5/38.0 23.2%
870/897 3.1% 961/760 20.9%
1.9/0.6 68.4% 1.0/0.6 40.0%
10.0/9.4 6.0%
26.0/17.3 33.5%
17.6/19.7 11.9%
38.4/23.9 37.8%
1364/867 36.4%
2.9/0.7 75.9%
10.0/17.2 72.0%
26.0/22.3 14.2%
17.6/22.1 25.6%
38.4/26.5 31.0%
1364/1029 24.6%
2.9/0.9 69.0%
6 Liang et al., 2006149
27
60 Prosp NC
STN
12
33
MMSE 29/29
Off time 1.9/1.2 (36.8%) S&E off 47.2/72.1 (52.8%) Off time 1.9/1.1 (42.1%) S&E off 47.2/66.7 (41.3%)
Portman et al., 2006150
20
Prosp NC
STN
12
Derost, 2007151
53
Prosp NC
STN
24
N/A
23/20 13.0% NS
46/33 28.3%
1242/751 39.5%
8.8/3.75 57.4%
3.7/8.5 1.3% 5.6/11.1 98.0%
18.0/15.6 13.3% 18.8/16.7 11.2%
N/A
45.0%
N/A
41.0%
1246/885 28.9% 1308/760 41.9%
3.4/0.7 79.4% 2.7/1.1 59.3%
4.5/8.5 88.9% 4.5/12.5 177.8%
23.7/12.5 47.3% 23.7/13.9 41.4%
14.1/12.5 11.3% 14.1/12.5 11.3%
42.2/21.0 50.2% 42.2/19.3 54.3%
1228/470 61.7% 1228/631 48.6%
9.0/1.9 78.9% 9.0/31.1 245.6%
N/A
N/A
12.5/10.4 16.8%
40.6/21.8 46.3%
1182/1216 2.9%
10.5/2.5 76.0%
2.3/5.1 121.7%
19.2/12.9 32.8%
NA
69.0%
57.0%
83.0%
DRS 140.5/140.5 (NS) FBA 48/47.5 (NS) MADRS 7/3 (improved)
61.0%
Cognitive decline in 7.7% Depression 18%
5.6/1.3 76.8%
S&E off 45.3/63.7 (40.6%) DRS 137.4/136 (-1.0%) BDI 8.1/6.4 (21.0%)
34 Gan et al., 2007152
N/A
36
Prosp NC
STN
24
STN
12
36 Rodriques et al., 2007153
11
Prosp NC
Gpi
7
Schu¨pbach et al., 2007154
10
Prosp NC Comp BMT
STN
18
Tir et al., 2007155
100
Prosp NC
STN
12
9.5/8 15.8%
27.5/19 30.9%
20/14.4 28.0%
50/29 42.0%
1222/721 41.0%
Vesper et al., 2007156
73
Prosp NC
STN
24
N/A
N/A
30/26 13.3%
50/25 50.0%
45.0%
Witjas et al., 2007157
40
Prosp NC
STN
12
8.8/4.7 46.6%
23.7/13.3 43.9%
11.8/6.9 41.5%
38/12.4 67.4%
1091/460 57.8%
S&E off 52/72 (38.5%) Off time 10%
DRS 135.9/137.4 (NS) BDI 12.8/11.6 (NS) DRS 135.9/135.5 (NS) BDI 12.8/16.1 (NS)
(continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 4 9
6 5 0
K l u g e r e t a l
Table 2 (continued ) Author, Year
N
Type
Target
Duration (mo)
Zibetti et al., 2007158
36
Prosp NC
STN
12
N/A
24
N/A
Wider et al., 2008159
50
Prosp NC
STN
6
UPDRS II ADL
10.0/11.5 15.0% 10.0/12.8 28.0% 10.0/18.9 89.0%
25.3/9.9 60.9% 25.3/10.3 59.3% N/A
24 60
UPDRS III Motor
N/A N/A 24.3/26.7 9.9% 24.3/27.7 14.0% 24.3/30.6 25.9%
N/A N/A
LE
LID
Comments
54.5/25.8 52.7% 54.5/24.1 55.8%
1023/405 60.4% 1023/417 59.2%
N/A
47.2/24.8 47.5% 47.2/24.9 47.3% 47.2/33.2 29.7%
1128/195 82.7% 1128/391 65.3% 1128/485 57.0%
4.8/0.7 85.4% 4.8/0.8 83.3% 4.8/0.7 85.4%
N/A
Off time 1.55/0.11 (92.9%) Off time 1.55/0.03 (98.1%)
Abbreviations: BDI, Beck’s Depression Inventory; BMT, Best medical treatment; DRS, Mattis Dementia rating scale; Dyskinesia, as measured by UPDRS IV-a (motor
complication) or AIMS (abnormal involuntary movements scale); FBA, frontal battery assessment scale; GPi, Globus pallidus part interna; ICH, intracerebral hemorrage; IVH, intraventricular hemorrage; LD, Levodopa dose only; LE, Levodopa equivalent (the method of calculation was not standardized across the studies); LID, levodopa induced dyskinesias; MADRS, Montgomery and Asberg depression rating scale; MDRS, Mattis Dementia Rating Scale; MMSE, Folstein mini mental status Examination; NS, nonsignificant; Off and On, applies to the medication state; Off time, Hours per day spent in clinically defined off period (immobile); PDQ, Parkinson disease quality-of-life questionnaire, total score; Prosp., NC, prospective noncontrolled clinical trial; S&E, Schwab and England disability scale; SDH, subdural hemorrage; STN, Subthalamic nucleus; Th, Thalamus; TIA, transient ischemic attack; UPDRS II—ADL, activities of daily living, maximum 52; UPDRS III, motor subscore, maximum 108. Results are represented as Preoperative/Postoperative, with the percentage change calculated as: [(Preoperative Postoperative)/Preoperative] 100. Data from Kenney C, Simpson R, Hunter C, et al. Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders. J Neurosurg 2007;106:621–5.
Surgical Treatment of Movement Disorders
settings. Common stimulation-related side effects may include paresthesias due to spread of current to lemniscal and sensory regions and muscle tightening due to spread of current to motor fibers (corticobulbar and corticospinal tracts). More significant side effects may include dysarthria, cognitive deficits (particularly declines in verbal fluency), and alterations in mood (including depression, anxiety, mania, and suicidality). The STN in particular may have a high risk for cognitive and mood side effects, including executive dysfunction, hypomania (up to 15% in some series), depression, anxiety and suicidality. 46 However, randomized comparative studies to confirm these clinical findings remain to be published. Although DBS has been repeatedly demonstrated to improve QOL, 47 there are often significant difficulties with social adjustment following DBS, particularly with marital and professional life. 48 This finding stresses the importance of preoperative counseling and discussions regarding the patient’s expectations of surgery. See Table 1 for a summary of DBS complications.
SPECIFIC MOVEMENT DISORDERS AND TARGETS Parkinson’s Disease
Successful patient outcomes in PD have been obtained with DBS directed toward 1 of 3 intracranial targets, namely, STN, GPi, and VIM. There is currently no consensus on which targets may be preferable for which symptoms; however, some important insights have emerged from the literature. We anticipate that further data will demonstrate differences in particular symptom efficacy and side effect profiles (mood, motor, cognitive, and QOL) so that the choice of an appropriate DBS target can be tailored to an individual. There is currently good evidence to show that VIM DBS is effective in the treatment of arm tremor but does not ameliorate other PD symptoms or capture leg tremor in many cases. 49 VIM DBS is generally not considered a first-line target in PD; however, elderly patients with symptoms mostly linked to medication refractory upper-extremity tremor who have impaired QOL or activities of daily living (ADLs) may obtain excellent results. 50 STN or GPi DBS may address tremor, bradykinesia, and rigidity but have less impact on gait and postural instability, with much of the outcome related to whether specific symptoms responded preoperatively to levodopa. DBS also does not prevent disease progression into areas such as gait, speech, and cognition. Other DBS targets are currently under investigation in PD. Emerging evidence has suggested that gait in PD may be improved by DBS directed to the pedunculopontine nucleus. 51 However, proper outcome studies and criteria to determine patient selection have not been performed. Zona incerta DBS is another potential target for tremor and other cardinal motor manifestations, and this remains under investigation. 52 Although the first randomized, double-blinded trials of STN versus GPi are currently underway, there is preliminary evidence for the potential of differential responses and/ or side effects from the 2 targets based on clinical observation. In general, both procedures are well tolerated and considered generally safe in appropriately selected patients, with meta-analyses showing comparable motor efficacy. 53 There is some evidence that STN DBS may be associated with a slightly greater motor/tremor benefit; however, there may also be a higher risk of cognitive, behavioral, and mood side effects.45 Although both STN and GPi improve dyskinesias and smooth on/off fluctuations, there may be reasons to favor a specific target site, as well as reasons to perform unilateral versus bilateral operations and to consider simultaneous versus staged bilateral procedures. These differences will potentially emerge as randomized studies are published. For example, STN DBS achieves dyskinesia reduction by reducing levodopa requirements, whereas GPi DBS has a direct antidyskinetic effect,
651
6 5 2
K l u g e r e t a l
Table 3 Summary of VIM thalamic DBS outcomes for ET Study
Sample Size
Study Type
Tremor Improvement
Nonmotor Outcomes
Pahwa et al., 2006
26
Prosp NC
46% (unilateral) and 78% (bilateral) FTM TRS
35%–50% improvement on ADLs (from TRS), drawing and pouring
Lee and Kondziolka, 2005161
18
Case series
75% improvement FTM TRS
64% improvement in handwriting
Putzke et al., 2005162
22
Case series
81% improvement FTM TRS
N/A
163
52
Case series
45% improvement FTM TRS
70% improvement in ADLs
5
Case series
62% improvement in FTM TRS
Tolerance to DBS developed in 2 of 5 patients
16
Case series
34% FTM TRS
45% improvement ADLs
35
Case series
56% FTM TRS improvement
Significant improvements in mood, QOL, and several cognitive outcomes
Rehncrona et al., 2003167
19
Prosp NC
46% improvement FTM TRS
N/A
Hariz et al., 200259
27
Prosp NC
47% improvement FTM TRS
Significant improvements in mood, QOL, and ‘‘emotional constraints’’ domain of QOL
Koller et al., 2001168
49
Case series
78% improvement FTM TRS
24% of patients required at least 1 additional surgical procedure
Obwegeser et al., 2001169
160
Putzke et al., 2004
Kumar et al., 2003164 165
Bryant et al., 2003 Fields et al., 2003
166
31
Case series
6-point reduction in FTM TRS
N/A
170
Pahwa et al., 2001
17
Case control (vs thalamotomy)
50% improvement FTM TRS
Equivalent benefit with less complications than thalamotomy
Krauss et al., 2001171
42
Case series
57% excellent outcome, 36% marked improvement
N/A
Troster et al., 199957
40
Prosp NC
51% reduction in FTM TRS
Significant improvements across multiple domains of QOL, anxiety, and cognitive function except verbal fluency.
Limousin et al., 1999110
37
Prosp NC
55% reduction in FTM TRS
Significant improvement in ADLs
Pahwa et al., 1999
172
9
Case series
57% improvement in FTM TRS
Significant improvement in ADLs
Kumar et al., 1999173
9
Case series
61% improvement FTM TRS
Significant improvement in ADLs and global disability
Koller et al., 1999174
38 (head tremor)
Case series
Head tremor improved in 75% of patients
N/A
Hariz et al., 1999175
36
Case series
48% improvement in FTM TRS
Significant improvement in ADLs
Lyons et al., 1998176
22
Case series
39% improvement in FTM TRS
57% improvement on tremor ADL scale
Ondo et al., 1998177
14
Case series
83% improvement in FTM TRS
>50% improvement in ADLs and disability scores
Koller et al., 1997178
29
Prosp NC
> 50% improvement in FTM TRS
Significant improvement in ADLs
10
Prosp NC
>50% improvement in both patient and clinician FTM TRS ratings
63% improvement in patient and clinician ratings of global disability
4
Case series
Sustained improvement in 75% of patients
No change in MMSE, verbal fluency, or Wisconsin Card Sort
Hubble et al., 1996
179
Blond et al., 1992180
Abbreviations: ADLs, activities of daily living; FTM TRS, Fahn Tolosa Marin tremor rating scale; MMSE, Folstein mini mental status examination; QOL, Quality of life.
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 5 3
6 5 4
Table 4 Summary of GPi DBS outcomes for dystonia
Author
N
Type of Dystonia
Target
Follow-up Period (mos)
Scale
Preoperative Score
Postoperative Score
Improvement (%)
Comments
Vercueil et al., 2001181
1
Primary generalized
GPi
12
BFMDRS (m/d)
N/A
N/A
67/81
Includes 12 patients with thalamic DBS alone and 3 with thalamic and GPi DBS.
