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Subthalamic nucleus stimulation in Parkinson's disease
Esselink, R.A.J.
Publication date
2007
Document Version
Final published version
Link to publication
Citation for published version (APA):
Esselink, R. A. J. (2007). Subthalamic nucleus stimulation in Parkinson's disease.
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Thesis University of Amsterdam, The Netherlands ISBN: 978-90-9022425-1
Cover: Uitwaaierend electrisch veld Door: Joyce Gulei, Extrapool, Nijmegen Printed by: Praktijkwerk, Zutphen Lay out: Marcel Janssen
IN PARKINSON’S DISEASE
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus
prof. dr. D.C. van den Boom
ten overstaan van een door het college voor promoties ingestelde commissie,
in het openbaar te verdedigen in de Aula der Universiteit op woensdag 28 november 2007, te 10.00 uur
door
Renate Albertien Johanna Esselink
geboren te Hengelo
Promotores Prof. Dr. M. Vermeulen Prof. Dr. R.J. de Haan Co-promotores Dr. J.D. Speelman
Dr. P.R. Schuurman Overige leden: Prof. dr. M.I. Hariz
Dr. B.R. Bloem Prof. dr. B.A. Schmand Prof. dr. M.J. Staal Prof. dr. W.P. Vandertop Prof. dr. M. de Visser Faculteit der Geneeskunde
This thesis was prepared at the Department of Neurology and the Department of Neurosurgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
The work in this thesis was supported by a grant from “Het Prinses Beatrix Fonds”.
Publication of this thesis was made possible by financial support of Department of Neurology, Radboud University Nijmegen Medical Centre, Stichting het Remmert Adriaan Laan Fonds, ApotheekZorg, Medtronic, Novartis, Valeant, Boehringer-Ingelheim, Teva Pharma, GE Healthcare en de heer en mw G.J. Esselink.
Voor Sander, Katrien en Hester
9 11 29 45 61 75 91 107 123 135 141 147 153 Preface Chapter 1
Introduction: Parkinson’s disease, pallidotomy, and deep brain stimulation: an overview Largely adapted from: Parkinson’s disease and deep brain stimulation
Chapter 2
Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial.
Chapter 3
Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in Parkinson’s disease: one year follow-up of a randomised observer-blind multi centre trial.
Chapter 4
Longterm superiority of bilateral subthalamic nucleus stimulation over unilateral pallidotomy: four years follow-up of a randomized controlled trial.
Chapter 5
Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a comparison of neuropsychological effects.
Chapter 6
Adverse events of bilateral subthalamic nucleus stimulation in Parkinson’s disease: a systematic review.
Chapter 7
The impact on Parkinson’s disease of electrical parameter settings in STN stimulation.
Chapter 8 General discussion Summary Samenvatting Dankwoord Curriculum vitae
Preface
Parkinson’s disease (PD) is a progressive neurodegenerative disorder clinically characterized by resting tremor, rigidity, bradykinesia, and postural instability. Stereotactic functional neurosurgery is a treatment option in advanced stages of the disease. Our group demonstrated that unilateral pallidotomy is an effective surgical treatment for patients with advanced PD who have severe limitations in functioning despite optimal pharmacologic treatment. In 1993 the Grenoble group introduced the subthalamic nucleus (STN) as a new target for deep brain stimulation (DBS) in PD; other groups confirmed their results in cohort studies. The Neurology and Neurosurgery departments of the Academic Medical Center in Amsterdam took the initiative to perform a multi-centre randomized clinical trial (RCT) comparing effects and adverse events of unilateral pallidotomy with bilateral STN stimulation. All Dutch centres experienced in both types of surgery participated in this study. The results of the RCT comprise the major part of this thesis.
Aims
The main aim of this thesis was to describe the effects and adverse events of bilateral subthalamic nucleus (STN) stimulation in Parkinson’s disease (PD).
Outline
Chapter 1 provides a general introduction of clinical and epidemiological aspects of PD, pharmacological treatment, the history of surgery in PD, and a review on pallidotomy and the two main types of DBS (STN stimulation and globus pallidus internus stimulation). The results of the randomized controlled trial comparing unilateral pallidotomy with bilateral STN stimulation at 6 months, 1 year and 4 years are described in chapter 2, 3, and 4. Chapter 5 describes and compares the neuropsychological effects of unilateral pallidotomy and bilateral STN stimulation at 6 months and 1 year after surgery. Chapter 6 presents a systematic review of the literature on adverse events of bilateral STN stimulation in Parkinson’s disease. In chapter 7 the effects of different stimulation parameter settings on parkinsonian symptoms were evaluated. Chapter 8 discusses the place of bilateral STN stimulation in the treatment of PD and future perspectives of surgery for PD. A summary in English and Dutch concludes this thesis.
1
Parkinson’s disease, pallidotomy, and deep brain
stimulation: an overview
Largely adapted from:
Esselink RAJ, de Bie RMA, Schuurman PR, Bosch DA, Speelman JD. Parkinson’s disease and deep brain stimulation.
Introduction
Parkinson’s disease (PD), which was first described by James Parkinson in 1817, is one of the most prevalent progressive neurodegenerative disorders.1 Approximately 0.3 % of the general population has PD, and it’s prevalence increases exponentially with age;2,3 0.3% for those aged 55 to 64 years, 1.0% for those 65 to 74, 3.1% for those 75 to 84, and 4.3% for those 85 to 94. Five to 10 % of patients have symptoms before the age of 40 (young-onset PD).
PD is characterized by the presence of the following symptoms: (1) rest tremor, (2) bradykinesia or akinesia, (3) rigidity, and (4) postural instability and gait disturbances. There are two important clinical diagnostic criteria sets for PD the so called Gelb criteria and the UK PD Society Brain Bank criteria.4,5 As part of both criteria at least two of the four above mentioned features of parkinsonism need to be present. According to the Gelb criteria tremor or bradykinesia needs to be one of them, according to the UK brain bank criteria only bradykinesia needs to be one of them. PD has to be distinguished from other diseases causing parkinsonism. On the basis of clinical criteria up to 10 - 25% is misdiagnosed.6 There is no biological marker during life that unequivocally confirms the diagnosis and the gold standard for the diagnosis of PD remains postmortem neuropathological examination, with Lewy bodies and Lewy neurites in the substantia nigra and other affected brain regions. The combination of asymmetric symptoms, the presence of resting tremor, and a good response to levodopa best differentiates PD from parkinsonism due to other causes.
