Pt.1 Comparison of Pallidal and Subthalamic Deep Brain Stimulation for the Treatment of Levodopa-Induced Dyskinesias

[John Cottingham <jcott@xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx>]

Source Robert A. Fink, MD

Pasted below is a message obtained from Medscape regarding the latest scoop 
on DBS.  It was too large for the List.  Can you re-post it?

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A recent "summary paper" on the current state of DBS treatment:

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Comparison of Pallidal and Subthalamic Deep Brain Stimulation for the
Treatment of Levodopa-Induced Dyskinesias


Kenneth A. Follett, M.D., Ph.D.
Neurosurg Focus 17(1):14-19, 2004. © 2004 American Association of
Neurological Surgeons

Posted 07/26/2004


Abstract and Introduction

Abstract
Deep brain stimulation (DBS) can relieve dyskinesias effectively and
safely. This modality is applied most commonly in the treatment of
dyskinesias associated with levodopa therapy for Parkinson disease. The
subthalamic nucleus (STN) and globus pallidus internus (GPi) are the most
common surgical targets. Deep brain stimulation of the GP has a direct
antidyskinetic effect, whereas relief of dyskinesias by DBS of the STN
depends on postoperative reduction of dopaminergic medications. Outcomes
are similar for DBS in these two sites despite the different mechanisms by
which the stimulation relieves dyskinesias. Deep brain stimulation of the
STN has become the surgical treatment of choice in many movement 
disorders
programs but this modality has not been compared with DBS of the GPi in
randomized controlled trials, and the superiority of one site over the
other remains unproven. In the absence of data demonstrating superiority,
selection of the stimulation target should be individualized to meet the
needs of each patient. Selection of the target should be based on the
patient's most disabling symptoms, response to medications (including side
effects), and the goals of therapy, with consideration given to the
different antidyskinetic effects of DBS of the STN and GPi.

Introduction
The introduction of levodopa in the 1960s[5] provided dramatic relief of
symptoms for many patients with PD and had a profound impact on surgical
therapies for this disease. Parkinson disease became viewed as a medical
rather than a surgical disorder.[2] Within a decade, however, the
limitations of levodopa became apparent. It did not prevent disease
progression and was frequently associated with complications and side
effects, including progressive shortening of the duration of action with
predictable loss of drug effect throughout the day ("wearing off");
unpredictable, abrupt loss of drug effect throughout the day ("on-off"
fluctuation); and involuntary movements (dyskinesias and dystonias). These
complications are observed in as many as 50% of individuals who have been
treated with levodopa for more than 5 years and in as many as 70% of
people who have been treated with levodopa for 10 years or more.[23] For
many patients these complications may be as disabling as the symptoms of
the underlying disease and may compromise the utility of levodopa in the
management of PD.

Dyskinesias can be functionally and cosmetically disabling. Reduction of
dyskinesias improves motor function and the performance of activities of
daily living, and it can have a significant beneficial effect on the
self-esteem of individuals who are affected by these involuntary
movements. Dyskinesias associated with levodopa therapy for PD can be
alleviated by adjustment of the medication dose. In some cases this
requires reduction of dopaminergic medications at the expense of loss of
control of cardinal PD symptoms. Individuals whose PD is managed in this
fashion are faced with a difficult choice between accepting more severe
dyskinesias with better control of PD symptoms or less severe dyskinesias
with worse control of PD symptoms. Surgical treatment can be very helpful
for these individuals.

Reduction of dyskinesias by surgery can be accomplished in either of two
ways. Surgical intervention (for example, DBS of the STN or
subthalamotomy) can be aimed directly at reducing PD symptoms, with the
hope that medications can then be reduced to provide relief from levodopa-
related side effects including dyskinesias. Alternatively, surgical
intervention (for example, pallidotomy, DBS of the GPi, thalamotomy, and
thalamic DBS) can be aimed at treating the dyskinesias directly. In
contemporary practice, DBS has become the preferred surgical treatment for
movement disorders.[7] Deep brain stimulation of the STN and the GPi has
become the preferred surgical treatment for dyskinesias associated with
PD. In this review these two variations of DBS treatment will be discussed
in detail.