1
GPi
6
BFMDRS (m/d)
N/A
N/A
70/50
1 1 1
Primary generalized Primary DYT11 Primary DYT1 Cranial-cervical
GPi GPi GPi
12 24 6
BFMDRS (m/d) BFMDRS (m/d) BFMDRS (m/d)
N/A N/A N/A
N/A N/A N/A
86/86 41/43 66/66
Bereznai et al., 2002182
3 1
Segmental Primary DYT11
GPi GPi
3–12 3–12
BFMDRS (m) Tsui scale
N/A N/A
N/A N/A
72.50 45
Krauss et al., 2002183
5
Cervical
GPi
20
TWSTRS (s/d/p)
20.5/40. 5/6
7.5/12.7/3
62/69/50
Cif et al., 2003184
15 Primary DYTI1 17 Primary DYT1
GPi GPi
24–36 24–36
BFMDRS (m/d) BFMDRS (m/d)
60.8/16.7 56.5/16.4
14.2/5.7 15.1/9.5
71/63 74/49
Katayama et al., 2003185
5
Primary
GPi
6
BFMDRS (m)
18–62
4–23
51–92
Krauss et al., 2003186
2
Primary DYT1
GPi
24
BFMDRS (m)
81
21.5
73
Kupsch et al., 2003187
1 3 1
Primary DYT11 Primary DYT1 Segmental
GPi GPi GPi
3–12 3–12 3–12
BFMDRS (m) BFMDRS (m) BFMDRS (m)
34.5 40 32
27 20 19
22 50% 41
Includes 1 patient with bilateral pallidotomy and 1 patient with unilateral pallidotomy
K l u g e r e t a l
Yianni et al., 2003188
12 Generalized
7
Cervical
GPi
4–184
BFMDRS (m)
79.7
57.8
45.3
46
GPi
2–12
TWSTRS (t)
23
59
Yianni et al., 2003189
2 Primary DYT11 11 Primary DYT1 7 Cervical
GPi GPi GPi
12 12 12
BFMDRS (m) N/A BFMDRS (m) N/A TWSTRS (s/d/p) 21.3/21.7/ 15.1
N/A N/A 10/14/8.3
85 46 50/38/43
Cif et al., 2004190
1
GPi
20
UMRS
69
13
81
BFMDRS (m/d)
9.5/9
1.5/1
84/89
24 24
BFMDRS (m) BFMDRS (m)
62.6 56.3
12.4 13.4
83 75
Myoclonusdystonia syndrome
GPi GPi
Includes the same patients as the other study by Yianni and colleagues, 2003
Coubes et al., 2004191
17 Primary DYT11 14 Primary DYT1
Detante et al., 2004192
13 Primary generalized STN 3 Secondary PKAN STN
3 3
N/A N/A
N/A N/A
N/A N/A
No improvement No improvement
Eltahawy et al., 200433
1
Primary DYT11
GPi
6
BFMDRS (m)
88
66
25
1 3
Primary DYT1 Cervical
GPi GPi
6 6
BFMDRS (m) TWSTRS (t)
48 37.7
16 16
21 57
Krause et al., 2004193
4 6 1
Primary DYT11 Primary DYT1 Cervical
GPi GPi GPi
12–66 12–66 12–66
BFMDRS (m) BFMDRS (m) BFMDRS (m)
72 73.9 6
34 50 6
53 32 0
Trottenberg et al., 2005194
5
Secondary tardive
GPi
6
BFMDRS (m/d)
32/8
N/A
87/96
Vayssiere et al., 2004195
19 Primary generalized
GPi
N/A
BFMDRS
N/A
N/A
>80
Study also includes pallidotomy patients
(continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 5 5
6 5 6
K l u g e r e t a l
Table 4 (continued ) Author
N
Type of Dystonia
Target
Follow-up Period (mos)
Scale
Preoperative Score
Postoperative Score
Improvement (%)
Comments
Bittar et al., 2005196
2
Primary DYT11
GPi
24
BFMDRS (t)
103.8
55.8
46
DYT11 and DYT1 analyzed together
4 6
Primary DYT1 Cervical
GPi GPi
24 24
TWSTRS (t)
57.8
23.7
59
Castelnau et al., 2005197
6
Secondary PKAN
GPi
21
BFMDRS (m/d)
75/20
20/9.6
74/53
Chou et al., 2005198
1
Cervical dystonia and ET
STN
6
TWSTRS (s/d)
14/20
3/0
79/100
Vidailhet, 200560
7 1
Primary DYT11 Primary DYT1
GPi GPi
12 12
BFMDRS (m/d) BFMDRS (m/d)
55.1/14.7 41.96/10.2
26.1/8.5 18.7/5.5
53/46 55.4/45
Zorzi et al., 2005199
1 8
Primary DYT11 Primary DYT1
GPi GPi
4 19
BFMDRS (m/d) BFMDRS (m/d)
47/11 68.9/17.9
14/6 46.5/12.6
70/45 32/37
Diamond et al., 2006200
5
Primary DYT11
GPi
5
UDRS
44.6
27.5
38
All groups analyzed together. 2 patients with pallidotomy
5 1
Primary DYT1 Hemidystonia
GPi GPi
5 3
6
Primary DYT11
GPi
6
BFMDRS (m/d)
36.4/10
20.2/5.9
45/41
All groups analyzed together
27 7
Primary DYT1 Primary
GPi GPi
6 6
Kupsch et al., 200663
Class 1 evidence
Starr et al., 2006201
6 3 1 1 1
Primary DYT11 Segmental Cranial-cervical (MS) Secondary PKAN Secondary cerebral palsy Secondary posttraumatic Secondary tardive Generalized
GPi GPi GPi GPi GPi
13 22 9 12 33
BFMDRS (m) BFMDRS (m) BFMDRS (m) BFMDRS (m) BFMDRS (m)
59.6 22.6 30 30 82
24.2 12 3 6 51
59 47 90 80 38
GPi
32
BFMDRS (m)
54
49.5
No improvement
GPi
20
BFMDRS (m)
46.5
24.6
47
GPi
11
BFMDRS (m)
83
72.8
12
1
Secondary tardive dystonia
STN
3
BFMDRS (m)
98.8
8
92
1
STN
3
BFMDRS (m)
26.5
2
91
STN
6
BFMDRS (m)
76
7
91
5
Secondary antiemetics Secondary neonatal anoxia Other secondary
STN
N/A
N/A
N/A
N/A
Did poorly
12
Primary DYT11
GPi
12
BFMDRS (m/d)
35/8
4/2
89/75
3
Primary DYT1
GPi
12
1 4 2 Zhang et al., 2006202
2
Alterman, 2007203
6 cases bilateral STN, 2 cases unilateral STN, 1 case left STN and right GPi
DYT1 1 and DYT1 analyzed together (continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 5 7
6 5 8
Table 4 (continued ) Target
Follow-up Period (mos) Scale
Preoperative Score
Postoperative Score
Improvement (%)
Comments
10 Secondary tardive
GPi
6
ESRS
73.1
27.8
62
50% improvement with doubleblind evaluation
AIMS
25
31.1
1
GPi
12
UPDRS-III
21
8
62
–
BFMDRS (t)
32.5
9.5
72
–
UDRS
36.9
16.1
56
BFMDRS GDS
25.6 29.3
13.1 10.3
61 67
All patients previously reported – –
Author
N
Damier et al., 2007204
Evidente et al., 2007205
Grips et al., 2007206
8
Type of Dystonia
X-linked dystonia Parkinsonism Segmental
GPi
N/A
GPi GPi
24
Hung et al., 200762
10 Cervical
GPi
12–67
TWSTRS (s/d/p) 21.9/18/11.7
9.9/7.4/5.8
55/52/51
–
Kiss et al., 2007207
10 Cervical
GPi
12
TWSTRS (s/d/p) 14.7/14.9/26.6 8.4/5.4/9.2
43/64/65
Class 1 evidence
Kleiner-Flisman et al., 2007208
1
Cervical
STN
12
1 1
Cervical Cervical
STN STN
12 12
1
Primary generalized
STN
12
BFMDRS (m/d) TWSTRS (s/d/p) TWSTRS (s/d/p) BFMDRS (m/d) TWSTRS (s/d/p) BFMDRS (m/d)
36.5/5 31/27/14 21/16/17 53/14 26/27/15.3 23/5
29/10 23/20/5.5 12/5/14.3 59/17 28/24/18.3 12/3
21/50 26/26/61 43/69/16 11/-21 8/11/ 20 72/40
1
Primary generalized
STN
29
BFMDRS (m/d)
N/A
N/A
23/42
Novak et al., 2007209
K l u g e r e t a l
Ostrem et al., 200767
6
Sun et al., 200766
12 Primary generalized 2 Secondary tardive
Tisch et al., 2007210 Vidailhet et al., 2007211
Cranial-cervical
7
Primary DYT11
8
Primary DYT1
7
Primary DYT11
15 Primary DYT1
GPi GPi
6 6
BFMDRS (m/d) TWSTRS (t)
22/6 39
6.1/3.7 17
72/38 54
STN
6–42
BFMDRS
N/A
N/A
76–100
Groups reported together
STN
6–42
GPi
6
BFMDRS (m/d)
38.9/9.0
11.9/4.1
70/58
DYT1 1 and DYT1 analyzed together
GPi
6
GPi
36
BFMDRS (m/d)
46.3/11.6
19.3/6.3
58/46
DYT11 and DYT1 analyzed together
GPi
36
Cervical GPi Primary generalized GPi
36 36
TWSTRS (s/d/p) 20.5/40.5/6 BFMDRS (m/d) 81/18.5
14.7/15.7/3.7 28.3/7.5
28/61/38 65/59
Magarinos-Ascone 10 Primary generalized GPi et al., 200864
12
BFMDRS (m/d)
57.8/18.1
20.0/8.6
65/52
Sako et al., 2008213
21
BFMDRS (m/d)
N/A
N/A
86/80
Loher et al., 2008212
4 2
6
Secondary tardive
GPi
1 patient DYT11
This table is an expanded version of that published in the work of Ostrem, 2007, with full permission from Elsevier Ltd. Abbreviations: BFMDRS (m/d), Burke-Fahn-Marsden dystonia rating scale (motor subscore, maximum 120/disability subscore, maximum 30); BFMDRS (t), BurkeFahn-Marsden dystonia rating scale, total score; PKAN, pantothenate kinase associated neurodegeneration; TWSTRS (s/d/p), Toronto western spasmotic torticolis rating scale (severity, maximum 35/disability, maximum 30/pain, maximum 18); UDRS, Unified dystonia rating scale; UPDRS-III, Unified Parkinson disease rating scale, motor subscore (maximum 108); UMRS, Unified myoclonus rating scale; ESRS, Extrapyramidal symptoms rating scale; AIMS, Abnormal involuntary movements scale; GDS, Global dystonia scale; Primary generalized, Primary generalized dystonia of an unknown etiology; Primary DYT1 1, Primary generalized DYT1 gene positive dystonia; Primary DYT1 -, Primary; generalized DYT1 gene negative dystonia, Percentage of change was calculated as [(Preoperative–Postoperative)/Preoperative]x100. For generalized and cervical dystonia, only reports with 5 or more cases were included. For other types of dystonia all published reports were included.
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 5 9
6 6 0
Table 5 Summary of DBS outcomes for other movement disorders
Study
Sample Size
Study Type
Dx
Target
Motor Improvement
Nonmotor Outcomes
Welter et al., 2008214
3
Randomized, controlled, doubleblinded, crossover
TS
GPiCM-Pf
78% and 45% reductions in Yale tic severity scale with GPi and CM-pf respectively. No further improvement with both targets
No change in neuropsychological testing. Mild improvements in impulsivity and depression were noted with CM-pf only
Dehning et al., 200875
1
Case study
TS
GPi
88% improvement in YGTSS
No change in neuropsychological testing
Shields et al., 200876
1
Case study
TS
Anterior IC and CM-Pf
23% improvement in YGTSS with IC; 46% improvement with CM
Depression with AIC
Servello et al., 200874
18
Prosp NC
TS
CM-Pf
Improvements in YGTSS not quantified
Improvements reported in psychiatric comorbidities. Neuropsychology testing performed but results not reported
Bajwa et al., 2007215
1
Case study
TS
CM
66% improvement in YGTSS
OCD symptoms also improved
Kuhn et al., 200777
1
Case study
TS
NAc
41% improvement in YGTSS
OCD symptoms also improved
Shahed et al., 2007216
1
Case study
TS
GPi
84% improvement in YGTSS
Improved OCD symptoms and QOL. Neuropsychology tests stable or improved, except mild decrease in memory
Maciunas et al., 2007217
5
Randomized, controlled, doubleblind, crossover
TS
CM-Pf
44% improvement in YGTSS
Trend toward decreased neuropsychology and improved mood. QOL significantly improved
K l u g e r e t a l
Ackermans et al., 2006218
2
Case study
TS
One patient GPi, other CM
85%–90% reduction in tics/minute both patients
Improved OCD symptoms
Flaherty et al., 2005219
1
Case study
TS
Anterior IC
25% improvement in YGTSS
Euthymic with optimal settings
Diederich et al., 2005220
1
Case study
TS
GPi
46% improvement in YGTSS
Depression and anxiety mildly improved. Neuropsychology stable
Houeto et al., 2005221
1
Case study
TS
CM-Pf and GPi
65% improvement in YGTSS with either or both sites
Neuropsychology stable or improved Mild improvements with depression and impulsivity with CM-Pf
VisserVandewalle et al., 2003222
3
Case series
TS
CM
82% reduction tics/minute
Mild decrease in 1 patient on timed neuropsychology tests
Vandewalle et al., 1999223
1
Case study
TS
CM
901% reduction tics/ minute
N/A
Fasano et al., 200897
1
Case study
HD
GPi
Complete resolution of chorea
Continued deterioration of cognition and gait
Hebb et al., 200698
1
Case study
HD
GPi
Significant improvement in total UPDRS and chorea
Noted weight gain and stable neuropsychology function over 12 mo
Moro et al., 2004224
1
Case study
HD
GPi
44% and 37% improvements in chorea and dystonia
Mild improvements in functional assessment and independence
Freund et al., 200799
1
Case study
SCA-2
VIM STN
Improved tremor
Improved speech and ADLs
Shimojima et al., 2005100
1
Case study
SCA (negative genetic testing)
VIM
45% improvement in FTM TRS
Improved ADLs
Foote and Okun, 200596
1
Case study
Traumatic Holmes tremor
VIM, VOA and VOP
40% improvement in FTM TRS
Significant improvement in disability (continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 6 1
6 6 2
Table 5 (continued ) Sample Size
Study Type
Dx
Target
Motor Improvement
Nonmotor Outcomes
Nikkhah et al., 200469
2
Case series
Holmes tremor
VIM
Improved tremor and dystonia
Improved speech
Kudo et al., 2001225
1
Case study
Holmes tremor
VIM
Improved tremor
N/A
Plaha et al., 200892
13
Case series
PD, MS, ET, Holmes, dystonic tremor
Zona Incerta
60%–90% improvement in all tremors
N/A
Lim et al., 200779
2
Case studies
MS and stroke
VIM/VOA and GPi (stroke only)
40% improvement in MS with VIM/VOA, 7% in stroke with GPi only
Mild improvements in ADL ratings for both patients
Foote et al., 200685
4
Case series
MS 1 Trauma 3
VIM VOA/VOP
23%–66% improvement in TRS, trend toward more improvement with dual leads in 2 patients
N/A
Moringlane et al., 200490
1
Case study
MS
VL
Improved tremor
No change in neuropsychology function, improved ADLs
Wishart et al., 200395
4
Case series
MS
VIM
Improved tremor
Dysarthria in 1 patient
Schulder et al., 200393
9
Case series
MS
VIM
68% improvement in Bain-Finchley TRS
Stimulation-related fatigue in 1 patient
Bittar et al., 200583
10
Case series
MS
VOP/ZI
64% and 36% improvement of postural and intention tremor on 10-point scale
N/A
Berk et al., 200282
12
Case series
MS
VIM
Overall tremor reduction 63% on Fahn rating scale
Improved ADLs. No change in SF-36 QOL
Study
K l u g e r e t a l
Schulder et al., 200393
9
Case series
MS
VIM
61% tremor reduction Bain-Finchley scale
Mild neuropsychology decline over 30 mo, possibly 2/2 disease progression
Hooper et al., 200287
10
Prospective
MS
Thalamic (targeted to tremor)
Significant reduction on Fahn-TRS
No change in neuropsychology Mild improvement in anxiety
Matsumoto et al., 200188
9
Case series
MS
VIM
Significant reduction in clinical TRS
No change in disability, mild decrease in QOL
Schuurman et al., 200094
5
Randomized (vs thalamotomy)
MS
VIM
Improvement on UPDRS tremor rating
N/A
Brice and McLellan, 198084
2
Case series
MS
Thalamus
Improved tremor
Dysarthria
Montgomery et al., 199989
15
Case series
MS
VIM
Improved clinical TRS
N/A
Benabid et al., 199681
4
Case series
MS
VIM
Tremor improved in 2 patients
N/A
Geny et al., 199686
13
Case series
MS
VIM
Significant decrease in tremor in 9 patients
Improvement in functional disability
Nguyen and Degos, 199391
4
Case series
MS, germinoma, TBI and mercury poisoning
VIM
Tremor improved from ‘‘severe’’ to mild or none in all subjects
Improved functional use of arm
Siegfried and Lippitz, 199480
11
Case series
MS (9), trauma, stroke
VIM
70%–100% of patients with tremor control (not reported by subgroup)
Tremor control limited in some patients by side effects, mainly dysarthria
Abbreviations: ADLs, activities of daily living; AIC, anterior internal capsule; CM-Pf, centromedian parafasicular, Dx, diagnosis; ET, essential tremor; FTM TRS, Fahn
Tolosa Marin tremor rating scale; HD, Huntington’s disease; IC, Internal capsule; MS, multiple sclerosis; NAc, nucleus accumbens; OCD, obsessive compulsive disorder; PD, Parkinson’s disease; QOL, Quality of life; SCA, spinocerebellar ataxia; SF-36, 36-item short-form health survey; TBI, traumatic brain injury TS, Tourette syndrome; VL, ventral lateral; YGTSS, Yale Global Tic Severity Scale. Data from Ostrem J, Marks WJ, Volz M, et al. Pallidal deep brain stimulation in patients with cranial-cervical dystonia (Meige syndrome). Mov Disord 2007;22(13):1885; with permission.
