Surgical movement disorders

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Surgical Treatment ofMovement Disord ers

Benzi M. Kluger, MDa,*, Olga Klepitskaya, MDa, Michael S. Okun, MDb,c

The past 2 to 3 decades have been marked by a resurgence in surgical approaches 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 neuro-

physiology and anatomy of movement disorders, (2) the refinement of DBS as

a surgical approach, (3) improvements in neurosurgery and neuroimaging, 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 themost 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 included lesions placed in the motor cortex,1 the corticospi-

nal tracts,2 and the cerebral peduncles.3 Early attempts at therapy were focused

mainly on treating hyperkinetic movement disorders, including tremor. Not surpris-

ingly, 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 by an American Academy of Neurology Foundation Clinical ResearchTraining 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, USAb Department of Neurology, University of Florida, 100 S. Newell Dr, Room L3-100, PO Box

100236, Gainesville, FL 32610, USAc 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: [email protected] (B.M. Kluger).

KEYWORDS

Movement disorders Surgical treatment Deep brain stimulation Parkinson’s disease Dystonia Essential tremor

Neurol Clin 27 (2009) 633–677doi:10.1016/j.ncl.2009.04.006 neurologic.theclinics.com0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.

mailto:[email protected]://neurologic.theclinics.com/http://neurologic.theclinics.com/mailto:[email protected]


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the late 1940s by Spiegel and colleagues,4 targeting very small subcortical structures

became a more realistic possibility. However, there was still a paucity of basic or clin-

ical scientific evidence to know which nodes of this circuitry would be most appro-

priate for surgical interventions. A breakthrough in our understanding came in 1953,

when Cooper accidentally ligated the anterior choroidal artery during a pedunculotomy,

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’s5 similar but later

cases. Although this procedure was abandoned as a result of unacceptable 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 struc-

tures. In 1955, Hassler6 reported that thalamotomy was more effective than pallidot-

omy for tremor. Cooper subsequently endorsed this surgical approach, adding that

results of thalamotomy were more consistent than those of pallidotomy. In 1960,

Svennilson and colleagues7 reported that the clinical results of pallidotomy were loca-

tion dependent, with posterior lesions demonstrating superior results to anterior

lesions. Although this article demonstrated that posteroventral pallidotomy improved

all the cardinal motor signs of PD, this research did not influence general clinical prac-

tice, 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 subthalamot-

omy 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 disor-

ders, beginning with the use of thalamotomy for severe drug-resistant tremor.11 In

1992 Laitinen and colleagues12 replicated Leksell’s benefits for posteroventral pallidot-

omy in all cardinal PD motor signs, and in 1997, Gill and Heywood13 reported their

results of bilateral subthalamotomy. This renewed interest in surgery was driven largely

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 colleagues16 observed that high-frequency electrical stimu-

lation to the ventral intermediate (VIM) nucleus of the thalamus, usually performed aspart of neurosurgical localization, could be left in place and have dramatic chronic

effects in improving tremor. This observation fueled the further development of

DBS as a means of treating basal ganglia disorders. Although there are no

adequately powered trials published to date comparing DBS to lesion therapy,

DBS has virtually supplanted surgical lesions mainly due to its reversibility, flexibility

in changing settings, and its improved tolerability in patients requiring bilateral

surgical treatment (eg, avoiding speech and swallowing problems). We focus on

DBS in this review, recognizing that the efficacy and general principles of lesion

therapy are similar and that there may be cases in which ablative surgery may be

advantageous.18

MECHANISMS OF ACTION

Ablative brain lesions seem to achieve their functional improvement through the

disruption of aberrant network activity. The pioneering work of Delong14 and Albin

and Young17 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 activity of both the globus pal-

lidus interna (GPi) and subthalamic nucleus (STN).19 These patterns have been

confirmed in humans by physiologic recordings from PD patients undergoing DBS

or ablative surgery.20 Moreover, ablative lesions within the GPi and STN appear

to somewhat normalize this abnormal physiologic activity and are associated with

functional improvements.15

Although DBS appears to produce an informational lesion (a term coined by Grill)

that may mimic many of the effects from ablative surgery, the physiologic mechanisms

are thought to be more complex.21 In simple terms, DBS is thought to work by inhibit-

ing cells close to the stimulating electrode and by exciting passing fiber tracts, but this

simplistic model does not consider many of the complex changes that may contribute

to DBS effects. There is currently evidence to support the existence of several poten-

tial sites of action including the following:

1. Inhibition of neuronal cell bodies in close proximity to the 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 mecha-

nism has fallen out of support of most experts in the field.

