Surgical Therapies for REVIEW ARTICLE

Parkinson Disease

C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Ashley E. Rawls, MD, MS

ABSTRACT
PURPOSE OF REVIEW: Parkinson disease (PD) is a progressive
neurodegenerative disorder that is often difficult to manage with
medications alone. This article reviews the current therapeutic surgical
interventions for PD, patient selection criteria, timing of patient referral to
surgical services, procedure overview, and future directions.

Adaptive, or closed-loop, deep brain stimulation is a

RECENT FINDINGS:
promising therapy that can detect ongoing circuit changes and deliver
appropriate stimulation based on the patient’s dominant symptom and
level of dopaminergic medication.

SUMMARY: Patients with PD can benefit from surgical interventions that can
be added to their medication regimen. These patients should be referred
to comprehensive centers that offer complete multidisciplinary screening
CITE AS:
evaluation to ensure appropriate patient selection and intervention CONTINUUM (MINNEAP MINN)
selection. With the appropriate surgical intervention and continued 2022;28(5, MOVEMENT DISORDERS):
1301–1313.
management from their care team, patients with PD can maximize their
quality of life. Address correspondence to
Dr Ashley E. Rawls, University of
Florida Norman Fixel Institute
for Neurological Diseases,
INTRODUCTION 3009 SW Williston Rd,
Gainesville, FL 32608,

P
arkinson disease (PD), the second most common neurodegenerative ashley.rawls@neurology.ufl.edu.
disorder after Alzheimer disease, involves continued degeneration of
RELATIONSHIP DISCLOSURE:
dopaminergic neurons in the substantia nigra, which leads to clinical Dr Rawls has received personal
signs of resting tremor, bradykinesia, and rigidity.1 Presynaptic compensation in the range of
storage of dopamine in neurons in the striatum acts as a buffer against $500 to $4999 for serving as an
editor, associate editor, or
fluctuation in plasma levodopa levels.2 Over time, these dopaminergic neurons editorial advisory board
are lost, and the clinical response to levodopa starts to follow plasma levels more member for JAMA Neurology
closely.2 As a result, patients develop more significant treatment-related motor and as a physician expert
panelist with Mediflix, Inc.
fluctuations, increased motor symptoms, worsening nonmotor symptoms, and
an overall worsening quality of life.3 Those with advanced PD are also at an UNLABELED USE OF

increased risk for cognitive and psychiatric issues.2 PRODUCTS/INVESTIGATIONAL

USE DISCLOSURE:
Surgical therapies for PD began in the early 1900s with lesioning techniques.4 Dr Rawls discusses the
Deep brain stimulation (DBS) was introduced in 1987, followed by levodopa/ unlabeled/investigational use of
closed-loop deep brain
carbidopa intestinal gel infusion systems in 2015, and then MRI-guided focused stimulation for the treatment of
ultrasound (MRIgFUS) in 2016. These treatment options are not cures but are Parkinson disease.
ways to provide relief for the levodopa-responsive symptoms of PD. Like other
medications and procedures used to treat PD, these surgical interventions do not © 2022 American Academy
reverse, slow down, or stop disease progression but are used to manage the of Neurology.

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https://doi.org/10.1212/con.0000000000001160
SURGICAL THERAPIES FOR PARKINSON DISEASE

symptoms associated with PD. Refer to TABLE 3-1 for a simplified overview of
surgical options in PD. This article explores the surgical and procedural
interventions for patients with PD, patient selection criteria, procedure
overview, and treatment outcomes.