Apart from the motor symptoms, PD is often associated with non-motor symptoms such as: (1) autonomic dysfunction (e.g. orthostatic hypotension, blurred vision, constipation, bladder dysfunction, erectile dysfunction), (2) affective and behavioral problems (e.g. depression, anxiety, apathy, and obsessive-compulsive behavior), (3) cognitive impairment (ranging from mild cognitive impairment to dementia), and (4) sleep disturbances (sleep fragmentation, nightmares).
Before the levodopa era Hoehn and Yahr reported a mean duration of PD of 9.7 years (range 1-33) and the mean age at death of PD patients was 67-69 years.7,8 After introduction of levodopa, some studies found that the life expectancy of PD patients increased to 72-73 years and mean disease duration increased to 13-14 years,8,9 others reported a similar disease duration to that in the era before levodopa.10 Eleven to 15 years after disease onset, 55 percent of patients are severely disabled or dead.8
Pathophysiology
End 1980’s animal studies by Albin et al., Alexander et al., and DeLong et al.11-13 shed new light on the basal ganglia-thalamo-cortical loops, and pathophysiological mechanisms in PD. Their proposed model is currently the most accepted model for basal ganglia functioning, although it has limitations (figure 1). The motor circuit originates in the
Figure 1. Schematic diagram of the basal ganglia-thalamocortical circuitry.
GPe = external part of globus pallidus, STN = subthalamic nucleus, SNc = Substantia nigra pars compacta, GPi = internal part of globus pallidus, SNr = substantia nigra pars reticulata,
PPN = pedunculopontine nucleus
Cortex
Striatum
D2 D1SNc
Thalamus
GPe
STN
Gpi / SNr
PPN
Spinal cord
Excitatory (glutamatergic) projection Inhibitory (gaba-ergic) projections Dopaminergic projections (excitatory via D1, inhibitory via D2 receptors)
Excitatory (glutamatergic and cholinergic) projections
precentral motor and postcentral somatosensory cortical areas. Cortical input to the basal ganglia project through the striatum, and the output travels to the globus pallidus internus (GPi) and the pars reticulata of the substantia nigra (SNr) by two parallel pathways, called “direct” and “indirect.” With the exception of the subthalamic nucleus (STN), all intrinsic and output projections from the basal ganglia (putamen, globus pallidus externa (GPe), GPi, and SNr) are mediated by gamma-aminobutyric acid and are inhibitory systems. Projections from the cortex to the striatum and from the thalamus to the cortex are excitatory. The loss of dopaminergic cells in the pars compacta of the substantia nigra (SNc) in PD has differential effects on the activities of the striatal cells in the direct and indirect pathways. In the direct pathway, this leads to a decrease in inhibitory activity from the striatum to the GPi, whereas in the indirect pathway reduction of striatal inhibition from the substantia nigra pars compacta leads to reduced activity in the GPe. Excessive excitation from the STN and GPi results in enhanced inhibition of thalamo-cortical pathways leading presumably to the parkinsonian signs of akinesia and rigidity.
The underlying pathophysiological mechanisms of tremor in PD are still unknown. It is hypothesized that a more selective neuronal loss of medial components in the SNc gives way to single or multiple oscillators in the basal ganglia loops. Connections of the STN with the pallidum, modified by cortical and nigral inputs, allow for the transfer of tremorogenic activity to the thalamus.14,15 Thalamo-cortical interactions, tempered by cerebellar input, generate the final common pathway for tremor production.
Connections between the basal ganglia thalamo-cortical loops and the pedunculo-pontine nucleus (via the STN) are thought to play a role in gait disturbance and postural instability.16
Pharmacotherapy
Levodopa (with a decarboxylase inhibitor) remains the most effective treatment for PD motor symptoms.17,18 Data on prevention and treatment of motor complications of levodopa are non-efficacious and insufficient.17,18
There are several dopamine-agonists, each with its own characteristic receptor binding profile, pharmacokinetic profile, and routes of administration.19 Most of the agonists can be used as monotherapy or as an adjunct to levodopa. Some of the dopamine-agonists are efficacious for the delay of motor complications.
Catechol-O- Methyltransferase (COMT) inhibitors enhance the bioavailability of levodopa and are therefore used as adjuncts to levodopa.20 They are efficacious for the symptomatic treatment as an adjunct to levodopa and for the treatment of motor complications.17,18 Monoamineoxidase-B (MAO-B) inhibitors, amantadine and anticholinergics are efficacious or likely efficacious as symptomatic monotherapy or as adjunct to levodopa, with only mild to moderate benefit.17,18 Anticholinergics are mainly efficacious for the treatment of tremor, but one must be aware of cognitive adverse effects especially in the older patients.
Amantadine is also efficacious for the treatment of dyskinesias.17,18 There is no evidence for a neuro-protective or neuro-toxic effect of the currently available drugs. 17,18
Short comings of pharmacotherapy: motor symptoms
The initial benefits of dopaminergic treatment are usually sustained after long-term use, but after four to six years of treatment motor complications can arise.21 Response fluctuations and dyskinesias are the most common of these problems. They are closely related to dopaminergic therapy because they were not observed before levodopa introduction in the 1960s. Response fluctuations are characterized by “wearing off” or ‘end of dose phenomena”, and sudden unexpected “on-off fluctuations”. The main risk factors for response fluctuations appear to be the duration of dopaminergic treatment,22 the dosage,22,23 and the disease duration at the start of the therapy.21,22 Dyskinesias are abnormal involuntary movements with a choreic, ballistic and/or dystonic character. These are divided according to the time of their appearance after individual doses: a) Peak dose dyskinesias occur at the peak of benefit (on phase), b) biphasic dyskinesias typically occur as mobility improves and/or as it wanes and often have a more dystonic aspect, c) off period dystonia is related to the off phase (most common is the early morning dystonia). The mechanisms responsible for dyskinesias are complex and not fully understood. The threshold for dyskinesias decreases over time.