Selection of the DBS Target
Deep brain stimulation of the STN is the surgical treatment of choice for
PD in many centers. Numerous studies have demonstrated the effectiveness
of this treatment in attenuating the cardinal symptoms of PD. In general,
DBS of the STN does not appear to have a direct antidyskinetic effect but
allows many or most patients to reduce their antiparkinsonian medications,
with an accompanying reduction in side effects, including dyskinesias. The
presence of persistent or worsened dyskinesias after DBS of the STN
usually indicates a need to reduce dopaminergic medications. The primary
disadvantage of this operation as a treatment for dyskinesia is its
indirect mechanism of action on these symptoms: dyskinesias improve only
if medications can be withdrawn or reduced after DBS of the STN. If a
sufficiently good response of PD symptoms to DBS of the STN to allow
medication reduction postoperatively is not attained, the dyskinesias will
continue unabated. In addition, this treatment is some times associated
with persistent dyskinesias, which may be a side effect of stimulation,
even in the setting of medication reduction.

In contrast, DBS of the GPi appears to have a direct antidyskinetic
effect. Patients undergoing this procedure typically do not receive lower
doses of medications postoperatively, yet they show significant
improvement of dyskinesias. Patients who obtain good relief of PD symptoms
with medications but who are bothered by dyskinesias may do well with DBS
of the GPi because they can continue PD medications at preoperative levels
but experience relief of the dyskinesias. Treatment with DBS of the GPi
can be especially useful for individuals in whom dyskinesias are a
dose-limiting side effect of medications. Direct treatment of dyskinesias
with DBS of the GPi can widen the therapeutic window for dopaminergic
medications and permit more aggressive drug therapy. Medication therapy
may, in fact, have a synergistic effect with DBS of the GPi,[3,11] which
is not seen after DBS of the STN.[3]

Selection of the target site may also be influenced by growing recognition
that withdrawal of medications after DBS for PD may not be desirable or
possible for all patients. Neuropsychological, cognitive, and psychiatric
dysfunction seem to occur more often after DBS of the STN than of the
GPi.[33] Some of these abnormalities appear to be related to postoperative
medication withdrawal because they can be reversed by reinstitution of the
drugs.[8,14] This argues for the relative superiority of pallidal DBS
because it can provide good relief of motor symptoms without the reduction
of medications that is usually necessary to relieve dyskinesias after DBS
of the STN.

Selection of the target should be based on the patient's most disabling
symptoms, response to medications (including side effects), and goals of
therapy, with consideration given to the different antidyskinetic effects
of DBS of the STN and GPi. If dyskinesias are a patient's most disabling
symptom, then DBS of the GPi can be offered with the knowledge that
regardless of changes in medication therapy after surgery there is a high
likelihood that dyskinesias will improve. The possibility also exists that
relief of dyskinesias, if they are a dose-limiting side effect, by DBS of
the GPi might widen the therapeutic window for dopaminergic agents and
allow more aggressive pharmacological therapy of PD, as has been shown
after pallidotomy.[28] In contrast, the same individual undergoing DBS of
the STN must hope for a sufficiently good response to DBS that his or her
medications can be reduced postoperatively. If the response of
parkinsonian symptoms to DBS of the STN is inadequate or if withdrawal of
medications precipitates or exacerbates nonmotor symptoms, continued
medication therapy will be necessary and the individual will continue to
suffer disabling dyskinesias. If a patient is affected primarily by
medication side effects other than dyskinesias, DBS of the STN may be the
preferable approach because it allows postoperative reduction of
medications.




Technical Considerations
For the most part, similar surgical methods are used to implant DBS
systems for the treatment of dyskinesias and for cardinal symptoms of PD.
A few subtle differences exist for implantation of pallidal DBS systems;
these variations are used because of possible differential antidyskinetic
effects of stimulation at different sites within the GP. Implantation of
leads is typically performed while patients are in the "off-medication"
state to reduce dyskinesias that can cause motion artifacts during
preoperative imaging (for example, magnetic resonance imaging or
computerized tomography studies) or during intraoperative microelectrode
recording, or that might cause a patient to slip out of pin fixation in
the stereotactic frame.