DEEP BRAIN STIMULATION

DBS uses electrical impulses provided by a fully implantable system to modulate
the three main symptoms of tremor, bradykinesia, and rigidity that are normally
levodopa responsive in patients with PD.5 DBS provides an adjustable and
reversible means of targeted therapy to modulate the pathologic state
contributing to these symptoms.5 The primary goal of DBS surgery is to improve
disabling or troublesome motor symptoms that have persisted despite optimized
medical therapy.6 With this in mind, the three broad indications for DBS in
patients with PD are (1) a very disabling off state that occurs more than 20% of
the day while awake; (2) troublesome dyskinesias when receiving optimal
medical therapy; and (3) treatment of patients with tremor that is inadequately
controlled despite optimized medical therapy (CASE 3-1).
All surgical candidates must have the diagnosis of clinically probable PD,
which can be evaluated via the Parkinson’s UK Brain Bank or Movement
Disorders Society criteria.6-8 The diagnosis of PD must be fairly certain, as
atypical forms of parkinsonism (eg, multiple system atrophy, progressive
supranuclear palsy, corticobasal syndrome, vascular parkinsonism,
neuroleptic-induced parkinsonism) have generally unfavorable outcomes with
DBS and are therefore part of the exclusionary conditions.6 Red flags indicating
that a patient may have an atypical parkinsonism include early falls, poor
levodopa response (except for resting tremor), vertical gaze palsy, early severe
autonomic dysfunction, and significant early cognitive impairment.6 Some
centers may survey a patient for at least 5 years following PD diagnosis to verify
that the diagnosis is not an atypical parkinsonism.6

TABLE 3-1 Simplified Overview of Surgical Options for Parkinson Disease

MRI-guided
Deep brain focused Levodopa/carbidopa Stereotactic
stimulation ultrasound intestinal gel infusion radiosurgery

Unilateral therapy only X X

Permanent implanted foreign bodies X X

Helps levodopa-resistant tremor X X X

Contraindicated in patients with severe X X X

cognitive impairment or dementia

Requires patient to be able to tolerate X X X

MRI scan

Requires several months after X X

procedure to titrate to optimal control

MRI = magnetic resonance imaging.

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 In 1999, selection criteria for DBS were created in the form of the Core
Assessment Program for Surgical Interventional Therapies in Parkinson’s Disease
(CAPSIT-PD).9 They were designed to facilitate clinical research but were then
also used for guidance in the clinical practice of DBS centers globally.9 Briefly,
CAPSIT-PD recommended that a patient should have a diagnosis of idiopathic
PD and a minimum disease duration of 5 years to exclude people with atypical
parkinsonism.9 The next recommendation from CAPSIT-PD was confirming
dopaminergic responsiveness via a levodopa or apomorphine challenge test,
demonstrating at least a 33% decrease in the Unified Parkinson Disease Rating
Scale (UPDRS) part III score during the best on medication state.9
Patients considering DBS should be referred to an experienced surgical center
where their candidacy can be assessed by a multidisciplinary team, including a
movement disorders–trained neurologist, stereotactic or functionally trained
neurosurgeon, psychiatrist, neuropsychologist, physical therapist, occupational
therapist, and speech therapist.6 These teams may be further augmented by a
social worker, nutritionist, and financial counselor.6 As part of the workup for
surgical candidacy, patients will need to have a brain MRI and
neuropsychological testing within 1 year prior to DBS surgery.6 Ideal DBS
candidates are younger, have little or no cognitive impairment, have motor

A 52-year-old woman presented with worsening symptoms of Parkinson CASE 3-1

disease (PD). The patient had presented 4 years earlier with symptoms of
bilateral asymmetric resting tremor, body stiffness, rigidity, and
decreased unilateral arm swing and shortly thereafter was diagnosed
with young-onset PD. She was prescribed antiparkinsonian medications,
which significantly improved her symptoms of rigidity and bradykinesia;
however, she continued to have bilateral hand tremor that was
uncontrolled despite best medical management.
The patient wished to have better control of her tremor bilaterally,
which was interfering with her job. Deep brain stimulation (DBS) was
considered the best surgical option for this patient, as she was young and
therefore would likely need therapy titration as PD progressed, and she
did not have significant medical comorbidities. Additionally, the patient
wanted control of her bilateral tremor, which could be addressed with
DBS, as focused ultrasound and lesional therapies are currently
performed unilaterally because of potential side effects.

This case exemplifies how to assess a patient appropriately for DBS for PD COMMENT
treatment, particularly for tremor that is inadequately treated despite
optimized medical therapy. The patient’s tremor did not appear to be
levodopa responsive, so levodopa/carbidopa intestinal gel infusion was
unlikely to treat this tremor effectively. Although this patient’s tremor did
not appear to be levodopa responsive, resting tremor responds well to DBS
regardless of medication responsiveness. It would have been reasonable,
therefore, for the physician to refer this patient to an experienced surgical
center with a multidisciplinary team to assess the patient’s candidacy.