After four to six years of dopaminergic treatment 40 percent of the patients experience response fluctuations and dyskinesias, which increases to 80-100 percent after 10 or more years of levodopa/dopaminergic therapy.21,24 Response fluctuations and dyskinesias are even more striking in patients with young onset PD who exhibit a marked vulnerability for development of motor complications early after initiation of levodopa.25 In advanced stages of PD, patients frequently cycle between episodes with parkinsonism associated with severe disability (‘off phase’) and episodes with good mobility (‘on phase’), usually with dyskinesias.
Short comings of pharmacotherapy: non-motor symptoms
A substantial proportion of patients with PD develop psychiatric complications of antiparkinsonian drugs treatment. These include vivid dreams, hallucinations, delusions, mania, delirium, confusion, hyper sexuality, pathologic gambling, compulsive shoping, and dopamine dysregulation syndrome.26 Hallucinations (mainly visual) are among the most common treatment-related complications with a prevalence of 15-20%.27,28 If milder symptoms such as illusions or feeling of presence of a person are included, their rate is as high as 40%.29 They can occur early in the course of treatment, but their prevalence rises with duration of disease.
History of stereotactic surgery for PD
In the first half of the 20th century surgery for PD consisted of open surgery in different parts of the nervous system. In 1939 Meyers was the first to performed open surgery in the striatum and ansa lenticularis in patients with parkinsonism.30 Stereotactic neurosurgery in humans was introduced in 1947 by Spiegel and Wycis.31 This technique was based on the work of Clarke and Horsley, who developed the first stereotactic instrument for application of intracerebellar animal experiments.32 The technique was primarily introduced for psychosurgery and in 1948 the first successful operation in a parkinsonian patient was performed. The principle of stereotactic neurosurgery is that any target structure in the brain can be accurately localized with a 3D coordinate frame that is attached to the patient’s skull. The position of target structures is determined relative to the location of specific landmarks in the brain (such as anterior and posterior commissures), visualized by ventriculography, CT, or MRI scanning, using a stereotactic atlas to extrapolate the location of the target nucleus from the landmarks.33 Nowadays with MRI targets can be directly visualized.
Initially the ansa lenticularis and the inner segment of the globus pallidus were the main targets for lesioning in PD.34,35
In 1954 Hassler and Riechtert reported that thalamotomy (by radiofrequency heating) reduced tremor in PD.36 Cooper reported favorable results of ligation of the anterior choroidal artery in parkinsonian patients.37 This, together with difficulty producing consistent benefit with pallidotomy and fear for hemorrhages, led to thalamotomies becoming the most common surgical intervention for PD.
Leksell used a more posteroventral target within the medial pallidum which produced a more consistent benefit.38 In the 1960s, surgery of the sub-thalamic region by lesioning the field H of Forel (= campotomy)39 and the zona incerta40,41 was used as an alternative to thalamic surgery to alleviate tremor and rigidity. The STN was avoided in these procedures for fear of inducing hemiballism.
After the introduction of levodopa in 1967 the number of operations for PD reduced dramatically.42,43 From the mid 1980s, levodopa induced motor complications were recognized and appeared to be persistent despite drug manipulation. In the mean time a new animal model for PD became available, as a by product of synthetic heroine (MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) appeared to cause parkinsonism in humans and animals,44,45 which led to the development of the currently used model for the basal ganglia and a better understanding of the pathophysiology of PD.11-13 Additionally, stereotactic techniques and equipments were improved, and MRI was introduced. All these factors have led to a revival of stereotactic surgery for PD.
In 1987 Benabid et al. described thalamic deep brain stimulation (DBS) as an alternative to thalamic lesioning for tremor-reduction.46 In DBS the stimulation electrode is connected to an internal programmable pulse generator usually located subcutaneously in
the subclavian area, comparable to a pacemaker device. The stimulation is accomplished via one or more of the four contacts on the distal end of the electrode. The pulse generator settings can be adjusted post-operatively by telemetry with respect to electrode configuration, voltage, amplitude, pulse width, and frequency. Thalamic DBS was assumed to be as effective as thalamotomy for tremor reduction, but associated with fewer complications than lesioning, which was later confirmed in a clinical trial.47
Following two publications by Laitinen in 1992, there was renewed interest for the posteroventral pallidotomy in the treatment of advanced PD, which produced improvement in the other motor symptoms of PD besides tremor, most notably dyskinesias.48,49 In 1993 the Grenoble group introduced bilateral STN stimulation for the treatment of advanced PD50 based on the pathophysiological model of PD11-13 and in 1994, Siegfried and Lippitz reported results of bilateral GPi stimulation.51
The exact mechanism of high-frequency DBS (> 100 Hz) is not known although the effect resembles that of lesioning. Various hypotheses are:52 (1) depolarization blocking of neuronal transmission through inactivation of voltage dependent ion channel, (2) jamming of information by imposing an efferent stimulation-driven high frequency pattern, (3) synaptic inhibition by stimulation of inhibitory afferents to the target nucleus, and (4) synaptic depression by stimulation induced neurotransmitter depletion, all leading to a changing of pathological neuronal discharge patterns in the basal ganglia.53
Effects and adverse events of pallidotomy, GPi stimulation, and STN stimulation
In the further part of this chapter we will focus on pallidotomy, GPi stimulation, and STN stimulation in PD, as these are currently the most applied interventions. To date there is almost no indication for thalamic stimulation or lesioning in PD, while it mainly improves tremor.47
Pallidotomy