2. Stimulation of axons in close proximity to the electrode. In fact, studies have shown

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 stim-

ulator frequency. Computer models have further suggested that the therapeutic

efficacy of STN is strongly linked to axonal activation.25

3. Stimulation of fiber tracts passing through the field of stimulation. DBS currents

sufficient for axonal activation may spread beyond the anatomic target to adjacent

fiber tracts. Several tracts important to basal ganglia functioning pass in close

proximity to the STN and have been hypothesized to contribute to the clinical effect

of DBS, including cerebellothalamic fibers (tremor reduction), nigrostriatal tracts

(increase striatal dopamine release), and the zona incerta (all cardinal 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 gluta-

mate and g-aminobutyric acid release within basal ganglia circuits.26

5. Alterations in network dynamics. DBS may interrupt pathologic neural output by

providing stimulation greater than a neuron’s spontaneous activity and thus pre-

empting intrinsic firing. This has been referred to as an ‘‘informational lesion,’’

because it replaces irregular pathologic activity with regular but ‘‘informationally’’

neutral output.21 Functional imaging studies have demonstrated changes in

multiple nodes of the motor circuitry, including the motor cortex, supplementarymotor area (SMA) and cerebellum with symptom improvement following DBS.

6. Chronic network changes. As discussed in the section on dystonia, many clinical

improvements take days to weeks, suggesting that they are dependent on neuro-

plastic changes. Consistent with this concept, studies have demonstrated long-

term changes in synaptic plasticity following DBS.27 There is also preliminary

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 thera-

peutic effects of DBS are the result of multiple mechanisms.26 Moreover, there is

evidence that the mechanisms of DBS may not be identical across disease states,29

subcortical targets,30 or stimulation parameters.31

SELECTION OF SURGICAL CANDIDATES

The evolution of DBS therapy has resulted in the acceptance that selection of appro-

priate patients is critically important to the therapeutic benefit. In fact, only a small

subset of patients (10%–20%) may be appropriate at any one time.32 Currently,

patients with PD, dystonia, and essential tremor (ET) may be considered surgical

candidates after they have failed medical management (DBS is Food and Drug Admin-

istration approved for these indications in the United States). Patients must be moti-

vated and have the resources available to participate in the extensive follow-up

required to program and monitor the DBS device. In addition, potential candidatesmust 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 espe-

cially hypertension. Among dystonia patients, primary and/or tardive 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-predict-

able responses to DBS.33 However, an increasing number of successes 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 on-off fluctuations, and decrease dyskinesias but, with the exception of

tremor, does not provide motor benefits that exceed the patient’s best ‘‘on’’ medica-

tion state (with the current available targets of STN or GPi). It is thus critical for poten-

tial 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 idio-

pathic PD, screening for depression and cognitive decline, and assessment for

minimal motor improvement of 30% based on UPDRS scores.35 One exception to

this 30% rule is medically refractory tremor in PD, which may occur in 20% or morepatients. 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 de-

layed operations ), cost savings, and the possibility that DBS may have a disease-

modifying effect.36 Caution is required in how we define ‘‘early’’ disease, particularly

in patients without significant disability, patients who have not received adequate trials

of standard medications, and in patients with short disease duration who may not have

a definitive diagnosis.

Although potential surgical candidates may be identified by general neurologists,

the decision to proceed through surgery is in the best circumstances made by anexperienced multidisciplinary/interdisciplinary team typically including a movement

disorders neurologist, neurosurgeon, psychiatrist, neuropsychologist, and, in some

circumstances, a social worker, speech therapist, occupational therapist, and/or

physical therapists ( Fig. 1 ).37 Each member of the multidisciplinary team should

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

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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 beencorrectly 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 iden-

tification 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 prevent-

able 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 compli-

cations; 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 neuro-

imaging, stereotactic localization (frameless or frame-based), and physiologic record-

ings. 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

Fig.1. Multidisciplinary team.