The lead implant for DBS of the STN or GPi can be guided using
computerized tomography, magnetic resonance imaging, and/or
ventriculography. Microelectrode recording has not been proven to be
essential but it is useful for confirmation of proper target location. For
both STN and GPi, identification of kinesthetically responsive cells for a
somatotopically relevant portion of the body confirms proper electrode
location. This confirmation is particularly useful for the STN because it
is a small target surrounded by structures that can give rise to
"dose-limiting" stimulation-related side effects from a malpositioned
electrode.[35] Microelectrode recording in the GPi is useful for
identification of the pallidal base and the medial border of the pallidum,
because lead placement that is too medial will predispose the patient to
undesirable, "dose-limiting" stimulation of the internal capsule. The
pallidal base can also be identified indirectly by locating the optic
tract underlying the GPi with microelectrode recording or stimulation.
Macroelectrode stimulation of STN and GPi by using the DBS lead or a
dedicated macrostimulation electrode confirms proper electrode position by
the absence of adverse stimulation side effects and, typically, by
improvement in parkinsonian symptoms.

Studies conducted in acute cases indicate that two different sites may
exist within the GPi, at which stimulation has opposite effects on
dyskinesias and response to levodopa.[1,16] It is unclear whether these
different zones are of practical significance in the long-term management
of disease, but the presence of these different functional zones in the
GPi should be kept in mind during surgical planning, selection of
stimulation electrode, positioning of stimulation lead within the GPi, and
during postoperative programming. The presence and locations of pro- and
antidyskinetic sites within the GPi are somewhat variable from patient to
patient.[16] In general, stimulation of the ventral pallidum relieves
levodopa-induced dyskinesias but may worsen akinesia, which indicates
general antagonism of levodopa effects (although the beneficial effects of
levodopa on rigidity are not affected by ventral pallidal DBS). Dorsal GPi
stimulation seems to mimic the action of levodopa: gait, akinesia, and
rigidity improve, and it is possible in some patients to induce
dyskinesias in the off-medication state. Stimulation of the middle portion
of the GPi seems to provide a good compromise between these two extremes.

Two DBS stimulation leads are commercially available at this time. One is
a four-contact lead with 1.5-mm spacing between adjacent contacts and a
total array span of 10.5 mm (model 3387; Medtronic Neurological, Inc.,
Minneapolis, MN) and the other is a four-contact lead with 0.5-mm spacing
between adjacent contacts and a total array span of 7.5 mm (model 3389;
Medtronic Neurological, Inc.). Implantation of a lead with larger
intercontact spacing (model 3387; Medtronic Neurological, Inc.) provides
greater leeway in lead positioning and postoperative programming. If the
surgeon chooses to implant a lead with close contact spacing, care must be
taken to place it near the midpoint or ventral in the GPi to provide
stimulation of the "antidyskinetic" functional zone within this structure.
In contrast, a lead with larger intercontact spacing can be positioned to
span a greater length of the GPi, with stimulation "sublocalization"
accomplished during postoperative programming. Wider rather than narrower
contact spacing may be advantageous for pallidal stimulation because of
interpatient variability in locations of pro- and antidyskinetic regions
within the GPi.




Postoperative Programming: GPi
The general approach to programming DBS systems is similar for DBS of the
STN and of the GPi, that is, the goal is to provide the best possible
relief of cardinal symptoms of PD. In general, programming should be
initiated in the off-medication state. This may require that
antiparkinsonian medications be withheld for at least 12 hours (usually
overnight) prior to a programming session. After programming to achieve
the best relief of symptoms is completed, the patient should take his or
her PD medications and return for reassessment, with special attention
being paid to dyskinesias. These symptoms may vary on a diurnal basis and
be better in the morning and worse in the afternoon. Monitoring for
development of dyskinesias is sometimes best accomplished in the
afternoon, particularly after the patient has taken several doses of
antiparkinsonian medications.[19] If programming in the off- medication
state provides good relief of PD symptoms and is not associated with the
development of dyskinesias in the on-medication state, no further
adjustment of stimulation is necessary. Alternatively, if the patient
returns for reassessment in the on-medication state and dyskinesias are
noted, reprogramming will be needed.

