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Neurosurg Clin N Am 15 (2004) 343357

Deep brain stimulation for the treatment of chronic,


intractable pain
Bradley A. Wallace, MD, PhDa,c,*, Keyoumars Ashkan, MRCP,
FRCS (SN)b,c, Alim-Louis Benabid, MD, PhDc
a
Department of Neurosurgery, University of Florida, PO Box 100265 Health Center, Gainesville, FL 32610, USA
b
Department of Neurosurgery, University of London, 3 Tina Court, 43 Edgehill, Wimbleton,
London SW19 4NP, England
c
Department of Clinical and Biological Neurosciences, Joseph Fourier University, INERM U318,
Preclinical Neurosciences, Pavillon B, CHU, 38043, Grenoble, France

Neurosurgical treatment of pain began with treat central neuropathic pain, MCS and DBS are
ablative techniques. Through technologic advan- competing modalities used at slightly dierent
ces, improved neuroanatomic and physiologic levels of the neuraxis to treat the same types of
understanding, and the realization that interrup- pain. Why DBS has given way to other forms of
tion of direct pain pathways eventually fails, stimulation does not seem to be based on ecacy
neurostimulation emerged and ultimately super- alone. Although the consensus seems to be that
seded ablative techniques. During the past decade, MCS is more ecacious than DBS, the fact is that
however, deep brain stimulation (DBS) for pain both lack prospective studies and their overall
has largely been supplanted by other forms of reported long-term outcomes (50%75%) are
neurostimulation, namely, precentral or motor comparable. This leaves other factors, such as
cortex stimulation (MCS) and spinal cord stimu- perceived ecacy, safety, and novelty, to poten-
lation (SCS). tially explain why DBS has been supplanted by
A crude but eective means of assessing the alternative modalities in the eld of pain.
general frequency with which each of these three The current article presents the history, indi-
modalities is currently used can be achieved by cations, technical aspects, and retrospective out-
surveying the number of articles published on comes of DBS for pain.
each modality during the past 5 years. The results
of a PubMed search limited to human subjects
since 1999 was ltered to include only articles History of deep brain stimulation for chronic
specically addressing the treatment of pain by intractable pain
these three forms of neurostimulation. SCS had
the highest number (42 articles), followed by MCS The rst deep brain structure reported to
(31 articles), leaving DBS with the fewest (11 provide pain relief when electrically stimulated
articles). Although SCS is generally not used to was the septal region by Heath [1] in 1954 for the
treatment of schizophrenia. Two years later, Pool
et al [2] reported pain relief from septal region
stimulation also performed in the setting of
All three authors have professional relationships
and either currently or previously received grant fund-
psychiatric disease. In 1960, Heath and Mickle
ing from Medtronic (Minneapolis, MN). [3] went on to successfully stimulate the septal
* Corresponding author. region exclusively for the treatment of pain. In
E-mail address: wallace@neurosurgery.u.edu 1966, Ervin et al [4] reported pain relief from
(B.A. Wallace). caudate stimulation. One year later, Gol [5]
1042-3680/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.nec.2004.03.004
344 B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357