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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, proprioceptivedysfunction

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/unknownPresence of ideomotor apraxia

1- RED FLAG—ideomotor apraxia present


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 diseaseonset


Presence of a wide-based gait

1- RED FLAG—wide-based gait present


Presence of more than mild dementia

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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 acci-

dents (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 appro-

priate 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.44,45Complications 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 inthis 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

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 brainstimulation in the treatment of movement disorders. J Neurosurg 2007;106:621–5.



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Table 2

(continued )

Author, Year N Type Target

Duration

(mo) UPDRS II ADL

UPDRS III

Motor LE

Jahanshahiet al., 2000115

7 NC (on/off) STN 2–26 62.7/25.160.0%

6 GPi 54.2/27.249.8%

Molinuevoet al., 2000116

15 Prosp NC STN 6 N/A 26.7/7.571.9%

N/A 49.6/16.965.9%

13380.4

Pillon, 2000117 48 NC STN 12 N/A N/A N/A 55.4/18.167.3%

11168.6

15 STN 6 N/A N/A N/A 56.1/19.465.4%

10656.3

8 GPi 12 N/A N/A N/A 55.4/37.133.0%

74417

5 GPi 6 N/A N/A N/A 41.6/27.035.1%

85013.

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


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DBS/PD studygroup, 2001120

96 Prosp DBlCrossover

STN 6 11.2/10.28.9%

28.4/16.043.7%

23.6/17.824.6%

54.0/25.752.4%

12137.3

38 Same GPi 6 12.7/8.830.7%

17.9/17.90.0%

24.1/16.531.5%

50.8/33.933.3%

109-2.8

Dujardin et al.,2001121 9 Prosp NC STN 3 8.66/7.6711.4% 31.55/13.7856.3% 22.44/13.4440.1% 62.9/32.648.2% NA

6 ProspNC

STN 12 9.2/7.518.5%

31.2/14.354.2%

21.6/17.220.4%

65.0/40.537.7%

NA

Faist et al.,2001122

8 Prosp NC STN 15 N/A N/A N/A 49.8/7.485.1%

N/A

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%

116

72.4Lopiano et al.,

200112420 Prosp NC STN 12 N/A N/A 19.8/16.8

5.0%58/25.156.7%

95476.