An added element of programming flexibility is present in patients whose
primary complaint is levodopa-induced dyskinesias. Symptoms in these
individuals can sometimes be managed easily by performing all programming
in the on-medication state when dyskinesias are present, with DBS
programming efforts being directed specifically at reducing the
dyskinesias. Care must be taken to en sure that beneficial medication
effects are not antagonized and that off-medication symptoms are not
exacerbated when using this approach.

As noted earlier, different regions in which stimulation has opposite
effects on dyskinesias appear to exist within the GPi. Dyskinesias may be
induced by stimulation of the dorsal GPi[1,16] and relieved by stimulation
of the ventral pallidum, although some variability in this response exists
among patients. In general, the best relief of dyskinesias is achieved
using deeper contacts, but this may antagonize some of the beneficial
effects of levodopa (especially in treating bradykinesia). Fortunately,
the antidyskinetic effects of DBS of the GPi occur at lower amplitudes
than those required to inhibit levodopa effects, so relief of dyskinesias
can usually be accomplished without antagonizing the beneficial effects of
medications for other PD symptoms. Use of deep contacts for treatment of
dyskinesias may be appropriate for individuals in whom this is the primary
symptom, and may widen the therapeutic window for levodopa so that any
inhibition of medication effects by DBS can be balanced by an increase in
medication. If ventral pallidal stimulation provides adequate relief of
dyskinesias but results in loss of beneficial medication effects, a
compromise can generally be found by using contacts near the central
portion of the GPi, which usually provides good relief of dyskinesias as
well as tremor, rigidity, and bradykinesia.[1,16,19] Alternatively,
bilateral pallidal DBS systems can be programmed asymmetrically by using a
more proximal contact on one side and a more distal contact on the
other.[1]




Postoperative Programming: STN
Programming DBS of the STN for the relief of dyskinesias is aimed at
relieving the cardinal symptoms of antiparkinsonianism to allow subsequent
reduction of antiparkinsonian medications. This modality mimics the
effects of levodopa in many regards and the effects of DBS of the STN are
best seen in patients in the off-medication state. With holding
antiparkinsonian medications for at least 12 hours (usually overnight) is
sufficient to achieve a satisfactory off-medication state for most
patients. After programming to achieve reduction of bradykinesia,
rigidity, and tremor is completed, patients should take their regular
doses of antiparkinsonian medications. During the subsequent on-medication
state, patients should be reevaluated for side effects of the combination
of DBS of the STN and medications, particularly dyskinesias. The time from
latency to onset of dyskinesias may be minutes to hours. Patients should
be able to contact the programming physician for several hours following
the procedure in the event that disabling dyskinesias occur after
stimulation adjustment.[15,35] During the first few weeks and months after
surgery, as stimulation is adjusted to provide the best relief of
parkinsonian symptoms, medication doses are titrated downward, and
dyskinesias tend to resolve. Persistent dyskinesias are generally treated
by reduction of medication.

In some instances, especially during the first few weeks after DBS
implantation, dyskinesias may be precipitated by DBS of the STN. The most
effective electrode contact for long-term therapy is often that which
produces dyskinesias in the early postoperative period.[15,35] Reducing
medication levels typically alleviates the dyskinesias, but if medication
reduction results in worsening of PD symptoms, medication doses may need
to be increased and stimulation amplitudes reduced. Over time (days to
weeks or months), the threshold for induction of dyskinesias typically
increases and stimulation amplitude can then be increased to provide
better relief of PD symptoms, allowing decreases in medication doses and
attenuation of levodopa-induced dyskinesias. Occasionally, stimulation
using the most effective (that is, the most "prodyskinetic") contact
precipitates dyskinesias that cannot be controlled except by reduction of
stimulation intensity. In this case, programming the stimulation system to
use a more proximal or distal contact in a monopolar configuration or
reprogramming to a bipolar configuration sometimes widens the therapeutic
window of stimulation to allow good relief of PD symptoms without
producing dyskinesias. Addition of an active DBS contact dorsal to the STN
may also provide better control of dyskinesias (W Marks and S Heath,
unpublished data).

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