Two randomized controlled trials comparing unilateral pallidotomy versus medical therapy were conducted with a follow-up period of six months.54,55 In one study 37 patients were randomized, in the other study 36 patients. In both studies off phase motor symptoms as measured with Unified Unified Parkinson’s Disease Rating Scale Rating Scale (UPDRS) motor part (the primary outcome measure in both studies), significantly improved (31 and 32% respectively) in the pallidotomy group, compared to mild worsening of scores in the medication groups (8% and 5%). In the study of Vitek et al. rigidity and tremor sub scores and timed tests contra lateral to the lesion in the pallidotomy group was found. In both trials axial symptoms (gait and postural stability), on phase dyskinesias, and ADL functioning improved in the pallidotomy group, whereas medication did not change. Cohort studies on unilateral pallidotomy showed about the same results.48,56-58
Four cohort studies with a follow-up period of four years after pallidotomy demonstrated that the improvements on off phase motor UPDRS and on phase dyskinesias compared to baseline sustained, whereas ADL functioning returned to the pre-operative level.57,59-61 A systematic review on adverse events of unilateral pallidotomy, including 12 prospective studies with 334 patients, demonstrated 30% risk of adverse effects, and 14% risk of permanent adverse effects. A symptomatic infarction or hemorrhage occurred in 4%. The mortality rate was 1%. The most frequent adverse effects were problems with speech (11%) and facial paresis (8%).62 Neuropsychological assessment revealed that unilateral pallidotomy is relatively safe with respect tot cognition and behavior. The only consistent finding is that left-sided pallidotomy may lead to minor deterioration in verbal fluency.63-66 Bilateral pallidotomy further reduces parkinsonism and dyskinesias, however, the effectiveness is limited by a higher complication rate (such as cognitive impairment, dysarthria and swallowing defects).67-71
Bilateral GPi stimulation
Table 1 summarizes the research findings of short-term follow-up (6 - 12 months) after GPi stimulation. The studies revealed that the improvement of the off phase Unified PD Rating Scale (UPDRS) motor score ranged between 33 and 56%.72-75 Tremor and gait (including posture) improved in most of the selected studies after surgery. Less consistent were improvements of rigidity, bradykinesia, balance, speech, and swallowing. The study of Volkmann et al. demonstrated a waning effect of surgery on separate UPDRS motor items between the six months and one year follow-up assessments after surgery.72
Off phase functioning in Activities of Daily Living (ADL) improved in all studies, but again, the study of Volkmann et al. indicated a waning effect after one year.72
For the on phase, most studies demonstrated an improvement of the total UPDRS motor part, although effects on individual motor symptoms were inconsistent. Ambiguous findings were also observed for on phase data of ADL functioning. On phase dyskinesias improved in all studies between 58 and 89%. The use of PD medication, expressed in levodopa equivalent daily dose (LED), did not change significantly after surgery.
Severe adverse events after bilateral GPi stimulation were limited and included intracranial hemorrhage, infection, and electrode dislodgement. Furthermore problems with speech, gait, and balance were observed. Studies on neuropsychological effects of GPi stimulation were scarce and revealed no significant changes after GPi stimulation.76-78
Bilateral STN stimulation Short-term follow-up (table 2)
Many cohort studies and a few randomized controlled trials with a short follow-up (6 - 12 months) are published on bilateral STN stimulation (Table 2). In these studies the off phase total UPDRS motor part improved 38-67%, with tremor, rigidity and bradykinesia individually improving 70-90%, 25-75%, 30-55%, respectively.64,72,73,75,79-88
Table 1.
R
esults of bilater
al GP
i stimulation at six months or one y
ear follo w-up. DBS PD study Volkmann Volkmann Loher Anderson gr oup 2001 73 2001 72 2001 72 2002 74 2005 75 N umber of patients 41 included 11 11 10 12 included 36 follo w-up data 10 follo w-up data Follo w-up 6 months 6 months 1 y ear 1 y ear 1 y ear Study design Cohor t Cohor t Cohor t Cohor t Randomiz ed (pr ospectiv e) (historical) (historical) (pr ospectiv e) contr olled trial
UPDRS motor par
t off/on 33*/27 * 56*/50* 51*/45* 41*/28* 39*/6
UPDRS ADL off/on
36*/31* 55*/51 42/52 34*/34* 24*/0 Tr emor off/on 59*/85* 88*/67 75/67 80*/ 79*/100 Rigidity off/on 30*/22 64/57 50/50 46*/ 47*/50 Bradykinesia off/on 26*/22 52*/47 48/13 40*/ 33*/- 14 Axial off/on 40*/0 Speech off/on 38/25 31/50 (speech + swallo wing) (speech + swallo wing) G ait off/on 35*/33 45*/45 64*/36 32*/26 (postur e+gait) (postur e+gait)
Postural stability off/on
27*/50* 26/14 Dyskinesias on 67 * 58 * 80 * 71* 89* LED change + 3 - 16 - 28 + 5 - 3 All v alues r epr esent per centages of change of pr e-operativ e scor es compar ed with follo w-up scor es unless other wise stated Positiv
e signs imply impr
ov
ement, negativ
e signs deterioration, ex
cept for LED (- means decr
ease in medication; + means incr
ease) UPDRS = U nified P ar kinson ’s D
isease Rating Scale
ADL = activities of daily living LED = lev
odopa equiv
alent daily dose
*= significant differ
ence compar
R
esults of bilater
al STN stimulation at six months to one 1 y
ear follo w-up. N o UPDRS UPDRS Tr emor Rigidity Brady-Axial G ait Speech Balance Dyskinesias LED patients motor ADL Off/O n Off/O n kinesia Off/O n Off/O n Off/O n Off/O n duration/ reduction Off/O n Off /O n Off/O n sev erity 79 24 49* / NS 55* / 80* /43 68*/50* 56* /12 55* /-17 22 /-44 61* /36 55 / 64 ±-50* 80 23 67* / 55* 66* / 77* /77* -61* 73 91 51* / 26* 44* /NS 79*/56* 61*/33* 42* /19* 55* /30* 50* /25 /50* -37* 72 16 60* / -9 56* /18 88*/100 75* /0 48* /-43 59* /25 24 /-38 / 90* -65* 81 38 48* / 37* / 72* -36* 82 20 45* / 0 37* /NS 76* / 62* / 30* / 46* / 92* /92* -79* d 2002 85 33 64* / 54* 66* /27 90* /76 72*/66* 55* /49* 64* /70 25 /14 62*/40* 86* /86* -19* zog 2003 83 48 51* / 21? 53* / 72* / 60* / 53* / 55* / 77* /85* -49* isman 84 25 51* / 15 33* /13 85*/55* 42* /20 40* /10 55* /38 59 /83* -45* 86 43 38* / NS 32* / 74* /NS 26* /NS 30 / NS 33* /NS 38* /NS -44* 87 33 51* / 13* 70* /33* 86* /78 48* /27 38* /5 60* /26 24 /29 49* /44 80* /87* -53* 88 27 42* / 7 17* / 75* / 58* / 39* / 10 / NS / significant -39* 64 20 49* / 38* 46* /25 ? 50* /100* -33* 75 12 48* / 0 28* /0 89* /NS 48* /NS 44* /NS 44* /NS DRS 62* -38* alues r epr esent per centages of change of pr e-operativ e scor es compar ed with follo w-up scor es unless other wise stated.