Volkmann et al.,2001125

16 Prosp NC STN 12 13.7/11.019.7%

28.8/12.656.3%

15.1/16.4-8.6%

56.4/22.460.3%

2.73

11 GPi 12 12.1/5.852.1%

21.0/12.142.4%

30.2/16.744.7%

52.5/16.768.2%

2.0/80.0

Durif et al.,2002126

6 GPi 6 N/A N/A Unchanged 36% N/A

6 GPi 12 N/A N/A Unchanged 26% N/A6 GPi 24 N/A N/A Unchanged 38% N/A

6 GPi 36 N/A N/A Unchanged 32% 14113.4


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Simuni et al.,2002134

12 Prosp NC STN 12 N/A N/A 19.3/19.82.6%

43.5/23.047.1%

1946/8755.0%

Thobois et al.,2002135

18 Prosp NC STN 6 5.3/8.152.8%

26.9/12.752.8%

17.9/15.215.1%

44.9/20.255.0%

1045/3635.5%

14 Prosp NC STN 12 5.3/7.541.5%

26.9/10.760.2%

17.9/1327.4%

44.9/1762.1%

same

Vesper et al.,2002136

38 Prosp NC STN 12 N/A N/A 27.7/17.437.2%

48.3/24.948.4%

900/58035.5%

Vingerhoetset al., 2002137

20 Prosp NC STN 21 N/A 21.0/13.337%

N/A 48.8/26.944.8%

1135/2379.7%

Voges et al.,2002138

15 Prosp NC STN 6–12 N/A NA N/A 55.3/22.758.9%

909/37458.9%

Welter et al.,2002139

41 Prosp NC STN 6 10.4/6.636.5%

29/11.161.7%

14.7/10.627.9%

51.4/18.564.0%

1459/4867.1%

Chen et al.,2003140

7 Prosp NC STN 6 N/A N/A 39.0/19.151.0%

65.7/32.850.0%

N/A

Daniele et al.,2003141

20 Prosp NC STN 12 10.1/6.238.6%

31.8/8.872.3%

24.0/22.17.9%

58.8/30.947.5%

1395/5064.2%

9 STN 18 12.4/5.456.5%

33.1/7.477.6%

25.0/17.330.8%

60.8/27.055.6%

1185/5354.8%

Funkiewiez et al.,2003142

50 Prosp NC STN 12 N/A N/A N/A N/A N/A

Herzog et al.,2003143

48 Prosp NC STN 6 N/A 22.6/10.752.6%

18.7/14.721.4%

44.2/21.750.9%

1425/7348.8%

32 STN 12 N/A 21.6/10.749.2%

18.1/12.431.5%

43.9/18.757.4%

42.4%

20 STN 24 N/A 23.4/13.243.2%

19.3/12.435.8%

44.9/19.257.2%

67.8%


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Table 2

(continued )


Duration

(mo) UPDRS II ADL

UPDRS III

Motor LE

Kleiner-Fismanet al., 2003144

25 Prosp NC STN 12 12.1/10.513.2%

25.8/17.432.6%

22.8/19.414.9%

50.1/24.650.9%

38

Krack et al.,2003145

49 Prosp NC STN 60 (5 y) 7.3/14.091.8%

30.4/15.648.7%

14.3/21.147.6%

55.7/25.853.7%

140963.2

Pahwa et al.,2003146

33 Prosp NC STN 12 N/A 21.1/14.332.2%

N/A 43.8/26.539.5%

10.444.2

19 STN 24 11.6/12.810.3%

21.1/15.327.5%

26.2/24.18.0%

41.3/29.827.8%

12.457.3

Varma et al.,2003147

7 Prosp NC STN 6 15/146.7%

38/25 34.2% 61% 206749.0

Volkmann et al.,2004148

9 Prosp NC Gpi 36 11.3/7.137.2%

20.9/15.525.8%

30.8/13.954.9%

52.8/26.849.2%

870/3.1

6 60 8.8/10.317.1%

19.5/19.81.5%

22.2/18.715.8%

49.5/38.023.2%

961/20.9

Liang et al.,2006149

27 Prosp NC STN 12 10.0/9.46.0%

26.0/17.333.5%

17.6/19.711.9%

38.4/23.937.8%

136436.4

33 10.0/17.272.0%

26.0/22.314.2%

17.6/22.125.6%

38.4/26.531.0%

136424.6


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Portman et al.,2006150

20 Prosp NC STN 12 N/A N/A 23/2013.0% NS

46/3328.3%

124239.5

Derost,2007151

53 Prosp NC STN 24 3.7/8.51.3%

18.0/15.613.3%

N/A 45.0% 124628.9

34 STN 24 5.6/11.198.0%

18.8/16.711.2%

N/A 41.0% 130841.9

Gan et al.,2007152

36 Prosp NC STN 12 4.5/8.588.9%

23.7/12.547.3%

14.1/12.511.3%

42.2/21.050.2%

122861.7

36 4.5/12.5177.8%

23.7/13.941.4%

14.1/12.511.3%

42.2/19.354.3%

122848.6

Rodriqueset al., 2007153

11 Prosp NC Gpi 7 N/A N/A 12.5/10.416.8%

40.6/21.846.3%

11822.9

Schüpbachet al., 2007154

10 Prosp NCComp BMT

STN 18 2.3/5.1121.7%

19.2/12.932.8%

NA 69.0% 57.0

Tir et al.,2007155

100 Prosp NC STN 12 9.5/815.8%

27.5/1930.9%

20/14.428.0%

50/2942.0%

122241.0

Vesper et al.,2007156

73 Prosp NC STN 24 N/A N/A 30/2613.3%

50/2550.0%

45.0

Witjas et al.,2007157

40 Prosp NC STN 12 8.8/4.746.6%

23.7/13.343.9%

11.8/6.941.5%

38/12.467.4%

109157.8


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Table 2(continued )