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SURGICAL THERAPIES FOR PARKINSON DISEASE

symptoms that fluctuate throughout the day, and are high functioning when
their medications are optimized. While there is not a specific age limitation for
this procedure, there are inherent surgical risks and medical comorbidities that
increase with age, and many surgical centers are reasonably reluctant to operate
on any patients aged 80 years or older.6
PD symptoms that are responsive to levodopa can be improved with DBS;
however, an exception to this is resting tremor, which may not be levodopa
responsive but can still improve with DBS.
The ability of DBS to improve levodopa-responsive PD symptoms (ie, resting
tremor, bradykinesia, and rigidity) should be discussed with the patient and their
caregiver early in the treatment course.6 However, symptoms that do not
respond well to levodopa, including gait problems, postural instability, and
speech difficulty, do not respond well to DBS.6 The one consistent exception to
this rule is that resting tremor can be refractory to levodopa treatment yet
respond well to DBS.6 Patients with tremor-predominant PD are often ideal
candidates for DBS therapy, and tremor that is inadequately treated despite
optimized medical therapy is one of the three primary indications for considering
DBS in a patient with PD.
Medical clearance should be obtained prior to surgery, as medical
comorbidities such as obesity, cardiac conditions, and pulmonary conditions can
increase surgical risk. Care should be taken to thoroughly evaluate patients for
neuropsychological performance below the expected norms for their age and
education level, as patients with pronounced executive and memory impairment
have a higher postoperative risk for worsened cognitive dysfunction.6 Cognitive
impairment severe enough to be categorized as dementia is generally an
exclusion for DBS surgery.
Risks of the surgery include infection of the implanted system, brain
hemorrhage, cognitive decline, and exacerbation of preexisting gait issues or
mood problems.6 These serious risks are reported in 1% to 5% of patients,
although this may differ between institutions.6
DBS surgery may be performed bilaterally at the same time or with each
side staged at different times, depending on the preference of the neurosurgeon
and the surgical center. Regardless, patient recovery generally takes several
days to weeks.6 In addition, optimal programming of the DBS device requires
several neurology clinic visits that occur over the course of 6 months after the
surgery.6 This expectation that improvement happens progressively over
6 months, rather than all at once, is critical for patients and families to
understand. Once programming is optimally adjusted, follow-up visits usually
occur every 3 to 6 months, depending on the patient’s needs.4,6 FIGURE 3-1
illustrates a schematic of an implanted DBS device.10 Patients and their
caregivers need to understand the risks and benefits of DBS and that it is not a
cure but, rather, another treatment option for their PD symptoms.6 This
conversation should begin early in the process, so that the patient and caregiver
can make an informed decision with their provider about whether this
intervention is appropriate to pursue.
Expected outcomes should be considered in light of the three indications for
DBS surgery: troublesome dyskinesias, frequent dosing because of troublesome
off time, and medication-resistant tremor. Large multicenter studies report that,
on average, daily off time and dyskinesias were improved by subthalamic
nucleus (STN) stimulation (69.1% and 62.5% of patients showed improvement,