e signs imply impr
ov
ement, negativ
e signs deterioration, ex
cept for LED (- means decr
ease in medication; + means incr
ease)
nified P
ar
kinson
’s D
isease Rating Scale
odopa equiv
alent daily dose
ed to pr
e-operativ
e v
Axial symptoms, gait and balance improved 35-65%, but speech did not. The off phase UPDRS ADL part showed an improvement of 30-70%.
The on phase UPDRS motor part improved by 15-55% in approximately half of the studies, whereas the other studies did not find a significant difference. Most studies did not show improvement in on phase individual symptoms tremor, rigidity, bradykinesia, or axial symptoms, including speech, gait and balance and on the UPDRS ADL part. Dyskinesias were measured in different ways and were reduced by 50-100% in nearly all studies. Dopaminergic medication could be reduced between 20 and 80% (mean 44%). Serious adverse events after bilateral STN stimulation include intracranial hemorrhage (1-2%), infection (1-3%), and cognitive decline (1-2%). Postoperative delirium or psychosis was the most frequent transient adverse event, speech problems were the most frequent persistent event, depression occurred in up to 10% of the patients, being reversible in most cases. Furthermore eyelid apraxia, gait and balance problems, disabling dyskinesias, hardware problems (often reversible) were observed.
Patient selection, evaluation, and follow-up
Clinical practice has taught us that the success of surgery largely depends on the careful selection of the appropriate patients, as a consequence selection criteria became more specified during the last decade. The emphasis should lie on selecting patients with good expected benefit and identifying those at risk for adverse events.
Patients eligible for stereotactic surgery should have: 1. Advanced idiopathic PD
2. Unequivocal reduction in off phase symptoms on levodopa (not necessary for tremor) and/or
3. Severe response fluctuations, dyskinesias or parkinsonism despite optimal adjustment of antiparkinsonian medication and/or
4. PD with dominating pharmacological treatment resistant tremor Contra indications for surgery are:
1. Dementia
2. Major depression or psychosis at time of surgery
3. History of severe psychosis and (hypo)mania that was not dopaminergic induced
4. Balance and/or speech as the most disabling symptom
5. General health condition making stereotactic surgery hazardous (e.g. cardiopulmonary disease)
6. Frail patients above 70 years of age
7. Still being largely ADL dependent in the best on phase (in case of severe tremor thalamic surgery can still be considered)
8. Severe brain atrophy or vascular encephalopathy on brain imaging (CT or MRI)
The Core Assessment Program for Neurosurgical Interventions and Transplantation in PD (CAPSIT-PD) protocol is generally used as a guideline for patient evaluation.89 Follow-up visits after STN and GPi stimulation are needed for adjustment of medication and stimulation parameters, requiring specific knowledge about programming the pulse generator.
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2
Unilateral pallidotomy versus bilateral subthalamic
nucleus stimulation in Parkinson’s disease:
a randomized, observer-blind, multi-center trial.
Neurology 2004;62:201-7
Abstract
Objective
To compare the efficacy of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson disease (PD) in a randomized, observer-blind, multicenter trial.
Methods
Thirty-four patients with advanced PD were randomly assigned to have unilateral pallidotomy or bilateral STN stimulation. The primary outcome was the change from baseline to 6 months in the motor part of the Unified PD Rating Scale (motor UPDRS) in the off phase. Secondary outcomes were parkinsonian symptoms in the on phase (motor UPDRS), dyskinesias (Clinical Dyskinesia Rating Scale and dyskinesias UPDRS), functional status (activities of daily living UPDRS and Schwab and England scale), PD Quality of Life questionnaire, changes in drug treatment, and adverse effects.
Results
The off phase motor UPDRS score improved from 46.5 to 37 points in the group of pallidotomy patients and from 51.5 to 26.5 in the STN stimulation patients (p = 0.002). Of the secondary outcome measures, on phase motor UPDRS and dyskinesias UPDRS improved significantly in favor of the STN stimulation patients. Reduction of antiparkinsonian drugs was greater after STN stimulation than after pallidotomy. One patient in each group had a major adverse effect.
Conclusions
Bilateral STN stimulation is more effective than unilateral pallidotomy in reducing parkinsonian symptoms in patients with advanced PD.
Introduction
Patients with advanced Parkinson disease (PD) and long-term pharmacologic treatment often have response fluctuations and dyskinesias. Frequently they cycle between episodes with parkinsonism associated with severe disability (off phase) and episodes with good mobility (on phase), usually with dyskinesias. Unilateral pallidotomy is an effective surgical treatment for patients with advanced PD who have severe limitations in functioning despite optimal pharmacologic treatment.1-3 Severity of parkinsonian symptoms in the off phase as measured by the motor examination section of the Unified PD Rating Scale4 (motor UPDRS) improves on average 30%. Levodopainduced dyskinesias decrease by 50% after surgery. Bilateral pallidotomy further reduces parkinsonian symptoms and dyskinesias; however, its effectiveness is limited owing to a high complication rate.5-7 Over the last 5 years, cohort studies have been reported, describing the effects of bilateral subthalamic nucleus (STN) stimulation in patients with advanced PD8-12; off phase motor UPDRS improved with approximately 50%, dyskinesias ameliorated significantly, and antiparkinsonian drugs could be reduced in the majority of patients. We conducted a randomized, observer-blind, multicenter trial to determine whether bilateral STN stimulation is more effective than unilateral pallidotomy in reducing severity of off phase parkinsonian symptoms and to compare the effects of both procedures on parkinsonian symptoms in the on phase, dyskinesias, functioning, quality of life, drug treatment, and adverse effects.