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 6 3
664
Kluger et al
and this may provide a rationale for target choice in an individual patient. 54 A summary of published studies for DBS for PD is provided in Table 2. Essential Tremor
VIM thalamic DBS has proven to be a generally well-tolerated and efficacious treatment for ET. 55 Candidates for ET DBS usually have postural and/or action tremors, which significantly interfere with ADLs and QOL and should be medication refractory, including maximally tolerated doses of primidone (and/or other anticonvulsants), propanolol (and/or other beta blockers), and a benzodiazepine (typically clonazepam). VIM DBS has been particularly efficacious for contralateral limb tremor, although it has some ipsilateral positive effects. 56 VIM DBS may improve vocal or head tremor, but, in our experience, it is not a reliable benefit when looking across patients. Botulinum toxin injections may be synergistic with DBS for these tremors, particularly if there is a dystonic component. Potential chronic side effects of VIM DBS include speech abnormalities (dysarthria and decreased verbal fluency) and difficulty with gait, particularly with bilateral stimulator placement, and if there are premorbid issues such as cerebrovascular disease or ventricular enlargement. Possibly with the exception of verbal fluency, cognitive and mood outcomes do not seem to decline with VIM DBS in the ET population.57 However, given recent data of neuropsychological impairments in ET and reports of mood disturbances and suicides following VIM DBS, careful screening is still appropriate.58 In Table 3 we provide a complete review of th e literature on VIM DBS outcomes for motor, mood, QOL, and cognitive outcomes. 59 Dystonia
Bilateral GPi DBS has been recently demonstrated by several groups as safe and efficacious in the treatment of primary generalized dystonias, 60 tardive dystonia,61 and in some cases of focal or segmental dystonia. 62,63 There have also been several case reports of successful treatment of myoclonus-dystonia syndrome with bilateral GPi DBS64 and thalamic DBS. 65 Although not commonly used, STN and thalamic DBS have shown efficacy in primary, tardive, and segmental dystonia. 66 In patients with nontardive secondary hemidystonia, segmental, or focal dystonia, the appropriate target(s) are not clear at this time. Patient selection follows similar principles to PD. Patients should have a definitive diagnosis of dystonia by a movement disorder neurologist/neurologist experienced in dystonia and have significant effects on QOL or ADLs despite maximally tolerated medical treatments, including anticholinergics, benzodiazepines, muscle relaxants, and antiepileptics. In patients with focal or limited segmental dystonia, an adequate trial of botulinum toxin injections should also be attempted. Mobile dystonia has been found to be more responsive to DBS regardless of the underlying etiology, and fixed orthopedic deformities are unlikely to be improved by DBS. In Table 4 we provide a review of the literature on GPi dystonia DBS outcomes. The majority of studies of DBS in dystonia have been performed in primary generalized dystonia, where patients have generally shown a 40%–60% improvement in dystonia severity. Similar results have been obtained in cervical dystonia, 62 Meige syndrome 67 and tardive dystonia. 61 Case reports of improvement in dystonia following GPi DBS have also been reported in dystonia secondary to trauma, stroke, and pantothenate kinase deficiency. 68–70 DBS for dystonia is notably different from other disorders in that DBS typically has a delayed benefit possibly owing to cortical remodeling due to stimulation effects, although the exact cause of this finding is currently unknown. 71 Similarly, following DBS, dystonic patients may experience lasting benefits after discontinuation of DBS therapy. Dystonia patients may also accumulate benefit over
Surgical Treatment of Movement Disorders
several months or even longer, suggesting that GPi DBS in dystonia may have both direct effects from stimulation and also induce longer-term neuroplastic changes or disease-modifying benefits. 23 The potential chronic side effects of GPi DBS for dystonia are similar to those seen in PD. With regard to mood disturbances, a careful neuropsychiatric evaluation, particularly in patients with tardive dystonia, is strongly recommended. 58 Patients with dystonia appear to have a lower risk of cognitive side effects after GPi DBS, possibly because they are younger and the underlying disease may be associated with less cognitive dysfunction and fewer comorbidities. 72 However, suicides in patients, particularly those with premorbid depression, have been reported following GPi DBS for dystonia. 73 Another side effect noted in a small case series of patients with Meige syndrome was the development of a subjective sense of clumsiness and slowness in previously unaffected body parts. 67 Although these symptoms were often not evident on examination, they were persistent and present only when DBS was turned on. Side effects from field spread into pallidal and surrounding regions are similar to what is seen in GPi DBS for PD. OTHER MOVEMENT DISORDERS
There have been several case series demonstrating the potential for DBS in Tourette syndrome (TS). These case series have used multiple separate targets and combinations of targets, including the centromedian thalamus-parafascicular complex (including the ventralis oralis complex of the thalamus), 74 GPi,75 the anterior limb of the internal capsule, 76 and the nucleus accumbens. 77 As a side benefit, many of these patients also noted improvements in comorbid psychiatric symptoms, including anxiety and obsessive-compulsive disorder. Principles of patient selection are similar to those in other movement disorders, namely, the use of a multidisciplinary team to carefully screen patients and failure to achieve adequate symptom control despite maximal medical management. The Tourette Syndrome Association has now published general guidelines for Tourette DBS.78 There are several small case series showing improvement in poststroke tremor,79,80 posttraumatic tremor,79,80 and multiple sclerosis (MS) tremor with DBS.79–95 These treatments typically target the VIM, although some authors have used multiple simultaneous thalamic or GPi and thalamic targets. 79,85,96 VIM in complex tremors may not be the target of choice, and other areas of thalamus will need to be explored ventralis oralis anterior, ventralis oralis posterior and centromedian (Voa, Vop, CM). In these patients, one must be careful to determine how much disability is due to tremor, which may improve with DBS, versus ataxia or weakness, which will not improve with DBS. Three case reports suggest that chorea in Huntington’s disease (HD) may be reduced with bilateral GPi DBS. 97,98 Case reports of efficacy in some of the spinal cerebellar ataxias have also been reported. 99,100 In Table 5 we provide a review of the literature on DBS outcomes in other movement disorders for motor, mood, QOL, and cognitive outcomes. In studies of mixed populations, we included only studies where specific outcome information was available for each diagnosis. SUMMARY
DBS is an efficacious treatment option for appropriately selected patients with PD, ET, and dystonia. Indications and options for DBS continue to expand rapidly. There are important side effects and benefits that may influence target selection for individual patients. Advances in our understanding of the pathophysiology of movement disorders combined with technological advances in our ability to precisely target neuroanatomical structures continue to push improvements in the efficacy and safety of DBS
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for basal ganglia disorders. Basic science advances need to be combined with welldesigned clinical trials to define rational treatment algorithms to improve motor, mood, cognitive, and QOL outcomes. ACKNOWLEDGMENT
The authors would also like to acknowledge Leah Gaspari for her assistance in the preparation of this manuscript. REFERENCES
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116. Molinuevo J, Valldeoriola F, Tolosa E, et al. Levodopa withdrawal after bilateral subthalamic nucleus stimulation in advanced Parkinson disease. Arch Neurol 2000;57(7):983–8. 117. Pillon B, Ardouin C, Damier P, et al. Neuropsychological changes between ‘‘off’’ and ‘‘on’’ STN or GPi stimulation in Parkinson’s disease. Neurology 2000;55(3): 411–8. 118. Alegret M, Junque C, Valldeoriola F, et al. Effects of bilateral subthalamic stimulation on cognitive function in Parkinson disease. Arch Neurol 2001;58(8):1223–7. 119. Capus L, Melatini A, Zorzon M, et al. Chronic bilateral electrical stimulation of the subthalamic nucleus for the treatment of advanced Parkinson’s disease. Neurol Sci 2001;22(1):57–8. 120. Deep Brain Sitmulation for Parkinson’s Disease Study Group. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med 2001;345(13):956–63. 121. Dujardin K, Defebvre L, Krystkowiak P, et al. Influence of chronic bilateral stimulation of the subthalamic nucleus on cognitive function in Parkinson’s disease. J Neurol 2001;248(7):603–11. 122. Faist M, Xie J, Kurz D, et al. Effect of bilateral subthalamic nucleus stimulation on gait in Parkinson’s disease. Brain 2001;124(Pt 8):1590–600. 123. Lopiano L, Rizzone M, Bergamasco B, et al. Deep brain stimulation of the subthalamic nucleus: clinical effectiveness and safety. Neurology 2001;56(4):552–4. 124. Lopiano L, Rizzone M, Perozzo P, et al. Deep brain stimulation of the subthalamic nucleus: selection of patients and clinical results. Neurol Sci 2001;22(1):67–8. 125. Volkmann J, Allert N, Voges J, et al. Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD. Neurology 2001;56(4):548–51. 126. Durif F, Lemaire J, Debilly B, et al. Long-term follow-up of globus pallidus chronic stimulation in advanced Parkinson’s disease. Mov Disord 2002;17(4):803–7. 127. Figueiras-Mendez R, Regidor I, Riva-Meana C, et al. Further supporting evidence of beneficial subthalamic stimulation in Parkinson’s patients. Neurology 2002;58(3):469–70. 128. Just H, Ostergaard K. Health-related quality of life in patients with advanced Parkinson’s disease treated with deep brain stimulation of the subthalamic nuclei. Mov Disord 2002;17(3):539–45. 129. Lagrange E, Krack P, Moro E, et al. Bilateral subthalamic nucleus stimulation improves health-related quality of life in PD. Neurology 2002;59(12):1976–8. 130. Loher T, Burgunder J, Pohle T, et al. Long-term pallidal deep brain stimulation in patients with advanced Parkinson disease: 1-year follow-up study. J Neurosurg 2002;96(5):844–53. 131. Martınez-Martın P, Valldeoriola F, Tolosa E, et al. Bilateral subthalamic nucleus stimulation and quality of life in advanced Parkinson’s disease. Mov Disord 2002;17(2):372–7. 132. Østergaard K, Sunde N, Dupont E. Effects of bilateral stimulation of the subthalamic nucleus in patients with severe Parkinson’s disease and motor fluctuations. Mov Disord 2002;17(4):693–700. 133. Romito L, Scerrati M, Contarino M, et al. Long-term follow up of subthalamic nucleus stimulation in Parkinson’s disease. Neurology 2002;58(10):1546–50. 134. Simuni T, Jaggi J, Mulholland H, et al. Bilateral stimulation of the subthalamic nucleus in patients with Parkinson disease: a study of efficacy and safety. J Neurosurg 2002;96(4):666–72. 135. Thobois S, Mertens P, Guenot M, et al. Subthalamic nucleus stimulation in Parkinson’s disease: clinical evaluationof 18 patients. J Neurol 2002;249(5):529–34.
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136. Vesper J, Klostermann F, Stockhammer F, et al. Results of chronic subthalamic nucleus stimulation for Parkinson’s disease: a 1-year follow-up study. Surg Neurol 2002;57(5):306–11. 137. Vingerhoets F, Villemure J, Temperli P, et al. Subthalamic DBS replaces levodopa in Parkinson’s disease: two-year follow-up. Neurology 2002;58(3):396–401. 138. Voges J, Volkmann J, Allert N, et al. Bilateral high-frequency stimulation in the subthalamic nucleus for the treatment of Parkinson disease: correlation of therapeutic effect with anatomical electrode position. J Neurosurg 2002;96(2):269–79. 139. Welter ML, Houeto JL, Tezenas du Montcel S, et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain 2002;125(Pt 3):575–83. 140. Chen C, Lee S, Wu T, et al. Short-term effect of bilateral subthalamic stimulation for advanced Parkinson’s disease. Chang Gung Med J 2003;26(5):344–51. 141. Daniele A, Albanese A, Contarino M, et al. Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003;74(2):175–82. 142. Funkiewiez A, Ardouin C, Krack P, et al. Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson’s disease. Mov Disord 2003;18(5):524–30. 143. Herzog J, Volkmann J, Krack P, et al. Two-year follow-up of subthalamic deep brain stimulation in Parkinson’s disease. Mov Disord 2003;18(11):1332–7. 144. Kleiner-Fisman G, Fisman D, Sime E, et al. Long-term follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease. J Neurosurg 2003;99(3):489–95. 145. Krack P, Batir A, Blercom NV, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003; 349(20):1925–34. 146. Pahwa R, Wilkinson S, Overman J, et al. Bilateral subthalamic stimulation in patients with Parkinson disease: long-term follow up. J Neurosurg 2003;99(1): 71–7. 147. Varma T, Fox S, Eldridge P, et al. Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson’s disease patients previously reliant on apomorphine. J Neurol Neurosurg Psychiatry 2003;74(2):170–4. 148. Volkmann J, Allert N, Voges J, et al. Long-term results of bilateral pallidal stimulation in Parkinson’s disease. Ann Neurol 2004;55(6):871–5. 149. Liang G, Chou K, Baltuch G, et al. Long-term outcomes of bilateral subthalamic nucleus stimulation in patients with advanced Parkinson’s disease. Stereotact Funct Neurosurg 2006;84(5–6):221–7. 150. Portman A, Laar Tv, Staal M, et al. Chronic stimulation of the subthalamic nucleus increases daily on-time without dyskinesia in advanced Parkinson’s disease. Parkinsonism Relat Disord 2006;12(3):143–8. 151. Derost P, Ouchchane L, Morand D, et al. Is DBS-STN appropriate to treat severe Parkinson disease in an elderly population? Neurology 2007;68(17):1345–55. 152. Gan J, Xie-Brustolin J, Mertens P, et al. Bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease: threeyears follow-up. J Neurol 2007;254(1):99–106. 153. Rodrigues J, Walters S, Watson P, et al. Globus pallidus stimulation in advanced Parkinson’s disease. J Clin Neurosci 2007;14(3):208–15. ˆ te D, Houeto J, et al. Neurosurgery at an earlier stage of Par154. Schu¨pbach W, Malte kinson disease: a randomized, controlled trial. Neurology 2007;68(4):267–71. 155. Tir M, Devos D, Blond S, et al. Exhaustive, one-year follow-up of subthalamic nucleus deep brain stimulation in a large, single-center cohort of parkinsonian patients. Neurosurgery 2007;61(2):297–304.
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156. Vesper J, Haak S, Ostertag C, et al. Subthalamic nucleus deep brain stimulation in elderly patients–analysis of outcome and complications. BMC Neurol 2007; 16(7):7. 157. Witjas T, Kaphan E, Regis J, et al. Effects of chronic subthalamic stimulation on nonmotor fluctuations in Parkinson’s disease. Mov Disord 2007;22(12): 1729–34. 158. Zibetti M, Torre E, Cinquepalmi A, et al. Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus. Eur Neurol 2007;58(4):218–23. 159. Wider C, Pollo C, Bloch J, et al. Long-term outcome of 50 consecutive Parkinson’s disease patients treated with subthalamic deep brain stimulation. Parkinsonism Relat Disord 2008;14(2):114–9. 160. Pahwa R, Lyons K, Wilkinson S, et al. Long-term evaluation of deep brain stimulation of the thalamus. J Neurosurg 2006;104(4):506–12. 161. Lee J, Kondziolka D. Thalamic deep brain stimulation for management of essential tremor. J Neurosurg 2005;103(3):400–3. 162. Putzke J, Uitti R, Obwegeser A, et al. Bilateral thalamic deep brain stimulation: midline tremor control. J Neurol Neurosurg Psychiatry 2005;76(5):684–90. 163. Putzke J, Wharen R Jr, Obwegeser A, et al. Thalamic deep brain stimulation for essential tremor: recommendations for long-term outcome analysis. Can J Neurol Sci 2004;31(3):333–42. 164. Kumar R, Lozano A, Sime E, et al. Long-term follow-up of thalamic deep brain stimulation for essential and parkinsonian tremor. Neurology 2003;61(11): 1601–4. 165. Bryant J, Salles AD, Cabatan C, et al. The impact of thalamic stimulation on activities of daily living for essential tremor. Surg Neurol 2003;59(6):479–84. 166. Fields J, Tro¨ster A, Woods S, et al. Neuropsychological and quality of life outcomes 12 months after unilateral thalamic stimulation for essential tremor. J Neurol Neurosurg Psychiatry 2003;74(3):305–11. 167. Rehncrona S, Johnels B, Widner H, et al. Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments. Mov Disord 2003; 18(2):163–70. 168. Koller W, Lyons K, Wilkinson S, et al. Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Mov Disord 2001; 16(3):464–8. 169. Obwegeser A, Uitti R, Witte R, et al. Quantitative and qualitative outcome measures after thalamic deep brain stimulation to treat disabling tremors. Neurosurgery 2001;48(2):274–81. 170. Pahwa R, Lyons K, Wilkinson S, et al. Comparison of thalamotomy to deep brain stimulation of the thalamus in essential tremor. Mov Disord 2001;16(1):140–3. 171. Krauss J, Simpson R Jr, Ondo W, et al. Concepts and methods in chronic thalamic stimulation for treatment of tremor: technique and application. Neurosurgery 2001;48(3):535–41. 172. Pahwa R, Lyons K, Wilkinson S, et al. Bilateral thalamic stimulation for the treatment of essential tremor. Neurology 1999;53(7):1447–50. 173. Kumar K, Kelly M, Toth C. Deep brain stimulation of the ventral intermediate nucleus of the thalamus for control of tremors in Parkinson’s disease and essential tremor. Stereotact Funct Neurosurg 1999;72(1):47–61. 174. Koller W, Lyons K, Wilkinson S, et al. Efficacy of unilateral deep brain stimulation of the VIM nucleus of the thalamus for essential head tremor. Mov Disord 1999; 14(5):847–50.