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 respectively).11 The STN target is thought KEY POINTS
to be associated with increased medication
● Surgical interventions do
reduction compared with the globus not slow down, stop, or
pallidus internus (GPi) target, while the reverse disease progression
GPi target is thought to be better at but are used to manage the
addressing dyskinesias.6 Neuropsychiatric symptoms associated with
Parkinson disease.
effects of STN-DBS include potential
worsening of depression and anxiety and ● The three indications for
impulse control disorders.12 Despite stable deep brain stimulation
improvements in global outcomes of DBS, surgery for the treatment of
patients can have worsening of gait Parkinson disease include
troublesome dyskinesias,
impairment and speech disturbances, as frequent dosing because of
well as persistent levodopa-resistant troublesome off time, and
freezing of gait.13 Overall, many studies medication-resistant
FIGURE 3-1 tremor.
Illustration of the deep brain show that no significant differences are
stimulation system. found in long-term control of motor ● Parkinson disease
Reprinted with permission from Xiao Y, et al, symptoms between the two sites.7 symptoms that are
10
IEEE Trans Biomed Eng. © 2021 IEEE.
Currently, clinical DBS therapy only responsive to levodopa can
involves “open-loop” neurostimulation, be improved with deep brain
stimulation; however, an
meaning that stimulation continues
exception to this is resting
to be applied at the parameters it was set at without sensing brain signals for tremor, which may not be
feedback.14 Future directions for DBS involve adaptive “closed-loop” therapy, in levodopa responsive but
which local field potentials of the target structure are recorded through can still improve with deep
brain stimulation.
implanted electrodes, which in turn deliver stimulation.14 The adaptive DBS
system can vary its current based on an input “biomarker” (such as beta band ● Disadvantages of deep
oscillations), which can decrease stimulation-induced long-term side effects such brain stimulation include
as dyskinesias or speech problems.15 The optimal closed-loop system would be risks associated with brain
able to concurrently sense and stimulate, while automatically adapting to the surgery, hardware failure,
infection risks, and concerns
patient’s dominant symptom and level of dopaminergic medication.14 about patients with
significant cognitive
MRI-GUIDED FOCUSED ULTRASOUND impairment.
MRIgFUS was approved by the US Food and Drug Administration (FDA) in 2016
● Deep brain stimulation
for the treatment of unilateral essential tremor, PD tremor, and PD-related
can be performed on both
dyskinesia.16,17 Bradykinesia and rigidity often respond well to levodopa in sides of the brain and is
patients with PD; however, as mentioned previously, resting tremor can be adjustable over time.
refractory to levodopa.1,6 Following creation of phased-array transducers in the
1990s, transferring energy through the cranium is now possible without ● Commercial deep brain
stimulation systems provide
requiring an incision.4 The transducer elements emit ultrasound beams, which continuous stimulation
result in ablation by thermal coagulation when focused on a target.18 For these without sensing brain signals
patients with clinically probable PD, MRIgFUS can be used as another method to for feedback (ie, open loop).
address symptoms poorly controlled with levodopa without a craniotomy, There is ongoing research on
deep brain stimulation
electrode penetration, anesthesia, or ionizing radiation.1,19 Patients may consider systems that sense brain
MRIgFUS when restrictions to DBS are present, such as surgical risks, concerns signals for feedback (ie,
about multiple clinic visits for stimulator setting optimization, or a patient’s closed loop).
reluctance to undergo brain surgery or have an implanted device.4,5
Contraindications to the MRIgFUS procedure include claustrophobia, inability to
lay flat for an extended period of time, inability to communicate during
procedures, and implants that are not MRI compatible.18 Some facilities may
exclude patients who have a history of craniotomy, as the imaging that is used for
planning may be inaccurate.18 Briefly, patients with PD with asymmetric tremor

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SURGICAL THERAPIES FOR PARKINSON DISEASE

and mild bradykinesia or rigidity may consider MRIgFUS with the target of the
ventral intermediate nucleus (VIM) of the thalamus.18 For patients with more
asymmetric bradykinesia and rigidity, the GPi target may be chosen.18 Initial
MRI and CT scans are taken the day prior to the procedure for planning, and then
the day of the procedure a stereotactic frame is attached to the patient’s head
with local anesthetic.18 A helmet-type transducer containing 1024 ultrasound
elements is placed on the patient’s head, and then the patient enters the MRI
scanner.18 The helmet-type transducer circulates chilled water to keep the scalp
from absorbing too much heat during the procedure.18 At the beginning of the
procedure, a low amount of energy is applied to confirm whether the target site
has a temperature increase, and then the patient’s symptoms are tested.18 All
throughout this process, the MRI scanner is taking real-time images and
thermometry to assess when the target lesion reaches appropriate
temperatures and measures adjacent structures for excessive heating.17 If the
patient’s tremor is suppressed without observed complications, then the
temperature is increased to create the final lesion.18 No consensus exists on the
target size of the final lesion in the VIM of the thalamus; however, general
practice is to make a large lesion while avoiding the internal capsule and the
ventral caudal thalamus.18
Although MRIgFUS does not involve a craniotomy or incision, an irreversible
lesion is made, which could potentially result in permanent neurologic deficits.16