Methods
Patients
Patients were recruited from all four Dutch hospitals experienced in pallidotomy and STN stimulation for PD between April 2000 and May 2001. Eligible patients had idiopathic PD13 with an unequivocal reduction in off phase symptoms on levodopa, and at least one of the following symptoms despite optimal pharmacologic treatment: severe response fluctuations, dyskinesias, or bradykinesia. Exclusion criteria were predominantly unilateral symptoms without severe response fluctuations, severe brain atrophy on CT or MRI scans, Hoehn and Yahr stage14 4 or 5 in the best on phase, Dementia Rating Scale15 score of less than 120, psychosis or depression at inclusion, previous stereotactic operation, or a physical condition making stereotactic surgery hazardous. At inclusion the neurologist or neurosurgeon at the treatment center registered the patient characteristics (age, sex, duration of disease, age at disease onset, and medication). All patients gave their written informed consent. The medical ethics committees of the participating hospitals approved the study.
Study design
assessment at the center of inclusion. R.M.A.B works and assessed the patients in center 1 but was not involved in the surgery or follow-up of patients. R.A.J.E. was involved in surgery and follow-up of patients in center 1 and she did the assessments in centers 2, 3, and 4. After baseline assessment, the necessary data were faxed for randomization to the Department of Clinical Epidemiology and Biostatistics (KEB) at the Academic Medical Center in Amsterdam. Patients were allocated randomly to unilateral pallidotomy or to bilateral STN stimulation by a computer program at the KEB. A minimization procedure16 was done according to severity of PD (Hoehn and Yahr ≤ 3 versus stage 4 or 5 in the off phase) and treatment center. The result of randomization was faxed to the neurologist or neurosurgeon at the treatment center. Six months after surgery, the outcome assessment was performed by the same assessor, who was blinded for the treatment allocation. The patients were instructed not to tell the assessor the treatment they received. Before assessment, a nurse provided bald patients with a headcap to conceal the presence of operation scars. At the end of the follow-up assessment the blinded assessor registered in a structured questionnaire which operation he thought the patient had had. We hypothesized that bilateral STN stimulation is more effective than unilateral pallidotomy in reducing severity of off phase parkinsonian symptoms.
Surgical treatment
Within 1 month after randomization, patients underwent stereotactic surgery under local anesthesia. Ventriculography, MRI, or CT scan was used to determine the position of the target structure. Semi-microelectrode recording was used in one STN patient. In patients assigned to unilateral pallidotomy the most severely affected side was operated. The target coordinates for pallidotomy were 2 mm anterior to the midcommissural point, 5 mm below the intercommissural line, and 22 mm lateral to the midplane of the third ventricle, and for STN stimulation 0 to 3 mm behind the midcommissural point, 4 to 6 mm below the intercommissural line, and 11 to 13 mm lateral to the midplane of the third ventricle according to the coordinates normally used in each center. A macroelectrode was used for test stimulation (1.0 x 4.0 mm bare tip) over a 10 mm distance for each trajectory to identify the optimal target. The final target location was the position where the parkinsonian symptoms decreased with the lowest current intensity of high frequency stimulation (100 µs and 130 Hz) and where the fewest side effects occurred with high and low frequency stimulation (maximum 6 V, 100 µs, and 130 Hz and 2 Hz). For pallidotomy radiofrequency thermo lesions (80 °C for 60 seconds) were made in 2 mm steps with the same macroelectrode. In STN stimulation a four contact electrode (model DBS-3389, Medtronic, Minneapolis, MN) was implanted with the second deepest contact at the final target location. The electrodes were connected to the implantable pulse generator (Itrel II, Soletra, or Kinetra, Medtronic), which was placed subcutaneously in the subclavian area under general anesthesia in the same session in two
centers, and after a few days of satisfying external stimulation in the other two centers.
Outcome measures
The clinical rating scales and their possible score ranges are listed in table 1. Assessments were done at baseline and at 6 months after surgery in standardized off and on phases. The off phase was defined as the condition of the patient after withholding antiparkinsonian drugs for 12 hours overnight. The on phase was the condition 1 hour after a suprathreshold levodopa dose. To analyze changes in drug treatment and to calculate the suprathreshold levodopa dose we pooled different drugs in a levodopa equivalent dose according to the following conversion formula: regular levodopa dose x 1 + slow release levodopa x 0.75 + bromocriptine x 10 + apomorphine x 10 + ropinirole x 20 + pergolide x 100 + pramipexole x 100 + [regular levodopa dose + (slow release levodopa x 0.75)] x 0.2 if taking entacapone.17,18 The suprathreshold levodopa dose was based on the preoperative usual first morning dose of antiparkinsonian drugs and calculated as follows: 120% of the levodopa equivalent dose for levodopa + 50% of the levodopa equivalent dose for dopamine agonists. The same dose was given at baseline and 6 months assessment. During the course of the study changes in drug treatment were allowed in both groups. At 6 months assessment the stimulator was turned on. The primary outcome was the change from baseline to 6 months in the off phase motor UPDRS.4
Secondary outcomes included symptom scales, functional scales, a quality of life scale, changes in drug treatment, and adverse effects. The symptom scales consisted of the on phase motor UPDRS4 (parkinsonian symptoms), Clinical Dyskinesia Rating Scale (dyskinesias severity during the on phase),19 and the dyskinesias UPDRS items 32 and 33 (questionnaire about duration and severity of dyskinesia in the past week).4 Functional scales in off and on phases were the activities of daily living (ADL) UPDRS4 and the Schwab and England scale.4 Patients rated their quality of life with the PD Quality of Life questionnaire (PDQL).20
The neurologist at the treatment center examined the patients and registered adverse effects during and immediately after surgery, during the first week after surgery, and during the 6 months after surgery. A photocopy of every completed adverse effect form was sent to the data monitoring and safety committee. The members of this committee were not otherwise involved in the study. No explicit stopping rules were formulated. Six months after surgery the stimulation parameters were registered. The protocol also included a neuropsychological assessment, timed tests, and patient diaries, but these results will be reported separately.