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175. Hariz M, Shamsgovara P, Johansson F, et al. Tolerance and tremor rebound following long-term chronic thalamic stimulation for parkinsonian and essential tremor. Stereotact Funct Neurosurg 1999;72(2–4):208–18. 176. Lyons K, Pahwa R, Busenbark K, et al. Improvements in daily functioning after deep brain stimulation of the thalamus for intractable tremor. Mov Disord 1998;13(4):690–2. 177. Ondo W, Jankovic J, Schwartz K, et al. Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson’s disease tremor. Neurology 1998;51(4):1063–9. 178. Koller W, Pahwa R, Busenbark K, et al. High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997; 42(3):292–9. 179. Hubble J, Busenbark K, Wilkinson S, et al. Deep brain stimulation for essential tremor. Neurology 1996;46(4):1150–3. 180. Blond S, Caparros-Lefebvre D, Parker F, et al. Control of tremor and involuntary movement disorders by chronic stereotactic stimulation of the ventral intermediate thalamic nucleus. J Neurosurg 1992;77(1):62–8. 181. Vercueil L, Pollak P, Fraix V, et al. Deep brain stimulation in the treatment of severe dystonia. J Neurol 2001;248(8):695–700. 182. Bereznai B, Steude U, Seelos K, et al. Chronic high-frequency globus pallidus internus stimulation in different types of dystonia: a clinical, video, and MRI report of six patients presenting with segmental, cervical, and generalized dystonia. Mov Disord 2002;17(1):138–44. 183. Krauss J, Loher T, Pohle T, et al. Pallidal deep brain stimulation in patients with cervical dystonia and severe cervical dyskinesias with cervical myelopathy. J Neurol Neurosurg Psychiatry 2002;72(2):249–56. 184. Cif L, Fertit HE, Vayssiere N, et al. Treatment of dystonic syndromes by chronic electrical stimulation of the internal globus pallidus. J Neurosurg Sci 2003;47(1): 52–5. 185. Katayama Y, Fukaya C, Kobayashi K, et al. Chronic stimulation of the globus pallidus internus for control of primary generalized dystonia. Acta Neurochir Suppl 2003;87:125–8. 186. Krauss J, Loher T, Weigel R, et al. Chronic stimulation of the globus pallidus internus for treatment of non-dYT1 generalized dystonia and choreoathetosis: 2-year follow up. J Neurosurg Sci 2003;98(4):785–92. 187. Kupsch A, Klaffke S, Ku¨hn A, et al. The effects of frequency in pallidal deep brain stimulation for primary dystonia. J Neurol 2003;250(10):1201–5. 188. Yianni J, Bain P, Giladi N, et al. Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit. Mov Disord 2003;18(4):436–42. 189. Yianni J, Bain P, Gregory R, et al. Post-operative progress of dystonia patients following globus pallidus internus deep brain stimulation. Eur J Neurol 2003; 10(3):239–47. 190. Cif L, Valente E, Hemm S, et al. Deep brain stimulation in myoclonus-dystonia syndrome. Mov Disord 2004;19(6):724–7. 191. Coubes P, Cif L, Fertit HE, et al. Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results. J Neurosurg 2004;101(2):189–94. 192. Detante O, Vercueil L, Thobois S, et al. Globus pallidus internus stimulation in primary generalized dystonia: a H215O PETstudy. Brain 2004;127(Pt 8):1899–908. 193. Krause M, Fogel W, Kloss M, et al. Pallidal stimulation for dystonia. Neurosurgery 2004;55(6):1361–8.
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The The past past 2 to 3 deca decade des s have have been been ma mark rked ed by a resu resurg rgen ence ce in surg surgic ical al appr approa oach ches es for for the treatment of movement disorders, specifically the creation of neuroanatomical lesions and deep brain stimulation (DBS). This renewed interest has been spurred on by several factors including (1) improvements in our understanding of the neurophys physio iolo logy gy and and anat anatom omy y of move moveme ment nt disor disorde ders rs,, (2) (2) the the refi refine neme ment nt of DBS DBS as a surgic surgical al approac approach, h, (3) improv improveme ements nts in neuros neurosurg urgery ery and neuroim neuroimagi aging, ng, which which have enhanced our ability to localize brain structures, and (4) an increasing role for surgical interventions, especially in circumstances in which current pharmacologic treatments have reached their limits. Appropriate patient selection for surgery can result in a compelling treatment option for a variety of movement disorders, with the most common to date including Parkinson’s disease (PD), dystonia, and essential tremor. HISTORY
Surgical treatments for movement disorders can be traced to the late 1800s and early 1900s where applications applications included included lesions lesions placed in the motor cortex, 1 the corticospinal tracts, tracts,2 and the cerebral peduncles. 3 Early Early att attemp empts ts at therap therapy y were were focuse focused d mainly on treating hyperkinetic movement disorders, including tremor. Not surprisingly, these early treatments had an unacceptable rate of side effects, particularly of motor weakness. With the introduction of the stereotactic head frame technology in
This work was supported supported by an American Academy of Neurology Neurology Foundation Foundation Clinical Clinical Research Training Fellowship (B.M.K.), and the National Parkinson Foundation Center of Excellence, Gainesville, FL. a University of Colorado Denver and Health Sciences Center, Academic Office 1 mailstop B185, PO Box 6511, Aurora, CO 80045, USA b Department of Neurology, University of Florida, 100 S. Newell Dr, Room L3-100, PO Box 100236, Gainesville, FL 32610, USA c University of Florida Movement Disorders Center, McKnight Brain Institute, 100 S. Newell Dr. Room L3-100, PO Box 100236, Gainesville, FL, USA * Corresponding author. E-mail address: benzi.kluger@ucdenver [email protected] .edu (B.M. (B.M. Kluger). Neurol Clin 27 (2009) 633–677 doi:10.1016/j.ncl.2009.04.006 neurologic.theclinics.com 0733-8619/09 0733-8619/09/$ /$ – see front matter ª 2009 Elsevier Inc. All rights rights reserved. reserved.
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the late 1940s 1940s by Spiegel and colleagues, colleagues, 4 targeting very small subcortical structures became a more realistic possibility. possibility. However, there was still a paucity paucity of basic or clinical scientific evidence to know which nodes of this circuitry would be most appropriate for surgical interventions. A breakthrough in our understanding came in 1953, when when Cooper Cooper acciden accidentall tally y ligated ligated the anteri anterior or choroi choroidal dal artery artery during during a peduncu pedunculot lotomy omy,, and this dramatically improved his patient’s tremor. The ligation interrupted the main blood supply to many structures in the basal ganglia, including the globus pallidus, a finding confirmed by pathologic examination of some of Cooper’s 5 similar but later cases. cases. Althoug Although h this procedure procedure was abando abandoned ned as a result result of unacce unaccepta ptable ble side effects, and because of difficulty in reproducing Cooper’s success, it was followed by more refined surgical approaches that focused largely on many subcortical structures. In 1955, Hassler 6 reported that thalamotomy was more effective than pallidotomy for tremor. Cooper subsequently endorsed this surgical approach, adding that result results s of thalam thalamoto otomy my were were more more consis consisten tentt than than those those of pallido pallidotom tomy. y. In 1960, 1960, 7 Svennilson and colleagues reported that the clinical results of pallidotomy were location depend dependent ent,, with poster posterior ior lesion lesions s demons demonstra tratin ting g superi superior or results results to anteri anterior or lesions. lesions. Although Although this article demonstrate demonstrated d that posteroventral posteroventral pallidotomy pallidotomy improved improved all the cardinal motor signs of PD, this research did not influence general clinical practice, which continued to favor the thalamotomy. In 1963, a few authors published results suggesting that subthalamotomy may obtain tremor improvement similar to that with thalamotomy. 8 However, the fear of inducing hemiballism and subsequent reports showing clinical improvements in only a minority of patients with subthalamotomy led to thalamotomy being the procedure of choice. 9 The introduction of levodopa in 1967 for the treatment of PD provided a remarkable therapeutic benefit, which initially threatened to make all surgical approaches to PD obsolete. 10 The 1980s brought a renewed interest in surgical approaches for movement d isorisor11 ders, beginning with the use us e of thalamotomy for severe drug-resistant tremor. In 1992 1992 Laitin Laitinen en and collea colleague gues s 12 replica replicated ted Leksel Leksell’s l’s benefi benefits ts for poster posterov oventral entral pallidotpallidot13 omy in all cardinal PD motor signs, and in 1997, Gill and Heywood reported their resu result lts s of bilat bilater eral al subth subthal alam amot otom omy. y. This This rene renewe wed d inte intere rest st in surg surger ery y was was drive driven n larg largel ely y by an increased recognition of the limitations of long-term levodopa therapy. Equally important were advances made in our understanding of basal ganglia circuitry and physiology,14 including the emergence of animal models of basal ganglia disease. 15 In 1987, Benabid and colleagues 16 observed that high-frequency electrical stimulation to the ventral intermediate (VIM) nucleus of the thalamus, usually performed as part of neurosurgical localization, could be left in place and have dramatic chronic effect effects s in improvi improving ng tremor tremor.. This This observ observati ation on fueled fueled the furthe furtherr develo developmen pmentt of DBS DBS as a me mean ans s of trea treati ting ng basa basall gang gangli lia a diso disord rder ers. s. Alth Althou ough gh ther there e are are no adequ adequat atel ely y powe powere red d trial trials s publis publishe hed d to date date compa compari ring ng DBS DBS to lesi lesion on ther therap apy, y, DBS has virtually supplanted surgical lesions mainly due to its reversibility, flexibility in chan changi ging ng se sett ttin ings gs,, and and its its impro improve ved d tole tolera rabil bility ity in pati patien ents ts requi requirin ring g bilat bilater eral al surgic surgical al treatm treatment ent (eg, (eg, avoidin avoiding g speech speech and swallo swallowing wing problem problems). s). We focus focus on DBS in this this review, review, recogniz recognizing ing that that the effica efficacy cy and genera generall principl principles es of lesion lesion therapy are similar and that there may be cases in which ablative surgery may be advantageous.18 MECHANISM MECHANISMS S OF ACTION
Ablative brain lesions seem to achieve their functional improvement through the disruption of aberrant network activity. The pioneering work of Delong 14 and Albin and Young 17 in describing the direct and indirect pathways as well as the parallel
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circuitry of the basal ganglia circuitry has laid the foundation for identifying potential regions where surgical interventions may improve symptoms. PD is known to result in increased firing rates and changes in the pattern of a of activity ctivity of both the globus pal19 lidus lidus interna interna (GPi) (GPi) and subtha subthalam lamic ic nucleu nucleus s (STN). (STN). Thes These e patte pattern rns s have have been been confirmed in humans human s by physiologic recordings from PD patients undergoing DBS or ablati ablative ve surger surgery. y.20 Moreov Moreover, er, ablati ablative ve lesion lesions s within within the GPi and STN appear appear to somewhat normalize thi t his s abnormal physiologic activity and are associated with 15 functional improvements. Although DBS appears to produce an informational lesion (a term coined by Grill) that that ma may y mimic mimic ma many ny of the the effe effect cts s from from ablat ablativ ive e surg surger ery, y, the the phys physio iolo logi gic c me mech chan anis isms ms 21 are thought to be more complex. In simple terms, DBS is thought to work by inhibitinhibiting cells close to the stimulating stimulating electrode and by exciting passing passing fiber tracts, but this simplistic model does not consider many of the complex changes that may contribute to DBS effects. effects. There is currently currently evidence to support the existence existence of several several potential sites of action including the following: 1. Inhibition Inhibition of neuronal neuronal cell bodies in close proximity to the electrode. electrode. Evidence from primate recordings demonstrates a reduction in firing rates of cells adjacent to stimulation electrodes during therapeutic stimulation of both STN and GPi. 22 This reduction in firing rate may be due to a depolarization block through alterations of potassium or sodium channels and/or alterations in the balance of presynaptic excitatory and inhibitory afferents. 23 Depolarization blockade as a singular mechanism has fallen out of support of most experts in the field. 2. Stim Stimul ulat atio ion n of axon axons s in clos close e prox proxim imit ity y to the the elec electr trod ode. e. In fact fact,, stud studie ies s have have show shown n increased output from an inhibited nucleus, which is believed to be due to action potentials initiated via axonal stimulation. 24 This activity is time locked to the stimulator frequency. Computer models have further sug gested gested that the therapeutic 25 efficacy of STN is strongly linked to axonal activation. 3. Stimula Stimulation tion of fiber fiber tracts tracts passing passing throug through h the field of stimula stimulatio tion. n. DBS curren currents ts sufficient for axonal activation may spread beyond the anatomic target to adjacent fiber tracts. Several tracts important to basal ganglia functioning pass in close prox proxim imity ity to the the STN STN and and have have been been hypo hypoth thes esiz ized ed to cont contrib ribut ute e to the the clin clinic ical al effe effect ct of DBS, including cerebellothalamic fibers (tremor reduction), nigrostriatal tracts (incre (increase ase striata striatall dopami dopamine ne release release), ), and the zona zona incert incerta a (all (all cardin cardinal al motor motor symptoms).23 4. Alterations in neurotransmitter release and synthesis. As noted above, activation of the nigrostriatal tract may increase striatal dopamine release. Other microdialysis studies of STN DBS in rats have demonstrated modulatory effects on both glutamate and g-aminobutyr -aminobutyric ic acid release release within basal ganglia ganglia circuits. circuits. 26 5. Alterations Alterations in network dynamics. dynamics. DBS may interrupt interrupt pathologic neural neural output by providing stimulation greater than a neuron’s spontaneous activity and thus preemptin empting g intrins intrinsic ic firing. firing. This This has been been referr referred ed to as an ‘‘infor ‘informat mation ional al lesion lesion,’ ,’’’ because it replaces irregular pathologic activity with regular but ‘‘informationally’’ neutra neutrall output output..21 Functi Functiona onall imagin imaging g studies studies have have demonst demonstrat rated ed change changes s in multiple nodes of the motor circuitry, including the motor cortex, supplementary motor area (SMA) and cerebellum with symptom improvement following DBS. 6. Chronic Chronic network changes. changes. As discussed discussed in the section on dystonia, many clinical clinical improvements take days to weeks, suggesting that they are dependent on neuroplastic changes. Consistent with this concept, studies have demonstrated longterm term change changes s in synapt synaptic ic plastic plasticity ity follow following ing DBS.27 There is also preli pr eliminary minary evidence to suggest that DBS may confer some neuroprotective effects. 28
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These mechanisms are not mutually exclusive, and it appears likely that the therapeutic effects of DBS are the result of multiple mechanisms. 26 Moreover, there is evidence that the me m echanisms of DBS may not be b e identical across disease disease states, states, 29 subcortical targets, 30 or stimulation parameters. 31 SELECTION SELECTION OF SURGICAL SURGICAL CANDIDATES CANDIDATES
The evolution of DBS therapy has resulted in the acceptance that selection of appropriate patients is critically important to the therapeutic benefit. In fact, only a small subs subset et of patie patient nts s (10% (10%–2 –20% 0%)) ma may y be appr appropr opria iate te at any any one one time time.. 32 Currently, patients with PD, dystonia, and essential tremor (ET) may be considered surgical cand ca ndida idate tes s afte afterr they they have have faile failed d me medic dical al ma mana nage geme ment nt (DBS (DBS is Food Food and and Drug Drug Admin Admin-istration approved for these indications in the United States). Patients must be motivated vated and have have the resour resources ces availab available le to partici participate pate in the extens extensive ive follow follow-up -up required to program and monitor the DBS device. In addition, potential candidates must have an acceptable risk benefit ratio favoring surgery. All indications (PD, ET, and dystonia) for DBS carry risks, especially with comorbidities such as age, cognitive dysfunction, frailty, psychiatric disease, cerebral atrophy, blood thinners, and especially hypertension. hypertension. Among dystonia dystonia patients, patients, primary and/or tardive dystonia dystonia seems to have the best response, whereas patients with other forms of secondary dystonia, including structural changes or neurometabolic diseases, tend to have less-predictable responses responses to DBS.33 Howeve However, r, an increa increasin sing g number number of succes successes ses may be seen in these secondary dystonias with appropriate selection of target and stimulus parameters.34 In PD, patients and clinicians should be aware that DBS will potentially benefit only symptoms that are levodopa responsive. 35 DBS can improve ‘‘on’’ time, reduce reduce on-off on-off fluctu fluctuatio ations, ns, and decrea decrease se dyskin dyskinesi esias as but, with the except exception ion of tremor, tremor, does not provide motor benefits that exceed the patient’s patient’s best ‘‘on’’ ‘on’’ medicamedication state (with the current available targets of STN or GPi). It is thus critical for potential PD DBS candidates to have the Unified Parkinson disease rating scale (UPDRS) completed in both the practically defined ‘‘on’’ and ‘‘off’’ states. In general, clinics should follow the Core Assessment Program for Surgical Intervention Therapies in PD criteria, which include a minimal disease duration of 5 years, a diagnosis of idiopathic pathic PD, screen screening ing for depres depressio sion n and cognit cognitive ive decline decline,, and assess assessmen mentt for 35 minimal motor improvement of 30% based on UPDRS scores. One exception to this 30% rule is medically refractory tremor in PD, which may occur in 20% or more patients. There is currently insufficient evidence to support the use of ‘‘early’’ DBS in any movement disorder, although considerations are being explored in research arenas, including effects on quality of life (QOL), decreased surgical mortality (vs delayed operations ), operations ), cost savings, and the possibility that DBS may have a diseasemodifying effect. 36 Caution is required in how we define ‘‘early’’ disease, particularly in patie patient nts s witho without ut sign signifi ifica cant nt disab disabili ility ty,, pati patien ents ts who who have have not not rece receiv ived ed adequ adequat ate e tria trials ls of stan standa dard rd me medic dicat atio ions ns,, and and in patie patient nts s with with shor shortt disea disease se dura duratio tion n who who ma may y not not have have a definitive definitive diagnosis. diagnosis. Although potential surgical candidates may be identified by general neurologists, the decision to proceed through surgery is in the best circumstances made by an experienced experienced multidisciplina multidisciplinary/inte ry/interdiscipl rdisciplinary inary team typically typically including including a movement movement disorders neurologist, neurosurgeon, psychiatrist, neuropsychologist, and, in some circums circumstan tances ces,, a social social worker worker,, speech speech therap therapist, ist, occupa occupation tional al therap therapist, ist, and/or and/or physic physical al therap therapists ists ( Fig. Each member member of the multidi multidisci sciplin plinary ary tea team m should should F ig. 1 ).37 Each have a specific role in this evaluation and should contribute to a discussion by the team regarding the diagnosis, scale changes, expectations of benefit, risk, financial
Surgical Treatment of Movement Disorders
Fig.1. Multidisciplinary team.