CASE 3-2 A 65-year-old man with a history of hypertension and hyperlipidemia

initially presented with a chief complaint of dominant hand resting tremor
that affected his daily activities, such as using utensils, writing, and
typing. On initial examination, he exhibited some mild rigidity and
bradykinesia with reduced unilateral arm swing, but these issues did not
inhibit his actions significantly.
The patient was diagnosed with tremor-predominant Parkinson
disease (PD), and he was administered various forms of levodopa,
dopamine agonists, and anticholinergics over a period of 5 years without
successful improvement in his tremor.
He wished to have better control of his dominant hand tremor, but he
did not wish to have a foreign device left in his body or trepanation of his
skull. MRI-guided focused ultrasound or gamma knife stereotactic
radiosurgery targeting the ventral intermediate nucleus (VIM) of the
thalamus was deemed appropriate for this patient, given that his main
symptom was unilateral tremor, and he did not wish to have an implanted
device.

COMMENT This case exemplifies options for a patient with tremor-predominant PD

who did not wish to have an implanted device or undergo brain surgery.
The patient should also be counseled that, as his PD progresses, he may
develop nondominant hand tremor; however, at this time, both MRI-guided
focused ultrasound and stereotactic radiosurgery targeting the VIM of the
thalamus are primarily performed unilaterally.

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Side effects can include motor weakness, ataxia, gait disturbance, sensory KEY POINTS
disturbance, and speech issues.16,18 A skilled operator is needed to balance the
● MRI-guided focused
potential side effects versus efficacy of the procedure as large lesions are ultrasound may be
expected to be more effective, although this increases the risk of side effects.16 considered when there are
CASE 3-2 presents a typical case, and FIGURE 3-2 illustrates a schematic of the restrictions to deep brain
MRIgFUS device.19 stimulation or other reasons
that prohibit brain surgery.
In the randomized controlled trial by Elias and colleagues,17 MRIgFUS reduced
total tremor scores in the contralateral hand by 47%, with only minimal ● MRI-guided focused
improvement in head and vocal tremors. Adverse events included gait ultrasound uses multiple
disturbances in 36% and sensory disturbances in 38% of participants, which ultrasound beams that
persisted at 1 year in 9% and 14% of participants, respectively.17 Maesawa and converge on a brain target to
create an irreversible lesion.
colleagues19 found that the therapeutic effect of MRIgFUS at 6 months could be
expected to persist for 2 years, although sometimes a recurrence of tremor ● An advantage of
occurred during the first year following treatment. MRI-guided focused
At this juncture, MRIgFUS is only FDA approved for unilateral tremor. If a ultrasound is that no foreign
bodies are present in the
patient has bilateral tremor or axial tremor involving head or neck, then DBS patient following surgery.
may be a more appropriate treatment choice.18 Current investigations use Disadvantages include that
MRIgFUS subthalamotomy at an early stage (EarlyFocus), which focuses on the US Food and Drug
short-term safety of MRIgFUS subthalamotomy in patients with PD for fewer Administration has only
approved this treatment for
than 5 years from diagnosis.20 Creating a lesion in the STN had been avoided in
one side of the brain, and it
the past, as this could lead to hyperkinetic complications of chorea and is not adjustable.
ballismus.18 A single-arm clinical trial is assessing early safety and efficacy of
bilateral treatment of medication-refractory essential tremor with MRIgFUS, ● During stereotactic
with estimated study completion date in March 2026.21 Additionally, the Bilateral radiosurgery, multiple
beams of radiation converge
Essential Tremor Treatment with FUS (BEST-FUS) study sponsored by on the brain target to create
University Health Network, Toronto, Canada, aims to perform contralateral an irreversible lesion.
MRIgFUS treatment on study participants who have previously undergone
successful unilateral MRIgFUS, with an estimated study date completion in ● An advantage of
stereotactic radiosurgery is
October 2024.19,22 that no foreign bodies are
present in the patient
OTHER LESIONAL THERAPIES following surgery.
Surgical therapies for PD began in the early 1900s with lesioning techniques, such Disadvantages include that
the US Food and Drug
as cryothalamotomy and chemothalamotomy.4 Following the introduction of
Administration has only
levodopa in 1968, which revolutionized the patient’s ability to treat clinical approved this treatment for
symptoms, ablative surgery for this indication decreased.4 The interest in one side of the brain, it is not
ablative techniques increased again, however, after the long-term side effects of adjustable, and there is
potential radiation risk.
levodopa became more prominent.4 Patients may select these therapies if they
have an aversion to having an implanted device. Similar to MRIgFUS, however, a
balance must be found between the lesion size and the risk of side effects, as
larger lesions are suspected to be more effective but have an increased frequency
of side effects.16 Depending on the target (eg, VIM of thalamus, GPi, STN), side
effects can include gait disturbance, paresthesia, dysarthria, ataxia, and weakness.18
Stereotactic radiosurgery uses externally generated ionized radiation to target
a specific site in the central nervous system.23 VIM of the thalamus is
preferentially targeted in patients with tremor-predominant symptoms, while
GPi or STN is targeted in those with advanced motor fluctuations.18 During this
procedure, multiple beams of radiation converge onto the target, delivering a
dose of radiation that can vary from 120 Gy to 200 Gy depending on the
institution.24 There is also a concern for latent radiation effects and potential risk
for secondary neoplasia.15,25 Niranjan and colleagues26 discussed using bilateral