Statistical analysis
The sample size calculation for the primary outcome measure was based on an unpaired t-test with (two-sided)œ = 0.05,ß = 0.20, and a SD of 10 points in change scores. A
difference of 10 points in change scores between the pallidotomy patients and the STN patients was considered a clinical important difference. We estimated that at least 34 patients were required in the study to detect significant differences. Analysis was done according to the intention-to-treat principle. Because most outcome scores turned out to be non-normally distributed all outcome measures were described in median scores, including interquartile range. The change scores of the pallidotomy and STN stimulation patients were compared with the Mann-Whitney U test. The score of blinding was evaluated using the x2 test.
Role of the funding sources
The study was designed, conducted, analyzed, interpreted, and the article was written and submitted for publication by the investigators independently of all funding sources.
Results
Patients and treatment
Thirty-four patients were enrolled: 14 were randomly assigned to unilateral pallidotomy and 20 to bilateral STN stimulation (figure). The baseline characteristics of the patients Table 1. Types of clinical outcome and measurement instruments used during the assessment
Types of clinical outcome Type of instrument Best score Worst score Phase Primary outcome
Motor symptoms Motor UPDRS 0 108 Off
Secondary outcome Symptom scales
Motor symptoms Motor UPDRS 0 108 On
Dyskinesia rating scale CDRS 0 28 On
Dyskinesia questionnaire Dyskinesias UPDRS On
Item 32* 0 4
Item 33* 0 4
Functional scales
ADL disability ADL UPDRS 0 52 Off/on
ADL disability Schwab and England 100 0 Off/on
Quality of life scale
Quality of life PDQL* 37 185 On
* The dyskinesias UPDRS and PDQL questionnaires were administered in the on phase, but patients were asked to rate their perceived dyskinesias and quality of life irrespective of off and on phase.
ADL=activities of daily living; UPDRS=Unified Parkinson’s Disease Rating Scale; CDRS=Clinical Dyskinesia Rating Scale; PDQL =Parkinson’s Disease Quality of Life questionnaire.
are shown in table 2. In the pallidotomy patients a median of two thermo lesions (range one to four) were made. One pallidotomy patient committed suicide 3 weeks after surgery. Data on 33 patients were therefore available for analysis. One STN patient was operated 4 months after baseline assessment for logistic reasons. Although outcome assessment in this patient was done 2 months after the operation the result of surgery was good and stable at that time. One STN patient was reoperated 3 months after the first operation because of electrode displacement. In two STN patients the assessor was unblinded; these patients told the assessor which operation they had had. In 31 patients the assessor was still blinded at the follow-up assessment. The assessor registered the correct operation 24 times and 7 times did not (p = 0.004).
Primary outcome
The median off phase motor UPDRS score in the group of pallidotomy patients improved from 46.5 to 37 points (20%) and in the group of STN patients from 51.5 to 26.5 (49%; table 3). There was a 12-point difference in median change scores between the two groups in favor of the STN patients (p = 0.002). Repeated analysis, without the data of the two STN patients for whom the assessor was unblinded, showed the same result. Repeated analysis while the patient who committed suicide was assigned the highest change score of the pallidotomy group on the primary outcome measure at follow-up showed the same result.
Figure. Study profile. STN = subthalamic nucleus.
34 patients were included, had baseline assessment in off and on phases, and were radomized
Allocated to and had unilateral Allocated to and had bilateral
pallidotomy (n=14) STN stimulation (n=20)
Lost to follow up Lost to follow up
(n=1, suicide) (n=0)
Completed study Completed study
Table 2. Baseline characteristics of the patients
Characteristics Pallidotomy, n = 14 STN stimulation, n = 20 Demographic variables
Age, y* 62 (57–68) 61 (55–66)
Sex, male/female 6/8 6/14
Duration of disease, y* 11 (9–16) 12 (9–17)
Age at disease onset, y* 47.5 (44–57) 46 (39–55)
Medication, daily levodopa equivalent dose* 1,260 (926–1,763) 935 (514–1,378)
Side of pallidotomy, right/left 10/4 —
Minimization variables, no. of patients
Hoehn and Yahr off ≤3 6 8
Hoehn and Yahr off 4 or 5 8 12
Center 1 7 10
Center 2 0 1
Center 3 3 5
Center 4 4 4
Clinical rating scales* Symptoms scales
Motor UPDRS off/on 46.5 (34–61)/15.5 (12–25) 51.5 (42–58)/21 (13–27)
CDRS on 9 (6–11) 8 (5–11)
Dyskinesias UPDRS on
Item 32 2 (1–2.3) 2 (2–3)
Item 33 2 (0.8–3) 2 (1–2.8)
Functional scales
ADL UPDRS off/on 27.5 (25–30)/10 (8–15) 27 (21–31)/10 (7–11) Schwab and England off/on 50 (40–70)/90 (80–90) 55 (40–70)/90 (80–90)
PDQL 111.5 (101–123) 99 (86–114)
* Values presented are medians (interquartile range).
STN = subthalamic nucleus; UPDRS = Unified Parkinson’s Disease Rating Scale; CDRS = Clinical Dyskinesia Rating Scale; CDRS = Clinical Dyskinesia Rating Scale; ADL = activities of daily living; PDQL = Parkinson’s Disease Quality of Life questionnaire.
Secondary outcomes
Off phase assessment
We found an improvement on the ADL UPDRS and the Schwab and England scale in both groups (see table 3). For the Schwab and England scale the difference in improvement between the groups tended to be in favor of the STN patients.