issues, QOL, target choice, staged versus simultaneous implantation if bilateral devices may be required, and the ability of the patient to meet the schedule of follow-up appointments. The neurologist must ensure that patients have been correctly diagnosed and that they present with symptoms likely to respond to DBS. They must have exhausted medical options and their symptoms carefully quantified with appropriate disease-specific scales (eg, on/off UPDRS for PD, tremor rating scale [TRS] for ET, and Burke-Fahn-Marsden dystonia rating scale [BFMDRS]). In the case of PD, it is recommended that the patient have at least 5 years of symptoms as it is frequently difficult to distinguish levodopa-responsive parkinsonian syndromes that may be manifesting in early stages. The Florida Surgical Questionnaire for Parkinson’s Disease (FLASQ-PD) was developed as a screening questionnaire to aid in the identification of surgical candidates with PD ( Box 1 ).37 It is important that the neurologist appropriately educates the patient, because unrealistic expectations regarding the benefits and convenience of DBS are a frequent cause of patient’s perception of DBS failure. As discussed later, significant nonmotor complications, including mood, cognition, and speech, may occur following DBS and may be in part preventable through the appropriate screening of high-risk patients. 38 There is some evidence that younger patients (younger than 70 years) may have less risk of cognitive complications; however, this is not an absolute rule, and many older patients have excellent outcomes following DBS. STIMULATOR PLACEMENT AND PROGRAMMING
The accurate localization of DBS targets requires a combination of high-quality neuroimaging, stereotactic localization (frameless or frame-based), and physiologic recordings. The superior resolution of subcortical structures evident on magnetic resonance imaging (MRI) has resulted in its use as the primary imaging modality at most centers. Many centers fuse computed tomography with MRI images to save time on the day of surgery (by performing the MRI the day before) and postoperatively to localize lead
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Box1 FLASQ-PD
A. Diagnosis of idiopathic Parkinson’s disease Diagnosis 1: Is Bradykinesia present? Yes/No (Please circle response) Diagnosis 2: (check if present): —Rigidity (Stiffness in arms, leg, or neck) —4–6 Hz resting tremor —Postural instability not caused by primary visual, vestibular, cerebellar, proprioceptive dysfunction Does your patient have at least 2 of the above? Yes/No (Please circle response) Diagnosis 3: (check if present): —Unilateral onset —Rest tremor —Progressive disorder —Persistent asymmetry affecting side of onset most —Excellent response (70%–100%) to levodopa —Severe levodopa-induced dyskinesia —Levodopa response for 5 y or more —Clinical course of 5 y or more Does your patient have at least 3 of the above? Yes/No (Please circle response) (‘‘Yes’’ answers to all 3 questions above suggest the diagnosis of idiopathic PD) B. Findings suggestive of Parkinsonism due to a process other than idiopathic PD Primitive reflexes 1- RED FLAG—presence of a grasp, snout, root, suck, or Myerson’s sign N/A—not done/unknown Presence of supranuclear gaze palsy 1- RED FLAG—supranuclear gaze palsy present N/A—not done/unknown Presence of ideomotor apraxia 1- RED FLAG—ideomotor apraxia present N/A—not done/unknown Presence of autonomic dysfunction 1- RED FLAG—presence of new severe orthostatic hypotension not due to medications, erectile dysfunction, or other autonomic disturbance within the first year or 2 of disease onset N/A—not done/unknown Presence of a wide-based gait 1- RED FLAG—wide-based gait present N/A—not done/unknown Presence of more than mild dementia
Surgical Treatment of Movement Disorders
1- RED FLAG—frequently disoriented or severe cognitive difficulties, severe memory problems, or anomia N/A—not done, not known Presence of severe psychosis 1- RED FLAG—presence of severe psychosis, refractory to medications N/A—not done, not known History of unresponsiveness to levodopa 1- RED FLAG—Parkinsonism is clearly not responsive to levodopa, patient is dopamine naı¨ve, or patient has not had a trial of levodopa N/A—not done, not known (Any of the ‘‘FLAGs’’ above may be contraindications to surgery)
positions. There is, however, even under the best circumstances, a chance for clinically significant errors from stereotactic targeting, frame shift, brain shift, or misinterpretation of microelectrode recordings (MER). Suboptimal lead placement by even a few millimeters may result in an unacceptable outcome. It should be noted that most DBS targets, including the thalamus (VIM), STN and GPi, have a somatotopic and functional organization that includes sensorimotor, cognitive (associative), and limbic regions. In fact, nonmotor regions have been estimated to make up roughly one-third of each target. 39 To ensure the accurate placement of DBS leads (or lesions) into the sensorimotor region of the intended target structure, most institutions will perform clinical examinations in the conscious patient and MER to ensure that they are within the correct region of their target site. Macrostimulation, which follows MER, involves delivering test stimulation with the actual DBS electrode. Macrostimulation may identify target areas on the basis of acute symptom improvement, and it may also clarify mislocalization on the basis of common side effects usually seen with the stimulation of nearby structures. Examples may include reports of phosphenes with stimulation in the region of the optic tract or muscle twitches or pulling with stimulation of the internal capsule. Some centers rely primarily on macrostimulation and do not routinely perform MER. MER involves the passage of a small micrometer-size recording tip (usually platinum iridium or tungsten) into the target region. As the microelectrode passes through various brain structures, the neurologist or physiologist can identify the relevant brain structures, including white matter and deep brain nuclei, on the basis of their unique firing rates and patterns of activity. These data may be supplemented by passive and active movements of the limbs and facilitate the identification of inhibition or driving activity that may define sensorimotor territories. Oscillatory activity may also be identified and correlated to a patient’s tremor. Although MER and macrostimulation data may aid the accuracy of DBS placement, there also may be some risk to using multiple passes through cerebral structures to generate a 3-dimensional representation that guides localization. 40,41 These risks may include a slightly higher rate of hemorrhage (especially in patients with uncontrolled hypertension) and cognitive or mood side effects, most prominently postoperative confusion, particularly when operations are performed in a simultaneous bilateral, as opposed to staged, procedure. Although there are 3 general tec hniques used for MER (target verification, multiple pass mapping, and Ben-Gunn), 41 these techniques have not been compared with regard to their risks or efficacy. Similarly,
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Table1 Deep brain stimulation complications Summary of Adverse Events Event
No. of Patients (%)
Intraoperative Vasovagal response
8 (2.5)
Syncope
4 (1.2)
Severe cough
3 (0.9)
IVH
2 (0.6)
ICH
2 (0.6)
Arrhythmia (junctional rhythm)
1 (0.3)
Confusion
1 (0.3)
Extreme anxiety
1 (0.3)
Laceration of soft palate
1 (0.3)
TIA
1 (0.3)
Perioperative (within 2 wk) Headache
48 (15.0)
Confusion
16 (5.0)
Hallucination
9 (2.8)
Nausea/vomiting
5 (1.6)
Seizure
4 (1.2)
Dysarthria
3 (0.9)
Dyskinesia
2 (0.6)
Hypertension
2 (0.6)
Paranoia
2 (0.6)
Paresthesia
2 (0.6)
Sore throat
2 (0.6)
TIA
2 (0.6)
Urinary retention
2 (0.6)
Angina
1 (0.3)
Arrhythmia (right bundle branch block)
1 (0.3)
Deep vein thrombosis
1 (0.3)
Depression
1 (0.3)
Dizziness
1 (0.3)
Insomnia
1 (0.3)
Pulmonary edema
1 (0.3)
SDH (evacuated)
1 (0.3)
Long-term (2 wk) Infection
14 (4.4)
Cognitive dysfunction
13 (4.0)
Dysarthria
13 (4.0)
Worsening gait
12 (3.8)
Agitation
5 (1.6)
Paresthesia
4 (1.2)
Depression
3 (0.9)
Headache
2 (0.6) (continued on next page)
Surgical Treatment of Movement Disorders
Table1 (continued ) Summary of Adverse Events Event
No. of Patients (%)
Psychogenic tremor
2 (0.6)
Urinary incontinence
2 (0.6)
Blepharospasm
1 (0.3)
Emotional lability
1 (0.3)
Insomnia
1 (0.3)
Metallic taste
1 (0.3)
Suicide
1 (0.3)
Data from Kenney C, Simpson R, Hunter C, et al. Short-term and long-term safety of deep brain
stimulation in the treatment of movement disorders. J Neurosurg 2007;106:621–5.
more research is needed to determine if staged or simultaneous procedures have distinct advantages and in which populations they should be applied. SURGICAL AND DBS COMPLICATIONS
DBS complications may be divided into risks associated with the surgical procedure and chronic complications of therapy that may or may not be device related. The most serious complications associated with DBS surgery are cerebrovascular accidents (including transient ischemic events) (0.9%), intracranial hemorrhage (1.2%), seizure (1.2%), device infection (4.4%), lead fracture (3.8%), and device movement or misplacement (3.2%),42 and the risks vary from study to study depending on many factors. Many centers do not prospectively assess adverse events, and this may lead to under-reporting. 43 These risks may be somewhat attenuated by appropriate screening and treatment of comorbid conditions, including hypertension, which increases hemorrhage risk during MER; diabetes, which increases the risk of infection; psychiatric disease, which increases the risk of depression and suicide; cognitive deficits, which increase the risk of postoperative confusion; and obesity or other significant cardiopulmonary diseases, which may increase the general risk of surgery.44,45 Complications of DBS may also occur following the acute operative period. These complications may occur from problems in triage, screening, inadequate patient counseling/unreasonable patient expectations, operative procedure (including DBS misplacement), medication adjustments, or device programming difficulties. In a series of patients seeking further management after suboptimal DBS outcomes, the most common reasons for poor DBS outcome/DBS failure included inadequate screening (no movement disorder neurologist or documented neuropsychological testing) (66%), inappropriate or missed diagnosis (22%), suboptimally placed electrodes (46%), inadequate programming follow-up (17%) or suboptimal DBS parameters (37%), and suboptimal medication management (73%). 38 Of the patients seen in this series, two-thirds had good outcomes (51%) or modest improvement (15%) after receiving appropriate interventions. Chronic side effects may occur in patients even when the device has been appropriately placed, and lead settings may be optimized for the greatest symptomatic benefit. Side effects may be stimulation related and may be reversible with a simple change in settings. However, some side effects may be due to microlesional effects of the DBS placement and thus not amenable to changes in
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Table 2 Summary of STN and GPi DBS outcomes for PD
Author, Year
N
Type
Target
Duration (mo)
Krack et al., 1997101
27
Prosp NC
STN
1–12
NA
Ghika et al., 1998102
6
Prosp NC
GPi
24
Krack et al., 1998103
8
Retrosp NC
STN
5
UPDRS III Motor
LE
NA
22/17 22.7%
63/28 55.6%
N/A
N/A
20/8 60.0%
31/10 67.7%
38/28 26.3%
66/33 50.0%
1080/960 11.1%
3.5/2.5 28.6%
6
7.9/4.6 41.8%
33.3/9.1 72.7%
4.0/1.4 65.0%
6
13.6/ 10.6 22.0%
27.8/ 15.0 46.0
57.5/ 17.1 70.3% 53.6/ 32.5 39.4%
1156/681 41.1%
GPi
18.2/ 14.7 19.2% 23.2/ 26.5 14.0%
865/1110 28.3%
4.8/1.2 75.0%
N/A
26.0% 40.0%
N/A
27.0% 41.0%
UPDRS II ADL
Kumar et al., 1998104
8 6
Prosp NC Prosp NC
GPi STN
3 3
Kumar et al., 1998105
7
Prosp DB
STN
6
10.5/ 12.4 18.1%
28.1/ 19.7 29.9%
30.1/ 17.7 41.2%
Limousin et al., 1998106
20
Prosp NC
STN
12
N/A
60.0%
10.0%
LID
Unchanged 30.0%
Comments
Decreased speech fluency; Dysarthria Improvement of executive function (marginal) Decreased off time from 40% to 10%
60.0% 41.0%