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SURGICAL THERAPIES FOR PARKINSON DISEASE

FIGURE 3-2
Illustration of MRI-guided focused ultrasound. The beams of ultrasound emerge from the
transducer (A) with 1024 elements (E) and are focused on the target (F) under the guidance of
MRI (D). Degassed chilled water is circulated inside the space between the membrane (B) and
the scalp (G) of the patient. Phased-array transducer (A), membrane (B), stereotactic frame
(C), MRI scanner (D), elements (E), target (F), and scalp (G).
Reprinted from Maesawa S, et al, Neurol Med Chir (Tokyo).19 © 2021 The Japan Neurosurgical Society.

CASE 3-3 An 83-year-old woman presented for gait disturbance. She had been
diagnosed with akinetic-rigid Parkinson disease 15 years prior. The patient
had initially done well on levodopa replacement; however, over the past
year, she experienced increased motor fluctuations and appeared to
have issues with gastric emptying. Although the patient was able to
perform her activities of daily living independently, her son, who she
lived with, managed the patient’s medications and finances. Her past
medical history was also notable for a history of stroke, ventricular
tachycardia for which she had an automatic implantable cardioverter-
defibrillator, hypertension, hyperlipidemia, diabetes, and cognitive
impairment. The patient’s medications included levodopa every 2 hours
with at least 2 dose failures per day, and the patient and family wanted to
explore other treatment options for consistent dopaminergic delivery.
Levodopa/carbidopa intestinal gel infusion was considered the
optimal treatment option for this patient since it could be managed with
the help of a caregiver. The patient’s automatic implantable
cardioverter-defibrillator was not MRI compatible, which precluded
MRI-guided focused ultrasound. Given the patient’s cognitive impairment
and medical comorbidities, deep brain stimulation was not considered
the best option for this patient.

COMMENT This case exemplifies the impact that cognitive impairment and other
clinical factors have on selecting surgical treatments for patients with
Parkinson disease.