On phase assessment
For on phase assessment the median motor UPDRS score in the pallidotomy patients worsened from 15.5 to 19 points and improved in the STN patients from 21 to 13, with a difference in median change scores of six points between the groups (p = 0.02; table 4). The median duration of dyskinesias (UPDRS item 32) did not improve in the pallidotomy patients and improved one point in the STN patients (p = 0.004). The severity of dyskinesias (UPDRS item 33 and Clinical Dyskinesia Rating Scale), ADL UPDRS, and PD Quality of Life questionnaire improved in both groups.
Drug treatment and stimulation parameters
The median daily levodopa equivalent dose in the pallidotomy patients was reduced by 12% from 1,260 to 1,110 and in the STN patients by 33% from 935 to 625 (p = 0.02). Two patients in the STN group used apomorphine before operation. In both patients apomorphine was stopped postoperatively. The median voltage of stimulation was 2.3 V (range 1.4 to 3.5), pulse width 60 µs (range 60 to 90), and frequencies 145 Hz (range 100 to 185). For STN stimulation it took weeks, sometimes months, before an optimal effect was established with frequent follow-up visits to adjust stimulation parameters and medication.
Adverse effects
Table 5 lists the adverse effects immediately after surgery and after 6 months follow-up. Ten of the 14 pallidotomy patients and 9 of the 20 STN patients had adverse effects. Adverse effects were persistent in 9 pallidotomy patients and in 8 STN patients. Two adverse effects were severe. One pallidotomy patient committed suicide 3 weeks after a successful pallidotomy; preoperatively she had symptoms of an anxiety disorder. One STN patient had severe fluctuating cognitive, behavioral, and mood disorders after the operation, not affected by switching off the stimulator. Brain CT did not show new lesions, but both electrodes appeared to be displaced and were therefore replaced 3 months later. Six months after the first operation neuropsychological examination showed severe cognitive deterioration. At present she stays in a nursing home. Six STN patients had emotionally lability versus none in the pallidotomy group. Three STN patients had equipment-related adverse effects; one patient had a tight extension lead in the neck, and in one center in the first two patients who got a Kinetra pulse generator the electrodes were displaced.
Table 3.
Primar
y and secondar
y outcome scor
es of clinical r
ating scales for standar
diz
ed off phase assessment*
Pallidotomy , n=14 STN stimulation, n=20 O utcomes Baseline 6 months M edian change Baseline 6 months M edian change p Value Primar y outcome M otor UPDRS 46.5 (34–61) 37 (23–45) 7 (5–16) 51.5 (42–58) 26.5 (20–39) 19 (13–27) 0.002 Secondar y outcome
Functional scales ADL UPDRS
27.5 (25–30) 18 (15–28) 7 (1–14) 27 (21–31) 14.5 (12–18) 12 (6–16) 0.15 Schwab and E ngland 50 (40–70) 80 (45–80) 10 (0–25) 55 (40–70) 80 (73–90) 20 (10–38) 0.08 Table 4. Secondar y outcome scor es of clinical r
ating scales for standar
diz ed on phase assessment* Pallidotomy , n=14 STN stimulation, n=20 Secondar y outcomes Baseline 6 months M edian change Baseline 6 months M edian change p Value Symptoms scales M otor UPDRS 15.5 (12–25) 19 (8–26) 1 ( 7–5) 21 (13–27) 13 (7–21) 7 (2–9) 0.02 CDRS 9 (6–11) 3 (1–7) 3 (1–6) 8 (5–11) 3.5 (2–6) 4.5 (1–6) 0.62
Dyskinesias UPDRS† Item 32
2 (1–2.3) 1 (1–2) 0 (0–1) 2 (2–3) 1 (0.3–1) 1 (1–2) 0.004 Item 33 2 (0.8–3) 0 (0–0.5) 1 (0–3) 2 (1–2.8) 0 (0–1) (0–2) 0.7
Functional scales ADL UPDRS
10 (8–15) 11 (6–15) 2 ( 3–3) 10 (7–11) 7.5 (4–11) 3 (1–4) 0.16 Schwab and E ngland 90 (80–90) 90 (80–90) 0 (0–10) 90 (80–90) 90 (90–90) 0 (0–10) 0.82 PDQL† 111.5 (101–123) 104 (87–119) 13 ( 9–25) 99 (86–114) 76 (67–89) 18 (8–36) 0.15 * Values pr esented ar e medians (inter quar tile range). Positiv e signs imply impr ov ement, negativ e signs deterioration. † The dyskinesias UPDRS and PDQL questionnair es w er e administer
ed in the on phase, but patients w
er
e asked to rate their per
ceiv
ed dyskinesias and quality of life irr
espectiv
e of off and on phase.
STN subthalamic nucleus; UPDRS U nified Par kinson ’s D isease Rating Scale; CDRS Clinical Dyskinesia Rating Scale; ADL activities of daily living; PDQL Par kinson ’s D isease Q
uality of Life questionnair
Table 5. Secondary outcome adverse effects
Pallidotomy, n=14 STN stimulation, n=20
One week after surgery Six months after surgery One week after surgery Six months after surgery None → 1 Suicide 1 Confusion, emotional → 1 Electrodes displaced
lability, anxiety, and replaced, delusions and confusion, shortterm memory emotional lability,
complaints, anxiety, delusions,
mild word-finding shortterm memory problems, perseveration, complaints, mild and mild disorientation word-finding to time and place problems,
perseveration, and mild disorientation
to time and place,
increased drooling 1 Tendency to collapse → None 1 CSF leakage; external → 1 Drooling, and unstable gait lumbar drain, bedridden worsening of during 5 days for 3 days, completely emotional lability,
recovered and postural instability 1 Transient confusion → 1 Memory complaints 1 Transient confusion → None
None →1 Dysarthria, reverses 1 Electrode displaced, → 1 Increased drooling left/right and reverses replaced during
order of numbers IPG implant
None → 1 Mild emotional
lability, mild dysphasia, dysarthria, dysphagia, and postural instability None → 1 Erectile dysfunction None → 3 Mild emotional
and transient global lability amnesia
None → 2 Drooling None → 1 Extension wire
strains in neck None → 1 Drooling, mild word
fluency disturbance None → 1 Drooling, postural
instability, freezing, mild concentration problems
None → 1 Mild eyelid apraxia STN = subthalamic nucleus.