55.7/ 19.4 65.2%
40.0%
1.8/0.3 83.3%
60.0%
1224/615 49.8%
11.0/7.7 30.0%
S&E off 29.0/73.2 (152.4%) Off time 2.2/0.6 (72.7%) FBA 39.6/37.4 (5.6%)
Volkmann et al., 1998107
9
Prosp NC
GPi
3
Ardouin et al., 1999108
26
Prosp
STN
3
Burchiel et al., 1999109
6
Prosp DBl
STN
12
N/A
78.0%
N/A
4
Prosp DBl
GPi
12
N/A
63.0%
Limousin et al., 1999110
73
Prosp NC
Th
12
N/A
Moro et al., 1999111
7
Prosp NC
STN
16
Pinter et al., 1999112
9
Prosp NC
STN
9
12.6/4.8 61.9%
20.6/8.4 59.2%
33.9/ 19.4 42.8%
54.1/ 23.9 55.8%
767/675 12.0% NS
2.6/0.4 84.6%
Weight gain ADL improved Decrease in verbal fluency S&E off 52.2/83.9 (60.7%) Stable results in 6, 9 and 12 mo
44.0%
51.0%
N/A
N/A
39.0%
Unchanged
11.6/3.8 67.2% 9.5/5.0 47.4%
13.85/ 9.24 33.3%
N/A
37.0/ 25.7 30.5%
649/610 (LD)
2.0/1.5 25.0%
S&E 72.35/82.77 (14.4%)
15.3/ 14.3 6.5%
36.1/ 17.3 52.1%
29.3/ 30.7 -4.8%
67.6/ 39.3 41.9%
1507/521 65.4%
Reduced
Sleep improved Weight gain 13% Neuropsychological testing unchanged
3
11.6/9.1 21.6%
29.6/ 12.6 57.4%
24.1/ 18.8 22.0%
60.0/ 27.8 53.7%
527/133 74.8%
2.9/0.5 82.8%
STN
12
11.6/9.3 19.8%
29.6/ 12.8 56.8%
24.1/ 18.8 22.0%
60.0/ 27.1 53.8%
527/211 60.0%
S&E off 47.5/82.5 (73.7%) Off time decreased 8.8/ 1.0 (88.6%) S&E off 47.5/80.0 0. (68.4%)
55.4/ 19.8 64.3%
N/A
Bejjani et al., 2000113
12
Prosp NC
STN
6
N/A
N/A
78.0%
64.0%
70.0%
83.0%
Motor fluctuations 88.0%
Houeto et al., 2000114
23
Prosp NC
STN
6
11/2 81.8%
30/10 66.7%
N/A
N/A
1340/820 38.8%
7.0/1.6 77.1%
Fluctuation 4.5/1.0 (77.8%) (continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 4 3
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Table 2 (continued ) Author, Year
N
Type
Target
Duration (mo)
Jahanshahi et al., 2000115
7
NC (on/off)
STN
2–26
6
UPDRS II ADL
UPDRS III Motor
LE
LID
Comments
62.7/25.1 60.0%
GPi
Improves some aspects of executive functioning
54.2/27.2 49.8%
Molinuevo et al., 2000116
15
Prosp NC
STN
6
N/A
26.7/7.5 71.9%
N/A
49.6/16.9 65.9%
1338/262 80.4%
Pillon, 2000117
48
NC
STN
12
N/A
N/A
N/A
55.4/18.1 67.3%
1110/348 68.6%
15
STN
6
N/A
N/A
N/A
8
GPi
12
N/A
N/A
N/A
5
GPi
6
N/A
N/A
N/A
56.1/19.4 65.4% 55.4/37.1 33.0% 41.6/27.0 35.1%
1063/465 56.3% 744/873 17.3% 850/735 13.5%
Alegret, 2001118
15
Prosp
STN
3
N/A
29.9/10.9 63.6%
N/A
53.6/23.2 56.7%
57.9%
Capus, 2001119
7
Prosp NC
STN
6
N/A
N/A
20.3%
50.6%
40.7%
80.6%
Off time 89.7% S&E 38.7/84 (117.1%) H&Y 3.8/1.9 (50.0%) Improved psychomotor speed and working memory
S&E 27.5/72.5 (-163.6%) H&Y 4.2/2.3 (45.2%) Moderate deterioration of verbal memory 73.5%
Motor fluctuations improvement 57.2% PDQ38 improvement 49.9%
DBS/PD study group, 2001120
96
Prosp DBl Crossover
STN
6
11.2/10.2 8.9%
28.4/16.0 43.7%
23.6/17.8 24.6%
54.0/25.7 52.4%
1218/764 37.3%
1.9/0.8 57.9%
38
Same
GPi
6
12.7/8.8 30.7%
17.9/17.9 0.0%
24.1/16.5 31.5%
50.8/33.9 33.3%
1090/1120 -2.8%
2.1/0.7 66.7%
9
Prosp NC
STN
3
Prosp NC
STN
12
31.55/13.78 56.3% 31.2/14.3 54.2%
22.44/13.44 40.1% 21.6/17.2 20.4%
62.9/32.6 48.2% 65.0/40.5 37.7%
NA
6
8.66/7.67 11.4% 9.2/7.5 18.5%
5.33/2.22 58.4% 4.33/0.5 88.5%
Slight impairment in executive function The same subjects as those in the previous group
Faist et al., 2001122
8
Prosp NC
STN
15
N/A
N/A
N/A
49.8/7.4 85.1%
N/A
N/A
Improves walking velocity Stride length S&E off 43.7/88.7 (103.0%)
Lopiano et al., 2001123
16
Prosp NC
STN
3
8.8/7.7 12.5%
28.3/9.1 67.8%
20.3/14.8 27.1%
59.8/25.9 56.7%
1162/321 72.4%
3.5/1.1 68.6%
Off time 2.0/0.3 (85%)
Lopiano et al., 2001124
20
Prosp NC
STN
12
N/A
N/A
19.8/16.8 5.0%
58/25.1 56.7%
954/228 76.1%
Volkmann et al., 2001125
16
Prosp NC
STN
12
GPi
12
28.8/12.6 56.3% 21.0/12.1 42.4%
15.1/16.4 -8.6% 30.2/16.7 44.7%
56.4/22.4 60.3% 52.5/16.7 68.2%
2.73%
11
13.7/11.0 19.7% 12.1/5.8 52.1%
2.0/0.4 80.0%
2.4/0.4 83.3% 836/605 27.6%
6
GPi
6
N/A
N/A
Unchanged
36%
N/A
60%
6 6 6
GPi GPi GPi
12 24 36
N/A N/A N/A
N/A N/A N/A
Unchanged Unchanged Unchanged
26% 38% 32%
N/A N/A 1415/1225 13.4%
30% 20% 40%
Dujardin et al., 2001121
Durif et al., 2002126
NA
Off time 49/19% (percentage of waking hours) Off time 37/24% (percentage of waking hours)
Neuropsychological assessment stable
Off time decreased by 50% 25% 40% 10% (continued on next page)
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6 4 6
K l u g e r e t a l
Table 2 (continued ) Author, Year
N
Type
Figueiras-Mendez 22 Prosp NC et al., 2002127
Duration Target (mo)
STN
UPDRS III Motor
LE
LID
Comments
1–12
16/9 43.8%
30/16 46.7%
24/10 58.3%
2 13/18 91.6%
32.0%
NA
11/5 54.6%
22/7 68.2%
23/12 47.8%
44/14 68.2%
N/A
28.1/0 100.0%
Off time 31/0% (percentage of waking hours) PDQ 39 38.4/22.3 (24.3%) Nonsurgical 41.3/42.7 (3.4%)
9.6/5.8 39.6%
BDI 10.5/8.5 (19.0%) PDQ 90.3/129 (42.9%)
Just and Ostergaard, 2002128
11 Prosp NC STN Nonsurgical
6
Lagrange et al., 2002129
60 Prosp NC
12
Loher et al., 2002130
10 Prosp NC
GPi
Martinez-Martin et al., 2002131
17 Prosp NC
11.3/11.4 29.6/23.4 0.1% 21.0%
53.7/24.3 20.3/18.8 54.7% 7.4%
1010/522 48.3%
12
37.6/24.9 34.9/22.9 33.8% 34.4%
34.7/24.9 63.4/37.5 28.2% 40.8%
1235.5/1300.6 9.8/5.0 48.9% 5.3%
STN
6
N/A
29.53/8.29 N/A 71.9%
Ostergaard et al., 26 Prosp NC 2002132
STN
12
9.3/6.8 26.9%
25.2/8.5 66.3%
23.5/10.7 51.3/18.3 54.5% 64.3%
1197/964 19.5%
Romito et al., 2002133
STN
24–36
N/A
31.6/10 68.4%
N/A
1505.9/491.7 67.4%
22 Prosp
STN
UPDRS II ADL
55.7/20.76 1400/509 62.7% 63.6%
60.2/29.9 50.3%
S&E Off 28.8/45.0 (56.3%) On 51.0/60.0 (17.6%)
N/A
Off time 1.8/0.3 (83.3%) PDQL 40.89/20.18 (50.6%)
2.1/0.3 85.7%
Weight increase 75/8 kg S&E off 49/84 (71.4%) Off periods 1.8/0.3 (83.3%) Hypophonia Dysarthria Improved sleep S&E off med 24.5/80.0 (226.5%)
Simuni et al., 2002134
12 Prosp NC
Thobois et al., 2002135
18 Prosp NC
STN
12
N/A
N/A
19.3/19.8 43.5/23.0 2.6% 47.1%
1946/875 55.0%
4.2/1.5 64.3%
1045/360 35.5% same
76.0%
STN
6
5.3/8.1 52.8% 5.3/7.5 41.5%
26.9/12.7 52.8% 26.9/10.7 60.2%
17.9/15.2 15.1% 17.9/13 27.4%
44.9/20.2 55.0% 44.9/17 62.1%
Off time 1.6/1.0 (37.5%) S&E off 39.6/77.5 (95.7%)
14 Prosp NC
STN
12
Vesper et al., 2002136
38 Prosp NC
STN
12
N/A
N/A
27.7/17.4 48.3/24.9 37.2% 48.4%
900/580 35.5%
3.2/0.9 71.9%
Off time 14.5/6 (58.6%)
Vingerhoets et al., 2002137
20 Prosp NC
STN
21
N/A
21.0/13.3 37%
N/A
48.8/26.9 44.8%
1135/230 79.7%
4.8/0.4 92%
50% of patients discontinued medications
Voges et al., 2002138
15 Prosp NC
STN
6–12
N/A
NA
N/A
55.3/22.7 58.9%
909/374 58.9%
NA
S&E off 42/77 (83.3%)
Welter et al., 2002139
41 Prosp NC
STN
6
10.4/6.6 36.5%
29/11.1 61.7%
14.7/10.6 51.4/18.5 27.9% 64.0%
1459/480 67.1%
2.1/0.2 90.5%
Chen et al., 2003140
7
Prosp NC
STN
6
N/A
N/A
39.0/19.1 65.7/32.8 51.0% 50.0%
N/A
Improved S&E off 22.9/70.0 (205.7%)
Daniele et al., 2003141
20 Prosp NC
STN
12
9
STN
18
10.1/6.2 38.6% 12.4/5.4 56.5%
31.8/8.8 72.3% 33.1/7.4 77.6%
24.0/22.1 7.9% 25.0/17.3 30.8%
58.8/30.9 47.5% 60.8/27.0 55.6%
1395/500 64.2% 1185/535 54.8%
Funkiewiez et al., 50 Prosp NC 2003142
STN
12
N/A
N/A
N/A
N/A
N/A
12/4 67%
BDI 13.9/11.5 (17.3%) MDRS 136.8/136.7 (0.1%) FS 40.8/39.5 (3.2%)
Herzog et al., 2003143
48 Prosp NC
STN
6
N/A
STN
12
N/A
STN
24
N/A
44.2/21.7 50.9% 43.9/18.7 57.4% 44.9/19.2 57.2%
1425/730 48.8% 42.4%
20
18.7/14.7 21.4% 18.1/12.4 31.5% 19.3/12.4 35.8%
2.6/1.9 26.9% 2.5/0.3 87.0% 2.4/0.3 85.0%
Temporary psychiatric adverse events
32
22.6/10.7 52.6% 21.6/10.7 49.2% 23.4/13.2 43.2%
67.8%
91.0%
PDQ 83.2/54.3 (34.7%) 87.7/49.7 (43.3%)
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S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 4 7
6 4 8
K l u g e r e t a l Table 2 (continued ) Author, Year
N
Type
Target
Duration (mo)
Kleiner-Fisman et al., 2003144
25
Prosp NC
STN
12
Krack et al., 2003145
49
Prosp NC
STN
60 (5 y)
Pahwa et al., 2003146
33
UPDRS II ADL
19
STN
12
STN
24
LE
12.1/10.5 13.2%
25.8/17.4 32.6%
22.8/19.4 14.9%
50.1/24.6 50.9%
7.3/14.0 91.8%
30.4/15.6 48.7%
14.3/21.1 47.6%
N/A
21.1/14.3 32.2%
11.6/12.8 10.3%
Prosp NC
UPDRS III Motor
LID
Comments
38.0%
46.4%
55.7/25.8 53.7%
1409/518 63.2%
4.0/1.4 65.0%
DRS 136/131 (3.7%) BDI 15.5/14.9 (3.9%) FBA 40.4/37.3 (7.7%)
N/A
43.8/26.5 39.5%
10.4/5.8 44.2%
18/4%
21.1/15.3 27.5%
26.2/24.1 8.0%
41.3/29.8 27.8%
12.4/5.3 57.3%
19/11%
Off time 44/20% (percentage of waking hours) Off time 43/17% (percentage of waking hours)
Varma et al., 2003147
7
Prosp NC
STN
6
15/14 6.7%
38/25
34.2%
61%
2067/1055 49.0%
44%
Volkmann et al., 2004148
9
Prosp NC
Gpi
36
11.3/7.1 37.2% 8.8/10.3 17.1%
20.9/15.5 25.8% 19.5/19.8 1.5%
30.8/13.9 54.9% 22.2/18.7 15.8%
52.8/26.8 49.2% 49.5/38.0 23.2%
870/897 3.1% 961/760 20.9%
1.9/0.6 68.4% 1.0/0.6 40.0%
10.0/9.4 6.0%
26.0/17.3 33.5%
17.6/19.7 11.9%
38.4/23.9 37.8%
1364/867 36.4%
2.9/0.7 75.9%
10.0/17.2 72.0%
26.0/22.3 14.2%
17.6/22.1 25.6%
38.4/26.5 31.0%
1364/1029 24.6%
2.9/0.9 69.0%
6 Liang et al., 2006149
27
60 Prosp NC
STN
12
33
MMSE 29/29
Off time 1.9/1.2 (36.8%) S&E off 47.2/72.1 (52.8%) Off time 1.9/1.1 (42.1%) S&E off 47.2/66.7 (41.3%)
Portman et al., 2006150
20
Prosp NC
STN
12
Derost, 2007151
53
Prosp NC
STN
24
N/A
23/20 13.0% NS
46/33 28.3%
1242/751 39.5%
8.8/3.75 57.4%
3.7/8.5 1.3% 5.6/11.1 98.0%
18.0/15.6 13.3% 18.8/16.7 11.2%
N/A
45.0%
N/A
41.0%
1246/885 28.9% 1308/760 41.9%
3.4/0.7 79.4% 2.7/1.1 59.3%
4.5/8.5 88.9% 4.5/12.5 177.8%
23.7/12.5 47.3% 23.7/13.9 41.4%
14.1/12.5 11.3% 14.1/12.5 11.3%
42.2/21.0 50.2% 42.2/19.3 54.3%
1228/470 61.7% 1228/631 48.6%
9.0/1.9 78.9% 9.0/31.1 245.6%
N/A
N/A
12.5/10.4 16.8%
40.6/21.8 46.3%
1182/1216 2.9%
10.5/2.5 76.0%
2.3/5.1 121.7%
19.2/12.9 32.8%
NA
69.0%
57.0%
83.0%
DRS 140.5/140.5 (NS) FBA 48/47.5 (NS) MADRS 7/3 (improved)
61.0%
Cognitive decline in 7.7% Depression 18%
5.6/1.3 76.8%
S&E off 45.3/63.7 (40.6%) DRS 137.4/136 (-1.0%) BDI 8.1/6.4 (21.0%)
34 Gan et al., 2007152
N/A
36
Prosp NC
STN
24
STN
12
36 Rodriques et al., 2007153
11
Prosp NC
Gpi
7
Schu¨pbach et al., 2007154
10
Prosp NC Comp BMT
STN
18
Tir et al., 2007155
100
Prosp NC
STN
12
9.5/8 15.8%
27.5/19 30.9%
20/14.4 28.0%
50/29 42.0%
1222/721 41.0%
Vesper et al., 2007156
73
Prosp NC
STN
24
N/A
N/A
30/26 13.3%
50/25 50.0%
45.0%
Witjas et al., 2007157
40
Prosp NC
STN
12
8.8/4.7 46.6%
23.7/13.3 43.9%
11.8/6.9 41.5%
38/12.4 67.4%
1091/460 57.8%
S&E off 52/72 (38.5%) Off time 10%
DRS 135.9/137.4 (NS) BDI 12.8/11.6 (NS) DRS 135.9/135.5 (NS) BDI 12.8/16.1 (NS)
(continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 4 9
6 5 0
K l u g e r e t a l
Table 2 (continued ) Author, Year
N
Type
Target
Duration (mo)
Zibetti et al., 2007158
36
Prosp NC
STN
12
N/A
24
N/A
Wider et al., 2008159
50
Prosp NC
STN
6
UPDRS II ADL
10.0/11.5 15.0% 10.0/12.8 28.0% 10.0/18.9 89.0%
25.3/9.9 60.9% 25.3/10.3 59.3% N/A
24 60
UPDRS III Motor
N/A N/A 24.3/26.7 9.9% 24.3/27.7 14.0% 24.3/30.6 25.9%
N/A N/A
LE
LID
Comments
54.5/25.8 52.7% 54.5/24.1 55.8%
1023/405 60.4% 1023/417 59.2%
N/A
47.2/24.8 47.5% 47.2/24.9 47.3% 47.2/33.2 29.7%
1128/195 82.7% 1128/391 65.3% 1128/485 57.0%
4.8/0.7 85.4% 4.8/0.8 83.3% 4.8/0.7 85.4%
N/A
Off time 1.55/0.11 (92.9%) Off time 1.55/0.03 (98.1%)
Abbreviations: BDI, Beck’s Depression Inventory; BMT, Best medical treatment; DRS, Mattis Dementia rating scale; Dyskinesia, as measured by UPDRS IV-a (motor
complication) or AIMS (abnormal involuntary movements scale); FBA, frontal battery assessment scale; GPi, Globus pallidus part interna; ICH, intracerebral hemorrage; IVH, intraventricular hemorrage; LD, Levodopa dose only; LE, Levodopa equivalent (the method of calculation was not standardized across the studies); LID, levodopa induced dyskinesias; MADRS, Montgomery and Asberg depression rating scale; MDRS, Mattis Dementia Rating Scale; MMSE, Folstein mini mental status Examination; NS, nonsignificant; Off and On, applies to the medication state; Off time, Hours per day spent in clinically defined off period (immobile); PDQ, Parkinson disease quality-of-life questionnaire, total score; Prosp., NC, prospective noncontrolled clinical trial; S&E, Schwab and England disability scale; SDH, subdural hemorrage; STN, Subthalamic nucleus; Th, Thalamus; TIA, transient ischemic attack; UPDRS II—ADL, activities of daily living, maximum 52; UPDRS III, motor subscore, maximum 108. Results are represented as Preoperative/Postoperative, with the percentage change calculated as: [(Preoperative Postoperative)/Preoperative] 100. Data from Kenney C, Simpson R, Hunter C, et al. Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders. J Neurosurg 2007;106:621–5.