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gamma knife thalamotomy for bilateral tremor; however, this therapy is KEY POINTS
generally applied unilaterally in clinical practice.24
● The levodopa/carbidopa
Stereotactic radiofrequency ablation is initiated by inserting a lesioning probe intestinal gel infusion
through a burr hole in the skull to the target area.4 The tip of the lesioning probe system provides levodopa
is heated to create an irreversible lesion by coagulating brain tissue at the target infusion through a
site.4,19 With this intervention, contralateral motor UPDRS score was improved percutaneous endoscopic
gastrojejunostomy,
by 41% and dyskinesias by 57% at 1 year following unilateral pallidotomy.23
providing continuous levels
Alternatively, unilateral subthalamotomy showed a 31% motor improvement on throughout the day.
the Unified Parkinson’s Disease Rating Scale at 2 years.27
● The levodopa/carbidopa
LEVODOPA/CARBIDOPA INTESTINAL GEL INFUSION intestinal gel infusion
system may not be
Levodopa/carbidopa intestinal gel infusion treatment offers another option for appropriate for patients
continuous dopaminergic therapy for patients with PD.3 In 2015, the FDA with poor response to
approved levodopa/carbidopa intestinal gel infusion in the United States for use in levodopa or who have
patients with PD with motor fluctuations.3,26 CASE 3-3 presents a typical case of a difficulty handling the
infusion pump.
patient for whom levodopa/carbidopa intestinal gel infusion may be appropriate,
and FIGURE 3-3 shows the levodopa/carbidopa intestinal gel infusion schematic.28
Levodopa taken orally can cause pulsatile receptor stimulation in
dopaminergic neurons because of the short half-life, leading to motor
fluctuations such as dyskinesias and frequent or sudden off periods.28 Gastric
emptying is a rate-limiting step for orally administered levodopa, which is
absorbed in the proximal small intestine.29 Thus, gastric motility issues can lead
to fluctuating plasma concentrations of levodopa, producing motor
fluctuations.30 The levodopa/carbidopa intestinal gel infusion system provides
continuous carbidopa and levodopa infusion through a percutaneous endoscopic
gastrojejunostomy (PEG-J) tube via a portable infusion pump.30 An advantage of
levodopa/carbidopa intestinal gel infusion over orally provided levodopa is that it
can deliver continuous rather than pulsatile medication throughout the day, and
delivery of the levodopa bypasses the stomach to the jejunum, avoiding problems
that arise with gastric emptying issues.26 By doing so, this stabilizes the motor
fluctuations during the awake period, as plasma levodopa concentrations reach a
steady state.2 Continuous infusion of levodopa/carbidopa intestinal gel has
shown extended “on” time without disabling dyskinesias, decreased “off” time,
and decreased unpredictable “off” periods.31 Levodopa/carbidopa intestinal gel
infusion may not be an appropriate treatment for patients with poor response to
levodopa or significant difficulty handling the infusion pump.32
A patient with PD will be evaluated by the neurologist for appropriate
candidacy for levodopa/carbidopa intestinal gel infusion treatment; this involves
identifying the presence of troublesome motor fluctuations not controlled with
optimal oral medical management and determining that the patient is still
responsive to levodopa.26 It is important to determine if the patient has the
understanding and physical ability to operate the levodopa/carbidopa intestinal
gel infusion system, and if not, then it must be determined if the patient has
sufficient caregiver support to assist them.26 The next step is to refer the patient
to a proceduralist to place the PEG-J tube (eg, a gastroenterologist, general
surgeon, or interventional radiologist).26 Standard of practice in the United
States is to wait at least 1 week following PEG-J tube placement to start levodopa/
carbidopa intestinal gel infusion to allow for adequate healing time.26 However,
in other countries, some clinicians will use the tube within 24 to 48 hours of
placing it; this can also be considered for patients who have logistical concerns

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SURGICAL THERAPIES FOR PARKINSON DISEASE

FIGURE 3-3
The levodopa/carbidopa intestinal gel system.
PEG = percutaneous endoscopic gastrojejunostomy.
Modified from Amjad F, et al, Adv Ther.28 © 2019 The Authors.

with travel.26 Over the next few visits, the levodopa/carbidopa intestinal gel
infusion pump will be titrated to achieve maximal therapeutic benefit based on
the input from the patient, the caregiver, and the clinic staff. Clinic appointments
are initially scheduled for every 2 to 6 weeks, depending on the patient’s
need, and then once the target infusion dosage is reached, clinic visits can resume
every 3 to 6 months.26 Many clinicians will wait to discontinue nonlevodopa
antiparkinsonian medications to lessen undesirable side effects, such as increased
akinesia, restless legs, and dopamine agonist withdrawal syndrome.26 During a
typical day, the levodopa/carbidopa intestinal gel infusion pump is usually
titrated for hours when the patient is awake, and then is turned off and
disconnected during sleep; during this time, the patient can take oral levodopa if
needed.26 Issues related to the placement of the PEG-J tube include granuloma
formation, abdominal pain, and peritonitis or stoma infection.3 Device-related
problems include dislocation and occlusion of tubing, broken connectors, and
accidental removal.3,31 Side effects from levodopa infusion itself can include
hyperkinesia, hallucinations, hyperhomocysteinemia, vitamin B12 deficiency,
and polyneuropathy.32
Several research studies have shown that levodopa/carbidopa intestinal gel
infusion treatment reduces off time by about 1.9 hours per day, increases on time
without troublesome dyskinesias by about 1.86 hours per day, and increases on
time without any dyskinesias by 2.28 hours per day when compared with oral
levodopa treatment.33 Compared to patients not taking antiparkinsonian
treatment, patients using levodopa/carbidopa intestinal gel infusion had off time
reduced by 4.4 hours per day, and on time without troublesome dyskinesias was
increased by 4.8 hours per day.33