reported pain relief by stimulation of the caudate in successful DBS treatment of pain is the correct
and the septal region. classication of the patients pain.
Thalamic stimulation for pain was rst re- Although numerous classication schemes ex-
ported by Mazars et al [6] in the ventropostero- ist, for the purpose of DBS treatment, pain can be
lateral nucleus (VPL) for bodily pain and by classied into two major categories: nociceptive
White [7] in the ventralis posteromedialis (VPM) pain and neuropathic pain. CH is discussed
for facial pain. These early cases used acute separately because it is a specic pain syndrome
stimulation only, however. In 1973, the VPL and that currently has a unique DBS target.
VPM were chronically stimulated for the rst time
by Mazars et al [8] and Hosobuchi et al [9], Nociceptive pain
respectively. Numerous other groups have since
Nociceptive pain is pain secondary to potential
conrmed the benet of chronic stimulation of the
tissue damage in the setting of a functionally
somatosensory thalamus and internal capsule (IC)
normal nervous system. The perception of poten-
[819].
tial tissue damage is relayed through pain path-
Stimulation of the periaqueductal gray matter
ways by activation of peripheral nociceptors in
(PAG) and periventricular gray matter (PVG) in
response to noxious somatic or visceral stimuli.
human beings as a treatment for pain was begun
Somatic nociceptive pain is often well localized and
in 1977 by two groups: Richardson and Akil
described as sharp, aching, or throbbing. Visceral
[20,21] and Hosobuchi et al [22]. These initial
nociceptive pain is less well localized and may
trials were based on Reynolds 1969 discovery that
include a cramping component if hollow viscera
low-frequency PAG stimulation produced analge-
are involved. Pharmacologically, nociceptive pain
sia in rats [23], a nding that ultimately led to the
is responsive to opioids, and its optimal target for
discovery of the brains endogenous opioids and
DBS treatment is the PVG/PAG. Specic examples
their receptors.
of nociceptive pain include the nonradicular com-
Most recently, Franzini et al [27] reported the
ponent of lumbar disk disease or failed back
successful treatment of cluster headaches (CHs)
syndrome and cancer pain among others.
using stimulation of the posteroinferior hypothal-
amus. This work was based on evidence that CHs
Neuropathic pain
may be the manifestation of posterior hypotha-
lamic hyperactivity [2426]. Knowing that high- Neuropathic pain is pain resulting from an
frequency stimulation (HFS) was eective in insult to the nervous system itself. The Interna-
treating movement disorders involving hyperac- tional Association for the Study of Pain (IASP)
tive nuclei, it was postulated that the same dened it as pain initiated or caused by a primary
principle might also apply to hyperactive hypo- lesion or dysfunction of the nervous system [37].
thalamic nuclei [27,28]. The two major subtypes of neuropathic pain are
Since the inception of stimulation for the deaerentation pain and central pain [38]. One
treatment of pain, numerous other deep brain possible mechanism is that neural injury or irrita-
nuclei have been assessed for pain-relieving prop- tion leads to abnormal somatosensory processing
erties. These include the parabrachial region in the peripheral or central nervous system. An-
[29,30]; the Kolliker-Fuse nucleus [31,32]; and other possible mechanism is that abnormal pro-
several other thalamic nuclei, including the dorsal cessing may arise from the loss of innervation from
medial nucleus, the parafascicular nucleus, and central pathways. Increased bursting of thalamic
the centromedian nucleus [3335]. neurons in rats was noted after deaerentation [39]
Additionally, several groups have reported abnor-
mal ring of somatosensory thalamic neurons
during intraoperative recordings of patients being
Classication of pain
treated for neuropathic pain [3941]. Loss of
In the treatment of pain using DBS, target peripheral input can lead to abnormal signal
selection is guided by the specic type of pain amplication by a process known as central
being treated. The importance of this was illus- sensitization, leading to allodynia [42].
trated by Levy [36] in his recent meta-analysis, Clinically, neuropathic pain is diverse. It may be
which showed that long-term success rates are characterized as burning, lancinating, shock-like,
strongly correlated with selecting the target ap- tingling, or shooting. It may be constant or episodic.
propriate for the type of pain. Thus, the rst step When episodic, it may occur spontaneously or in
B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357 345