Surgical Treatment of Movement Disorders
settings. Common stimulation-related side effects may include paresthesias due to spread of current to lemniscal and sensory regions and muscle tightening due to spread of current to motor fibers (corticobulbar and corticospinal tracts). More significant side effects may include dysarthria, cognitive deficits (particularly declines in verbal fluency), and alterations in mood (including depression, anxiety, mania, and suicidality). The STN in particular may have a high risk for cognitive and mood side effects, including executive dysfunction, hypomania (up to 15% in some series), depression, anxiety and suicidality. 46 However, randomized comparative studies to confirm these clinical findings remain to be published. Although DBS has been repeatedly demonstrated to improve QOL, 47 there are often significant difficulties with social adjustment following DBS, particularly with marital and professional life. 48 This finding stresses the importance of preoperative counseling and discussions regarding the patient’s expectations of surgery. See Table 1 for a summary of DBS complications.
SPECIFIC MOVEMENT DISORDERS AND TARGETS Parkinson’s Disease
Successful patient outcomes in PD have been obtained with DBS directed toward 1 of 3 intracranial targets, namely, STN, GPi, and VIM. There is currently no consensus on which targets may be preferable for which symptoms; however, some important insights have emerged from the literature. We anticipate that further data will demonstrate differences in particular symptom efficacy and side effect profiles (mood, motor, cognitive, and QOL) so that the choice of an appropriate DBS target can be tailored to an individual. There is currently good evidence to show that VIM DBS is effective in the treatment of arm tremor but does not ameliorate other PD symptoms or capture leg tremor in many cases. 49 VIM DBS is generally not considered a first-line target in PD; however, elderly patients with symptoms mostly linked to medication refractory upper-extremity tremor who have impaired QOL or activities of daily living (ADLs) may obtain excellent results. 50 STN or GPi DBS may address tremor, bradykinesia, and rigidity but have less impact on gait and postural instability, with much of the outcome related to whether specific symptoms responded preoperatively to levodopa. DBS also does not prevent disease progression into areas such as gait, speech, and cognition. Other DBS targets are currently under investigation in PD. Emerging evidence has suggested that gait in PD may be improved by DBS directed to the pedunculopontine nucleus. 51 However, proper outcome studies and criteria to determine patient selection have not been performed. Zona incerta DBS is another potential target for tremor and other cardinal motor manifestations, and this remains under investigation. 52 Although the first randomized, double-blinded trials of STN versus GPi are currently underway, there is preliminary evidence for the potential of differential responses and/ or side effects from the 2 targets based on clinical observation. In general, both procedures are well tolerated and considered generally safe in appropriately selected patients, with meta-analyses showing comparable motor efficacy. 53 There is some evidence that STN DBS may be associated with a slightly greater motor/tremor benefit; however, there may also be a higher risk of cognitive, behavioral, and mood side effects.45 Although both STN and GPi improve dyskinesias and smooth on/off fluctuations, there may be reasons to favor a specific target site, as well as reasons to perform unilateral versus bilateral operations and to consider simultaneous versus staged bilateral procedures. These differences will potentially emerge as randomized studies are published. For example, STN DBS achieves dyskinesia reduction by reducing levodopa requirements, whereas GPi DBS has a direct antidyskinetic effect,
651
6 5 2
K l u g e r e t a l
Table 3 Summary of VIM thalamic DBS outcomes for ET Study
Sample Size
Study Type
Tremor Improvement
Nonmotor Outcomes
Pahwa et al., 2006
26
Prosp NC
46% (unilateral) and 78% (bilateral) FTM TRS
35%–50% improvement on ADLs (from TRS), drawing and pouring
Lee and Kondziolka, 2005161
18
Case series
75% improvement FTM TRS
64% improvement in handwriting
Putzke et al., 2005162
22
Case series
81% improvement FTM TRS
N/A
163
52
Case series
45% improvement FTM TRS
70% improvement in ADLs
5
Case series
62% improvement in FTM TRS
Tolerance to DBS developed in 2 of 5 patients
16
Case series
34% FTM TRS
45% improvement ADLs
35
Case series
56% FTM TRS improvement
Significant improvements in mood, QOL, and several cognitive outcomes
Rehncrona et al., 2003167
19
Prosp NC
46% improvement FTM TRS
N/A
Hariz et al., 200259
27
Prosp NC
47% improvement FTM TRS
Significant improvements in mood, QOL, and ‘‘emotional constraints’’ domain of QOL
Koller et al., 2001168
49
Case series
78% improvement FTM TRS
24% of patients required at least 1 additional surgical procedure
Obwegeser et al., 2001169
160
Putzke et al., 2004
Kumar et al., 2003164 165
Bryant et al., 2003 Fields et al., 2003
166
31
Case series
6-point reduction in FTM TRS
N/A
170
Pahwa et al., 2001
17
Case control (vs thalamotomy)
50% improvement FTM TRS
Equivalent benefit with less complications than thalamotomy
Krauss et al., 2001171
42
Case series
57% excellent outcome, 36% marked improvement
N/A
Troster et al., 199957
40
Prosp NC
51% reduction in FTM TRS
Significant improvements across multiple domains of QOL, anxiety, and cognitive function except verbal fluency.
Limousin et al., 1999110
37
Prosp NC
55% reduction in FTM TRS
Significant improvement in ADLs
Pahwa et al., 1999
172
9
Case series
57% improvement in FTM TRS
Significant improvement in ADLs
Kumar et al., 1999173
9
Case series
61% improvement FTM TRS
Significant improvement in ADLs and global disability
Koller et al., 1999174
38 (head tremor)
Case series
Head tremor improved in 75% of patients
N/A
Hariz et al., 1999175
36
Case series
48% improvement in FTM TRS
Significant improvement in ADLs
Lyons et al., 1998176
22
Case series
39% improvement in FTM TRS
57% improvement on tremor ADL scale
Ondo et al., 1998177
14
Case series
83% improvement in FTM TRS
>50% improvement in ADLs and disability scores
Koller et al., 1997178
29
Prosp NC
> 50% improvement in FTM TRS
Significant improvement in ADLs
10
Prosp NC
>50% improvement in both patient and clinician FTM TRS ratings
63% improvement in patient and clinician ratings of global disability
4
Case series
Sustained improvement in 75% of patients
No change in MMSE, verbal fluency, or Wisconsin Card Sort
Hubble et al., 1996
179
Blond et al., 1992180
Abbreviations: ADLs, activities of daily living; FTM TRS, Fahn Tolosa Marin tremor rating scale; MMSE, Folstein mini mental status examination; QOL, Quality of life.
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 5 3
6 5 4
Table 4 Summary of GPi DBS outcomes for dystonia
Author
N
Type of Dystonia
Target
Follow-up Period (mos)
Scale
Preoperative Score
Postoperative Score
Improvement (%)
Comments
Vercueil et al., 2001181
1
Primary generalized
GPi
12
BFMDRS (m/d)
N/A
N/A
67/81
Includes 12 patients with thalamic DBS alone and 3 with thalamic and GPi DBS.
1
GPi
6
BFMDRS (m/d)
N/A
N/A
70/50
1 1 1
Primary generalized Primary DYT11 Primary DYT1 Cranial-cervical
GPi GPi GPi
12 24 6
BFMDRS (m/d) BFMDRS (m/d) BFMDRS (m/d)
N/A N/A N/A
N/A N/A N/A
86/86 41/43 66/66
Bereznai et al., 2002182
3 1
Segmental Primary DYT11
GPi GPi
3–12 3–12
BFMDRS (m) Tsui scale
N/A N/A
N/A N/A
72.50 45
Krauss et al., 2002183
5
Cervical
GPi
20
TWSTRS (s/d/p)
20.5/40. 5/6
7.5/12.7/3
62/69/50
Cif et al., 2003184
15 Primary DYTI1 17 Primary DYT1
GPi GPi
24–36 24–36
BFMDRS (m/d) BFMDRS (m/d)
60.8/16.7 56.5/16.4
14.2/5.7 15.1/9.5
71/63 74/49
Katayama et al., 2003185
5
Primary
GPi
6
BFMDRS (m)
18–62
4–23
51–92
Krauss et al., 2003186
2
Primary DYT1
GPi
24
BFMDRS (m)
81
21.5
73
Kupsch et al., 2003187
1 3 1
Primary DYT11 Primary DYT1 Segmental
GPi GPi GPi
3–12 3–12 3–12
BFMDRS (m) BFMDRS (m) BFMDRS (m)
34.5 40 32
27 20 19
22 50% 41
Includes 1 patient with bilateral pallidotomy and 1 patient with unilateral pallidotomy
K l u g e r e t a l
Yianni et al., 2003188
12 Generalized
7
Cervical
GPi
4–184
BFMDRS (m)
79.7
57.8
45.3
46
GPi
2–12
TWSTRS (t)
23
59
Yianni et al., 2003189
2 Primary DYT11 11 Primary DYT1 7 Cervical
GPi GPi GPi
12 12 12
BFMDRS (m) N/A BFMDRS (m) N/A TWSTRS (s/d/p) 21.3/21.7/ 15.1
N/A N/A 10/14/8.3
85 46 50/38/43
Cif et al., 2004190
1
GPi
20
UMRS
69
13
81
BFMDRS (m/d)
9.5/9
1.5/1
84/89
24 24
BFMDRS (m) BFMDRS (m)
62.6 56.3
12.4 13.4
83 75
Myoclonusdystonia syndrome
GPi GPi
Includes the same patients as the other study by Yianni and colleagues, 2003
Coubes et al., 2004191
17 Primary DYT11 14 Primary DYT1
Detante et al., 2004192
13 Primary generalized STN 3 Secondary PKAN STN
3 3
N/A N/A
N/A N/A
N/A N/A
No improvement No improvement
Eltahawy et al., 200433
1
Primary DYT11
GPi
6
BFMDRS (m)
88
66
25
1 3
Primary DYT1 Cervical
GPi GPi
6 6
BFMDRS (m) TWSTRS (t)
48 37.7
16 16
21 57
Krause et al., 2004193
4 6 1
Primary DYT11 Primary DYT1 Cervical
GPi GPi GPi
12–66 12–66 12–66
BFMDRS (m) BFMDRS (m) BFMDRS (m)
72 73.9 6
34 50 6
53 32 0
Trottenberg et al., 2005194
5
Secondary tardive
GPi
6
BFMDRS (m/d)
32/8
N/A
87/96
Vayssiere et al., 2004195
19 Primary generalized
GPi
N/A
BFMDRS
N/A
N/A
>80
Study also includes pallidotomy patients
(continued on next page)
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6 5 6
K l u g e r e t a l
Table 4 (continued ) Author
N
Type of Dystonia
Target
Follow-up Period (mos)
Scale
Preoperative Score
Postoperative Score
Improvement (%)
Comments
Bittar et al., 2005196
2
Primary DYT11
GPi
24
BFMDRS (t)
103.8
55.8
46
DYT11 and DYT1 analyzed together
4 6
Primary DYT1 Cervical
GPi GPi
24 24
TWSTRS (t)
57.8
23.7
59
Castelnau et al., 2005197
6
Secondary PKAN
GPi
21
BFMDRS (m/d)
75/20
20/9.6
74/53
Chou et al., 2005198
1
Cervical dystonia and ET
STN
6
TWSTRS (s/d)
14/20
3/0
79/100
Vidailhet, 200560
7 1
Primary DYT11 Primary DYT1
GPi GPi
12 12
BFMDRS (m/d) BFMDRS (m/d)
55.1/14.7 41.96/10.2
26.1/8.5 18.7/5.5
53/46 55.4/45
Zorzi et al., 2005199
1 8
Primary DYT11 Primary DYT1
GPi GPi
4 19
BFMDRS (m/d) BFMDRS (m/d)
47/11 68.9/17.9
14/6 46.5/12.6
70/45 32/37
Diamond et al., 2006200
5
Primary DYT11
GPi
5
UDRS
44.6
27.5
38
All groups analyzed together. 2 patients with pallidotomy
5 1
Primary DYT1 Hemidystonia
GPi GPi
5 3
6
Primary DYT11
GPi
6
BFMDRS (m/d)
36.4/10
20.2/5.9
45/41
All groups analyzed together
27 7
Primary DYT1 Primary
GPi GPi
6 6
Kupsch et al., 200663
Class 1 evidence
Starr et al., 2006201
6 3 1 1 1
Primary DYT11 Segmental Cranial-cervical (MS) Secondary PKAN Secondary cerebral palsy Secondary posttraumatic Secondary tardive Generalized
GPi GPi GPi GPi GPi
13 22 9 12 33
BFMDRS (m) BFMDRS (m) BFMDRS (m) BFMDRS (m) BFMDRS (m)
59.6 22.6 30 30 82
24.2 12 3 6 51
59 47 90 80 38
GPi
32
BFMDRS (m)
54
49.5
No improvement
GPi
20
BFMDRS (m)
46.5
24.6
47
GPi
11
BFMDRS (m)
83
72.8
12
1
Secondary tardive dystonia
STN
3
BFMDRS (m)
98.8
8
92
1
STN
3
BFMDRS (m)
26.5
2
91
STN
6
BFMDRS (m)
76
7
91
5
Secondary antiemetics Secondary neonatal anoxia Other secondary
STN
N/A
N/A
N/A
N/A
Did poorly
12
Primary DYT11
GPi
12
BFMDRS (m/d)
35/8
4/2
89/75
3
Primary DYT1
GPi
12
1 4 2 Zhang et al., 2006202
2
Alterman, 2007203
6 cases bilateral STN, 2 cases unilateral STN, 1 case left STN and right GPi
DYT1 1 and DYT1 analyzed together (continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 5 7
6 5 8
Table 4 (continued ) Target
Follow-up Period (mos) Scale
Preoperative Score
Postoperative Score
Improvement (%)
Comments
10 Secondary tardive
GPi
6
ESRS
73.1
27.8
62
50% improvement with doubleblind evaluation
AIMS
25
31.1
1
GPi
12
UPDRS-III
21
8
62
–
BFMDRS (t)
32.5
9.5
72
–
UDRS
36.9
16.1
56
BFMDRS GDS
25.6 29.3
13.1 10.3
61 67
All patients previously reported – –
Author
N
Damier et al., 2007204
Evidente et al., 2007205
Grips et al., 2007206
8
Type of Dystonia
X-linked dystonia Parkinsonism Segmental
GPi
N/A
GPi GPi
24
Hung et al., 200762
10 Cervical
GPi
12–67
TWSTRS (s/d/p) 21.9/18/11.7
9.9/7.4/5.8
55/52/51
–
Kiss et al., 2007207
10 Cervical
GPi
12
TWSTRS (s/d/p) 14.7/14.9/26.6 8.4/5.4/9.2
43/64/65
Class 1 evidence
Kleiner-Flisman et al., 2007208
1
Cervical
STN
12
1 1
Cervical Cervical
STN STN
12 12
1
Primary generalized
STN
12
BFMDRS (m/d) TWSTRS (s/d/p) TWSTRS (s/d/p) BFMDRS (m/d) TWSTRS (s/d/p) BFMDRS (m/d)
36.5/5 31/27/14 21/16/17 53/14 26/27/15.3 23/5
29/10 23/20/5.5 12/5/14.3 59/17 28/24/18.3 12/3
21/50 26/26/61 43/69/16 11/-21 8/11/ 20 72/40
1
Primary generalized
STN
29
BFMDRS (m/d)
N/A
N/A
23/42
Novak et al., 2007209
K l u g e r e t a l
Ostrem et al., 200767
6
Sun et al., 200766
12 Primary generalized 2 Secondary tardive
Tisch et al., 2007210 Vidailhet et al., 2007211
Cranial-cervical
7
Primary DYT11
8
Primary DYT1
7
Primary DYT11
15 Primary DYT1
GPi GPi
6 6
BFMDRS (m/d) TWSTRS (t)
22/6 39
6.1/3.7 17
72/38 54
STN
6–42
BFMDRS
N/A
N/A
76–100
Groups reported together
STN
6–42
GPi
6
BFMDRS (m/d)
38.9/9.0
11.9/4.1
70/58
DYT1 1 and DYT1 analyzed together
GPi
6
GPi
36
BFMDRS (m/d)
46.3/11.6
19.3/6.3
58/46
DYT11 and DYT1 analyzed together
GPi
36
Cervical GPi Primary generalized GPi
36 36
TWSTRS (s/d/p) 20.5/40.5/6 BFMDRS (m/d) 81/18.5
14.7/15.7/3.7 28.3/7.5
28/61/38 65/59
Magarinos-Ascone 10 Primary generalized GPi et al., 200864
12
BFMDRS (m/d)
57.8/18.1
20.0/8.6
65/52
Sako et al., 2008213
21
BFMDRS (m/d)
N/A
N/A
86/80
Loher et al., 2008212
4 2
6
Secondary tardive
GPi
1 patient DYT11
This table is an expanded version of that published in the work of Ostrem, 2007, with full permission from Elsevier Ltd. Abbreviations: BFMDRS (m/d), Burke-Fahn-Marsden dystonia rating scale (motor subscore, maximum 120/disability subscore, maximum 30); BFMDRS (t), BurkeFahn-Marsden dystonia rating scale, total score; PKAN, pantothenate kinase associated neurodegeneration; TWSTRS (s/d/p), Toronto western spasmotic torticolis rating scale (severity, maximum 35/disability, maximum 30/pain, maximum 18); UDRS, Unified dystonia rating scale; UPDRS-III, Unified Parkinson disease rating scale, motor subscore (maximum 108); UMRS, Unified myoclonus rating scale; ESRS, Extrapyramidal symptoms rating scale; AIMS, Abnormal involuntary movements scale; GDS, Global dystonia scale; Primary generalized, Primary generalized dystonia of an unknown etiology; Primary DYT1 1, Primary generalized DYT1 gene positive dystonia; Primary DYT1 -, Primary; generalized DYT1 gene negative dystonia, Percentage of change was calculated as [(Preoperative–Postoperative)/Preoperative]x100. For generalized and cervical dystonia, only reports with 5 or more cases were included. For other types of dystonia all published reports were included.