Duration

(mo) UPDRS II ADL

UPDRS III

Motor LE

Zibetti et al.,2007158

36 Prosp NC STN 12 N/A 25.3/9.960.9%

N/A 54.5/25.852.7%

24 N/A 25.3/10.359.3%

N/A 54.5/24.155.8%

Wider et al.,2008159

50 Prosp NC STN 6 10.0/11.515.0%

N/A 24.3/26.79.9%

47.2/24.847.5%

24 10.0/12.828.0% N/A 24.3/27.714.0% 47.2/24.947.3%

60 10.0/18.989.0%

N/A 24.3/30.625.9%

47.2/33.229.7%

Abbreviations: BDI, Beck’s Depression Inventory; BMT, Best medical treatment; DRS, Mattis Dementia rating scale; complication) or AIMS (abnormal involuntary movements scale); FBA, frontal battery assessment scale; GPi, Globuorrage; IVH, intraventricular hemorrage; LD, Levodopa dose only; LE, Levodopa equivalent (the method of calculaLID, levodopa induced dyskinesias; MADRS, Montgomery and Asberg depression rating scale; MDRS, Mattis Demestatus Examination; NS, nonsignificant; Off and On, applies to the medication state; Off time, Hours per day spent iParkinson disease quality-of-life questionnaire, total score; Prosp., NC, prospective noncontrolled clinical trial; Ssubdural hemorrage; STN, Subthalamic nucleus; Th, Thalamus; TIA, transient ischemic attack; UPDRS II—ADL, ac

motor subscore, maximum 108. Results are represented as Preoperative/Postoperative, with the percentage chantive)/Preoperative] 100.Data from Kenney C, Simpson R, Hunter C, et al. Short-term and long-term safety of deep brain stimulation in the

2007;106:621–5.


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Table 3

Summary of VIM thalamic DBS outcomes for ET

Study Sample Size Study Type Tremor Improvement

Pahwa et al., 2006160 26 Prosp NC 46% (unilateral) and 78%(bilateral) FTM TRS

Lee and Kondziolka, 2005161 18 Case series 75% improvement FTM TRS

Putzke et al., 2005162 22 Case series 81% improvement FTM TRS

Putzke et al., 2004163 52 Case series 45% improvement FTM TRS

Kumar et al., 2003164 5 Case series 62% improvement in FTM TRS

Bryant et al., 2003 165

16 Case series 34% FTM TRS Fields et al., 2003166 35 Case series 56% FTM TRS improvement

Rehncronaet al., 2003167

19 Prosp NC 46% improvement FTM TRS

Hariz et al., 200259 27 Prosp NC 47% improvement FTM TRS

Koller et al., 2001168 49 Case series 78% improvement FTM TRS

Obwegeser et al., 2001169 31 Case series 6-point reduction in FTM TRS

Pahwa et al., 2001170 17 Case control(vs thalamotomy)

50% improvement FTM TRS

Krauss et al., 2001171 42 Case series 57% excellent outcome, 36%marked improvement


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Troster et al., 199957 40 Prosp NC 51% reduction in FTM TRS

Limousin et al., 1999110 37 Prosp NC 55% reduction in FTM TRS

Pahwa et al., 1999 172 9 Case series 57% improvement in FTM TRS

Kumar et al., 1999173 9 Case series 61% improvement FTM TRS

Koller et al., 1999174 38 (headtremor)

Case series Head tremor improved in 75% patients

Hariz et al., 1999175 36 Case series 48% improvement in FTM TRS

Lyons et al., 1998176 22 Case series 39% improvement in FTM TRS

Ondo et al., 1998177 14 Case series 83% improvement in FTM TRS

Koller et al., 1997178 29 Prosp NC > 50% improvement in FTM TR

Hubble et al., 1996179 10 Prosp NC >50% improvement in bothpatient and clinician FTM TRSratings

Blond et al., 1992180 4 Case series Sustained improvement in 75%patients

Abbreviations: ADLs, activities of daily living; FTM TRS, Fahn Tolosa Marin tremor rating scale; MMSE, Folstein mini m


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Yianni et al.,2003188

12 Generalized GPi 4–184 BFMDRS (m) 79.7 45.3

7 Cervical GPi 2–12 TWSTRS (t) 57.8 23 Yianni et al.,

20031892 Primary DYT11 GPi 12 BFMDRS (m) N/A N/A 11 Primary DYT1 GPi 12 BFMDRS (m) N/A N/A 7 Cervical GPi 12 TWSTRS (s/d/p) 21.3/21.7/