1310 OCTOBER 2022

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 Future directions of levodopa/carbidopa intestinal gel infusion include KEY POINTS
making smaller pump devices for easier transportation. Furthermore, adding
● Typically, the levodopa/
entacapone to the levodopa/carbidopa intestinal gel has been considered, which carbidopa intestinal gel
would aim to increase levodopa’s length of action; this could lead to a reduction infusion pump is on during
of solution volume needed while decreasing the treatment costs associated with the day and is shut off at
each cassette.32 night.

● Advantages of the
HEALTH DISPARITIES IN SURGICAL THERAPIES levodopa/carbidopa
The accelerated implementation of telehealth during the COVID-19 pandemic intestinal gel infusion
has increased outreach of physicians to patients who may be homebound, have system include that the
pump can be disconnected
transportation difficulties, or have other restrictions. Although there has been a
when not in use and can be
dramatic increase in households with Internet access, differences in access may used in patients with
continue, especially for those with financial constraints, those with lower significant cognitive
education levels, and patients who are not proficient in English.34 It is imperative impairment. Disadvantages
include risks associated with
that future outreach and research consider limited access or understanding of
percutaneous endoscopic
technology in relation to patient care.34 Regarding DBS, several studies have gastrojejunostomy tube
shown that this therapy is underused by certain populations, particularly African placement and
Americans.35 The proportion of African American patients diagnosed with PD maintenance.
ranges from 4.8% to 28%; however, only 0.6% of patients who undergo DBS are
African American.36 African American and Hispanic/Latino patients may seek
treatment later in the disease course, have less access to practitioner visits, and
have less secure social support networks.35,36 Future research is necessary to
identify barriers that underrepresented and underserved populations face when
considering surgical interventions for PD, and more education is necessary to
bring awareness to the medical community regarding bias and disparities in
offering these more invasive, yet highly effective, interventions to all eligible
patients with PD.

CONCLUSION
PD is a progressive neurodegenerative disorder, and as the disease advances,
patients may have increased motor complications and treatment-related
fluctuations, and surgical therapies may offer a highly effective therapeutic
route. Referrals for surgical interventions for PD should be made to either
multidisciplinary centers or groups that have significant experience with that
intervention. It is the responsibility of the referring provider to discuss with
patients that these surgical interventions do not slow, reverse, or stop PD
progression. Conversely, the appropriate intervention for the patient can
improve quality of life by potentially decreasing dyskinesia, decreasing off times,
increasing on times, and providing more stable therapy on a daily basis. Refer to
TABLE 3-1 for a simplified overview of surgical options in PD.

USEFUL WEBSITES
FOCUSED ULTRASOUND FOUNDATION
This website provides information regarding how
focused ultrasound is used for the treatment of
tremor and where to find institutions that are
providing this treatment.
fusfoundation.org
AMERICAN ASSOCIATION OF NEUROLOGICAL SURGEONS
This website provides an overview of deep brain
stimulation and the workup needed for referral for
implantation.
aans.org/en/Patients/Neurosurgical-Conditions-and-
Treatments/Deep-Brain-Stimulation#:~:text=DBS%
20is%20a%20surgical%20intervention,obsessive%
2Dcompulsive%20disorder%20and%20epilepsy

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SURGICAL THERAPIES FOR PARKINSON DISEASE

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