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 5 9
6 6 0
Table 5 Summary of DBS outcomes for other movement disorders
Study
Sample Size
Study Type
Dx
Target
Motor Improvement
Nonmotor Outcomes
Welter et al., 2008214
3
Randomized, controlled, doubleblinded, crossover
TS
GPiCM-Pf
78% and 45% reductions in Yale tic severity scale with GPi and CM-pf respectively. No further improvement with both targets
No change in neuropsychological testing. Mild improvements in impulsivity and depression were noted with CM-pf only
Dehning et al., 200875
1
Case study
TS
GPi
88% improvement in YGTSS
No change in neuropsychological testing
Shields et al., 200876
1
Case study
TS
Anterior IC and CM-Pf
23% improvement in YGTSS with IC; 46% improvement with CM
Depression with AIC
Servello et al., 200874
18
Prosp NC
TS
CM-Pf
Improvements in YGTSS not quantified
Improvements reported in psychiatric comorbidities. Neuropsychology testing performed but results not reported
Bajwa et al., 2007215
1
Case study
TS
CM
66% improvement in YGTSS
OCD symptoms also improved
Kuhn et al., 200777
1
Case study
TS
NAc
41% improvement in YGTSS
OCD symptoms also improved
Shahed et al., 2007216
1
Case study
TS
GPi
84% improvement in YGTSS
Improved OCD symptoms and QOL. Neuropsychology tests stable or improved, except mild decrease in memory
Maciunas et al., 2007217
5
Randomized, controlled, doubleblind, crossover
TS
CM-Pf
44% improvement in YGTSS
Trend toward decreased neuropsychology and improved mood. QOL significantly improved
K l u g e r e t a l
Ackermans et al., 2006218
2
Case study
TS
One patient GPi, other CM
85%–90% reduction in tics/minute both patients
Improved OCD symptoms
Flaherty et al., 2005219
1
Case study
TS
Anterior IC
25% improvement in YGTSS
Euthymic with optimal settings
Diederich et al., 2005220
1
Case study
TS
GPi
46% improvement in YGTSS
Depression and anxiety mildly improved. Neuropsychology stable
Houeto et al., 2005221
1
Case study
TS
CM-Pf and GPi
65% improvement in YGTSS with either or both sites
Neuropsychology stable or improved Mild improvements with depression and impulsivity with CM-Pf
VisserVandewalle et al., 2003222
3
Case series
TS
CM
82% reduction tics/minute
Mild decrease in 1 patient on timed neuropsychology tests
Vandewalle et al., 1999223
1
Case study
TS
CM
901% reduction tics/ minute
N/A
Fasano et al., 200897
1
Case study
HD
GPi
Complete resolution of chorea
Continued deterioration of cognition and gait
Hebb et al., 200698
1
Case study
HD
GPi
Significant improvement in total UPDRS and chorea
Noted weight gain and stable neuropsychology function over 12 mo
Moro et al., 2004224
1
Case study
HD
GPi
44% and 37% improvements in chorea and dystonia
Mild improvements in functional assessment and independence
Freund et al., 200799
1
Case study
SCA-2
VIM STN
Improved tremor
Improved speech and ADLs
Shimojima et al., 2005100
1
Case study
SCA (negative genetic testing)
VIM
45% improvement in FTM TRS
Improved ADLs
Foote and Okun, 200596
1
Case study
Traumatic Holmes tremor
VIM, VOA and VOP
40% improvement in FTM TRS
Significant improvement in disability (continued on next page)
S u r g i c a l T r e a t m e n t o f M o v e m e n t D i s o r d e r s 6 6 1
6 6 2
Table 5 (continued ) Sample Size
Study Type
Dx
Target
Motor Improvement
Nonmotor Outcomes
Nikkhah et al., 200469
2
Case series
Holmes tremor
VIM
Improved tremor and dystonia
Improved speech
Kudo et al., 2001225
1
Case study
Holmes tremor
VIM
Improved tremor
N/A
Plaha et al., 200892
13
Case series
PD, MS, ET, Holmes, dystonic tremor
Zona Incerta
60%–90% improvement in all tremors
N/A
Lim et al., 200779
2
Case studies
MS and stroke
VIM/VOA and GPi (stroke only)
40% improvement in MS with VIM/VOA, 7% in stroke with GPi only
Mild improvements in ADL ratings for both patients
Foote et al., 200685
4
Case series
MS 1 Trauma 3
VIM VOA/VOP
23%–66% improvement in TRS, trend toward more improvement with dual leads in 2 patients
N/A
Moringlane et al., 200490
1
Case study
MS
VL
Improved tremor
No change in neuropsychology function, improved ADLs
Wishart et al., 200395
4
Case series
MS
VIM
Improved tremor
Dysarthria in 1 patient
Schulder et al., 200393
9
Case series
MS
VIM
68% improvement in Bain-Finchley TRS
Stimulation-related fatigue in 1 patient
Bittar et al., 200583
10
Case series
MS
VOP/ZI
64% and 36% improvement of postural and intention tremor on 10-point scale
N/A
Berk et al., 200282
12
Case series
MS
VIM
Overall tremor reduction 63% on Fahn rating scale
Improved ADLs. No change in SF-36 QOL
Study
K l u g e r e t a l
Schulder et al., 200393
9
Case series
MS
VIM
61% tremor reduction Bain-Finchley scale
Mild neuropsychology decline over 30 mo, possibly 2/2 disease progression
Hooper et al., 200287
10
Prospective
MS
Thalamic (targeted to tremor)
Significant reduction on Fahn-TRS
No change in neuropsychology Mild improvement in anxiety
Matsumoto et al., 200188
9
Case series
MS
VIM
Significant reduction in clinical TRS
No change in disability, mild decrease in QOL
Schuurman et al., 200094
5
Randomized (vs thalamotomy)
MS
VIM
Improvement on UPDRS tremor rating
N/A
Brice and McLellan, 198084
2
Case series
MS
Thalamus
Improved tremor
Dysarthria
Montgomery et al., 199989
15
Case series
MS
VIM
Improved clinical TRS
N/A
Benabid et al., 199681
4
Case series
MS
VIM
Tremor improved in 2 patients
N/A
Geny et al., 199686
13
Case series
MS
VIM
Significant decrease in tremor in 9 patients
Improvement in functional disability
Nguyen and Degos, 199391
4
Case series
MS, germinoma, TBI and mercury poisoning
VIM
Tremor improved from ‘‘severe’’ to mild or none in all subjects
Improved functional use of arm
Siegfried and Lippitz, 199480
11
Case series
MS (9), trauma, stroke
VIM
70%–100% of patients with tremor control (not reported by subgroup)
Tremor control limited in some patients by side effects, mainly dysarthria
Abbreviations: ADLs, activities of daily living; AIC, anterior internal capsule; CM-Pf, centromedian parafasicular, Dx, diagnosis; ET, essential tremor; FTM TRS, Fahn
Tolosa Marin tremor rating scale; HD, Huntington’s disease; IC, Internal capsule; MS, multiple sclerosis; NAc, nucleus accumbens; OCD, obsessive compulsive disorder; PD, Parkinson’s disease; QOL, Quality of life; SCA, spinocerebellar ataxia; SF-36, 36-item short-form health survey; TBI, traumatic brain injury TS, Tourette syndrome; VL, ventral lateral; YGTSS, Yale Global Tic Severity Scale. Data from Ostrem J, Marks WJ, Volz M, et al. Pallidal deep brain stimulation in patients with cranial-cervical dystonia (Meige syndrome). Mov Disord 2007;22(13):1885; with permission.
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and this may provide a rationale for target choice in an individual patient. 54 A summary of published studies for DBS for PD is provided in Table 2. Essential Tremor
VIM thalamic DBS has proven to be a generally well-tolerated and efficacious treatment for ET. 55 Candidates for ET DBS usually have postural and/or action tremors, which significantly interfere with ADLs and QOL and should be medication refractory, including maximally tolerated doses of primidone (and/or other anticonvulsants), propanolol (and/or other beta blockers), and a benzodiazepine (typically clonazepam). VIM DBS has been particularly efficacious for contralateral limb tremor, although it has some ipsilateral positive effects. 56 VIM DBS may improve vocal or head tremor, but, in our experience, it is not a reliable benefit when looking across patients. Botulinum toxin injections may be synergistic with DBS for these tremors, particularly if there is a dystonic component. Potential chronic side effects of VIM DBS include speech abnormalities (dysarthria and decreased verbal fluency) and difficulty with gait, particularly with bilateral stimulator placement, and if there are premorbid issues such as cerebrovascular disease or ventricular enlargement. Possibly with the exception of verbal fluency, cognitive and mood outcomes do not seem to decline with VIM DBS in the ET population.57 However, given recent data of neuropsychological impairments in ET and reports of mood disturbances and suicides following VIM DBS, careful screening is still appropriate.58 In Table 3 we provide a complete review of th e literature on VIM DBS outcomes for motor, mood, QOL, and cognitive outcomes. 59 Dystonia
Bilateral GPi DBS has been recently demonstrated by several groups as safe and efficacious in the treatment of primary generalized dystonias, 60 tardive dystonia,61 and in some cases of focal or segmental dystonia. 62,63 There have also been several case reports of successful treatment of myoclonus-dystonia syndrome with bilateral GPi DBS64 and thalamic DBS. 65 Although not commonly used, STN and thalamic DBS have shown efficacy in primary, tardive, and segmental dystonia. 66 In patients with nontardive secondary hemidystonia, segmental, or focal dystonia, the appropriate target(s) are not clear at this time. Patient selection follows similar principles to PD. Patients should have a definitive diagnosis of dystonia by a movement disorder neurologist/neurologist experienced in dystonia and have significant effects on QOL or ADLs despite maximally tolerated medical treatments, including anticholinergics, benzodiazepines, muscle relaxants, and antiepileptics. In patients with focal or limited segmental dystonia, an adequate trial of botulinum toxin injections should also be attempted. Mobile dystonia has been found to be more responsive to DBS regardless of the underlying etiology, and fixed orthopedic deformities are unlikely to be improved by DBS. In Table 4 we provide a review of the literature on GPi dystonia DBS outcomes. The majority of studies of DBS in dystonia have been performed in primary generalized dystonia, where patients have generally shown a 40%–60% improvement in dystonia severity. Similar results have been obtained in cervical dystonia, 62 Meige syndrome 67 and tardive dystonia. 61 Case reports of improvement in dystonia following GPi DBS have also been reported in dystonia secondary to trauma, stroke, and pantothenate kinase deficiency. 68–70 DBS for dystonia is notably different from other disorders in that DBS typically has a delayed benefit possibly owing to cortical remodeling due to stimulation effects, although the exact cause of this finding is currently unknown. 71 Similarly, following DBS, dystonic patients may experience lasting benefits after discontinuation of DBS therapy. Dystonia patients may also accumulate benefit over
Surgical Treatment of Movement Disorders
several months or even longer, suggesting that GPi DBS in dystonia may have both direct effects from stimulation and also induce longer-term neuroplastic changes or disease-modifying benefits. 23 The potential chronic side effects of GPi DBS for dystonia are similar to those seen in PD. With regard to mood disturbances, a careful neuropsychiatric evaluation, particularly in patients with tardive dystonia, is strongly recommended. 58 Patients with dystonia appear to have a lower risk of cognitive side effects after GPi DBS, possibly because they are younger and the underlying disease may be associated with less cognitive dysfunction and fewer comorbidities. 72 However, suicides in patients, particularly those with premorbid depression, have been reported following GPi DBS for dystonia. 73 Another side effect noted in a small case series of patients with Meige syndrome was the development of a subjective sense of clumsiness and slowness in previously unaffected body parts. 67 Although these symptoms were often not evident on examination, they were persistent and present only when DBS was turned on. Side effects from field spread into pallidal and surrounding regions are similar to what is seen in GPi DBS for PD. OTHER MOVEMENT DISORDERS
There have been several case series demonstrating the potential for DBS in Tourette syndrome (TS). These case series have used multiple separate targets and combinations of targets, including the centromedian thalamus-parafascicular complex (including the ventralis oralis complex of the thalamus), 74 GPi,75 the anterior limb of the internal capsule, 76 and the nucleus accumbens. 77 As a side benefit, many of these patients also noted improvements in comorbid psychiatric symptoms, including anxiety and obsessive-compulsive disorder. Principles of patient selection are similar to those in other movement disorders, namely, the use of a multidisciplinary team to carefully screen patients and failure to achieve adequate symptom control despite maximal medical management. The Tourette Syndrome Association has now published general guidelines for Tourette DBS.78 There are several small case series showing improvement in poststroke tremor,79,80 posttraumatic tremor,79,80 and multiple sclerosis (MS) tremor with DBS.79–95 These treatments typically target the VIM, although some authors have used multiple simultaneous thalamic or GPi and thalamic targets. 79,85,96 VIM in complex tremors may not be the target of choice, and other areas of thalamus will need to be explored ventralis oralis anterior, ventralis oralis posterior and centromedian (Voa, Vop, CM). In these patients, one must be careful to determine how much disability is due to tremor, which may improve with DBS, versus ataxia or weakness, which will not improve with DBS. Three case reports suggest that chorea in Huntington’s disease (HD) may be reduced with bilateral GPi DBS. 97,98 Case reports of efficacy in some of the spinal cerebellar ataxias have also been reported. 99,100 In Table 5 we provide a review of the literature on DBS outcomes in other movement disorders for motor, mood, QOL, and cognitive outcomes. In studies of mixed populations, we included only studies where specific outcome information was available for each diagnosis. SUMMARY
DBS is an efficacious treatment option for appropriately selected patients with PD, ET, and dystonia. Indications and options for DBS continue to expand rapidly. There are important side effects and benefits that may influence target selection for individual patients. Advances in our understanding of the pathophysiology of movement disorders combined with technological advances in our ability to precisely target neuroanatomical structures continue to push improvements in the efficacy and safety of DBS
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for basal ganglia disorders. Basic science advances need to be combined with welldesigned clinical trials to define rational treatment algorithms to improve motor, mood, cognitive, and QOL outcomes. ACKNOWLEDGMENT
The authors would also like to acknowledge Leah Gaspari for her assistance in the preparation of this manuscript. REFERENCES
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