15.110/14/8

Cif et al.,2004190

1 Myoclonus-dystoniasyndrome

GPi 20 UMRS 69 13

BFMDRS (m/d) 9.5/9 1.5/1

Coubes et al.,2004191

17 Primary DYT11 GPi 24 BFMDRS (m) 62.6 12.4 14 Primary DYT1 GPi 24 BFMDRS (m) 56.3 13.4

Detante et al.,2004192

13 Primary generalized STN 3 N/A N/A N/A 3 Secondary PKAN STN 3 N/A N/A N/A

Eltahawy et al.,200433

1 Primary DYT11 GPi 6 BFMDRS (m) 88 66

1 Primary DYT1 GPi 6 BFMDRS (m) 48 16 3 Cervical GPi 6 TWSTRS (t) 37.7 16

Krause et al.,2004193

4 Primary DYT11 GPi 12–66 BFMDRS (m) 72 34 6 Primary DYT1 GPi 12–66 BFMDRS (m) 73.9 50

1 Cervical GPi 12–66 BFMDRS (m) 6 6 Trottenberg et al.,

20051945 Secondary

tardiveGPi 6 BFMDRS (m/d) 32/8 N/A

Vayssiere et al.,2004195

19 Primarygeneralized

GPi N/A BFMDRS N/A N/A


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Starr et al.,2006201

6 Primary DYT11 GPi 13 BFMDRS (m) 59.6 24.2 3 Segmental GPi 22 BFMDRS (m) 22.6 12 1 Cranial-cervical (MS) GPi 9 BFMDRS (m) 30 3 1 Secondary PKAN GPi 12 BFMDRS (m) 30 6 1 Secondary

cerebral palsyGPi 33 BFMDRS (m) 82 51

1 Secondary

posttraumatic

GPi 32 BFMDRS (m) 54 49.5

4 Secondarytardive

GPi 20 BFMDRS (m) 46.5 24.6

2 Generalized GPi 11 BFMDRS (m) 83 72.8

Zhang et al.,2006202

1 Secondary tardivedystonia

STN 3 BFMDRS (m) 98.8 8

1 Secondaryantiemetics

STN 3 BFMDRS (m) 26.5 2

2 Secondaryneonatalanoxia

STN 6 BFMDRS (m) 76 7

5 Other secondary STN N/A N/A N/A N/A

Alterman,2007203

12 Primary DYT11 GPi 12 BFMDRS (m/d) 35/8 4/2

3 Primary DYT1 GPi 12


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Table 4

(continued )

Author N Type of Dystonia Target

Follow-up

Period (mos) Scale

Preoperative

Score

Postopera

Score Damier et al.,

200720410 Secondary tardive GPi 6 ESRS 73.1 27.8

AIMS 25 31.1

Evidente et al.,2007205

1 X-linkeddystoniaParkinsonism

GPi 12 UPDRS-III 21 8

BFMDRS (t) 32.5 9.5

Grips et al.,2007206

8 Segmental GPi N/A UDRS 36.9 16.1

GPi BFMDRS 25.6 13.1 GPi GDS 29.3 10.3

Hung et al.,200762

10 Cervical GPi 12–67 TWSTRS (s/d/p) 21.9/18/11.7 9.9/7.4/5.8

Kiss et al.,2007207

10 Cervical GPi 12 TWSTRS (s/d/p) 14.7/14.9/26.6 8.4/5.4/9.2

Kleiner-Flisman

et al., 2007208

1 Cervical STN 12 BFMDRS (m/d) 36.5/5 29/10

TWSTRS (s/d/p) 31/27/14 23/20/5.5 1 Cervical STN 12 TWSTRS (s/d/p) 21/16/17 12/5/14.31 Cervical STN 12 BFMDRS (m/d) 53/14 59/17

TWSTRS (s/d/p) 26/27/15.3 28/24/18.31 Primary

generalizedSTN 12 BFMDRS (m/d) 23/5 12/3

Novak et al.,2007209


STN 29 BFMDRS (m/d) N/A N/A


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Ostrem et al.,200767

6 Cranial-cervical GPi 6 BFMDRS (m/d) 22/6 6.1/3.7 GPi 6 TWSTRS (t) 39 17

Sun et al.,200766


STN 6–42 BFMDRS N/A N/A

2 Secondary tardive STN 6–42

Tisch et al.,

2007210

7 Primary DYT11 GPi 6 BFMDRS (m/d) 38.9/9.0 11.9/4.1


Vidailhet et al.,2007211

7 Primary DYT11 GPi 36 BFMDRS (m/d) 46.3/11.6 19.3/6.3


Loher et al.,2008212

4 Cervical GPi 36 TWSTRS (s/d/p) 20.5/40.5/6 14.7/15.7/2 Primary generalized GPi 36 BFMDRS (m/d) 81/18.5 28.3/7.5

Magarinos-Asconeet al., 200864

10 Primary generalized GPi 12 BFMDRS (m/d) 57.8/18.1 20.0/8.6

Sako et al.,2008213 6 Secondary tardive GPi 21 BFMDRS (m/d) N/A N/A

This table is an expanded version of that published in the work of Ostrem, 2007, with full permission from Elsevie Abbreviations: BFMDRS (m/d), Burke-Fahn-Marsden dystonia rating scale (motor subscore, maximum 120/disabil

Fahn-Marsden dystonia rating scale, total score; PKAN, pantothenate kinase associated neurodegeneration; TWSTrating scale (severity, maximum 35/disability, maximum 30/pain, maximum 18); UDRS, Unified dystonia rating scascale, motor subscore (maximum 108); UMRS, Unified myoclonus rating scale; ESRS, Extrapyramidal symptoms raments scale; GDS, Global dystonia scale; Primary generalized, Primary generalized dystonia of an unknown etDYT1 gene positive dystonia; Primary DYT1 -, Primary; generalized DYT1 gene negative dystonia, Percentage of cherative)/Preoperative]x100. For generalized and cervical dystonia, only reports with 5 or more cases were included. Fwere included.


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Ackermans et al.,2006218

2 Case study TS One patient GPi,other CM

85%–90% reductionin tics/minute bothpatients

Flaherty et al.,2005219

1 Case study TS Anterior IC 25% improvementin YGTSS

Diederich et al.,2005220

1 Case study TS GPi 46% improvementin YGTSS

Houeto et al.,2005221

1 Case study TS CM-Pf and GPi 65% improvementin YGTSS with eitheor both sites

Visser-Vandewalleet al., 2003222

3 Case series TS CM 82% reductiontics/minute

Vandewalle et al.,1999223

1 Case study TS CM 901% reductiontics/ minute

Fasano et al.,200897

1 Case study HD GPi Complete resolutionof chorea

Hebb et al.,200698

1 Case study HD GPi Significant improvemein total UPDRS andchorea

Moro et al.,2004224

1 Case study HD GPi 44% and 37% improvein chorea anddystonia

Freund et al.,200799

1 Case study SCA-2 VIM STN Improved tremor

Shimojima et al.,2005100

1 Case study SCA (negativegenetictesting)

VIM 45% improvement inFTM TRS

Foote and Okun,200596

1 Case study TraumaticHolmestremor

VIM, VOAand VOP

40% improvement inFTM TRS


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Table 5

(continued )

Study

Sample

Size Study Type Dx Target Motor Improvement

Nikkhah et al.,200469

2 Case series Holmes tremor VIM Improved tremor andystonia

Kudo et al.,2001225

1 Case study Holmes tremor VIM Improved tremor

Plaha et al.,200892

13 Case series PD, MS, ET,Holmes,dystonictremor

Zona Incerta 60%–90% improvemin all tremors

Lim et al.,200779

2 Case studies MS and stroke VIM/VOA andGPi (stroke

only)

40% improvement MS with VIM/VOA

in stroke with GPFoote et al.,

2006854 Case series MS 1 Trauma 3 VIM VOA/VOP 23%–66% improvem

in TRS, trend towmore improvemedual leads in 2 pa

Moringlane et al.,200490

1 Case study MS VL Improved tremor

Wishart et al.,200395

4 Case series MS VIM Improved tremor

Schulder et al.,200393

9 Case series MS VIM 68% improvement Bain-Finchley TRS

Bittar et al.,200583

10 Case series MS VOP/ZI 64% and 36%improvement ofpostural and intetremor on 10-poiscale

Berk et al.,200282

12 Case series MS VIM Overall tremor redu63% on Fahn ratiscale


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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 combina-

tions 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 thosein 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 improve-

ment 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 disor-

ders combined with technological advances in our ability to precisely target neuroan-

atomical 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 well-

designed 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.

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