response to nonpainful stimuli (allodynia). There manner. If the patient has signicant pain relief
may be associated focal neurologic decits, such as after receiving between 10 and 25 mg of morphine,
weakness or autonomic changes. Trophic skin which is then reversed by naloxone, the pain is
changes have also been described [42]. Pharmaco- classied as nociceptive. Pain relief with less than
logically, this type of pain is responsive to antiepi- 10 mg is indicative of inadequate pharmacologic
leptic drugs or antidepressants and is classically management. Pain unresponsive to greater than 25
refractory to standard opioid treatment. The opti- mg of morphine and having qualities consistent
mal target for DBS treatment is the VPL or VPM with neuropathic pain is diagnosed as such. Pa-
for bodily or facial pain, respectively. Specic tients with pain that does not respond to high-dose
examples of neuropathic pain include poststroke morphine and has questionable characteristics
pain, thalamic pain, pain from multiple sclerosis, can be weaned o morphine using l-tryptophan
pain from Parkinsons disease, spinal cord injury, and reassessed to ensure that the initial failure is
syringomyelia, plexus avulsion, phantom pain after not secondary to opiate tolerance [50]. In 1987,
amputation, and painful mononeuropathies (eg, Young and Chambi [51] reported that the
radicular component of low back pain, lancinating morphine naloxone test did not predict successful
neuralgias, entrapment neuropathies). Although PVG stimulation. More recently, in an unpub-
controversial, complex regional pain syndrome is lished study by Young and Kroening, further
often included in this category [42]. doubt was cast on the validity of the morphine
naloxone test, reporting no statistically signicant
Cluster headache dierence in outcomes between groups using and
not using the test [36]. Notably, the l-tryptophan
CH is a unique pain syndrome comprising the
portion of this test has been completely abandoned
sudden onset of severe unilateral pain involving the
because it is no longer deemed medically safe [36].
eye, temple, and cheek, and it may include signs of
autonomic dysfunction. Patients often have daily
attacks for a period of 6 to 12 weeks, followed by Patient selection and indications for treatment
a variable period of complete remission. Recur-
rences classically have a seasonal pattern. Al- The rst step is to ensure that the patient
though the origin of CHs was previously thought fullls the general criteria used to screen candi-
to be exclusively vascular, recent evidence involv- dates for any neurosurgical pain intervention. The
ing positron emission tomography (PET) scanning second step is to determine if DBS, as opposed to
[24,25,43], functional MRI, and electrophysiologic other neurosurgical pain procedures, is the most
recordings [27] has implicated hyperactivity of the appropriate treatment modality. Once DBS has
dorsal hypothalamus as playing a key role in CH. been deemed appropriate, the nal step is choos-
Although most CHs are successfully treated with ing the optimal DBS target for the patients pain.
medications [44,45], approximately 4% may be
completely refractory to medical management [46].
Although numerous ablative techniques have been General selection criteria
used to treat CHs [47], they have a high incidence
The pain
of associated sensory loss and recurrence [45]. The
only known DBS target for CH is the ipsilateral The pain must be incapacitating and refractory
posteroinferior hypothalamus recently described to maximum conservative management and other
by Franzini et al [27]. less invasive yet eective treatment modalities if
available. The pain must be chronic. Patients
Diculties in classifying pain generally should have pain for a minimum of
1 year, with at least 6 months of maximal non-
Pain classication may be clouded by ambigu-
neurosurgical pain management before consider-
ous clinical presentations. The most commonly
ation of any intervention. The pain must have
used tool to help classify dicult cases is the
a clearly dened cause.
morphine naloxone test; until recently, this test
was considered a valuable aid in classifying pain to
The patient
select the appropriate target for stimulation
[22,4850]. The test consists of administering The inuence of patient selection on the out-
5-mg increments of morphine sulfate or saline come of neurosurgical pain management should
intravenously every 10 minutes in a double-blinded not be underestimated. The patients general
346 B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357

medical condition should be adequate to tolerate treat them appropriately if possible. In the setting
the lengthy procedure required for implantation of of CHs, the team should include a neurologist
a deep brain stimulator. Signicant comorbidities, with experience in headache treatment.
such as cardiovascular disease or bleeding diathe-
ses, must be addressed before surgery. The impor-
tance of age or life expectancy should be considered Deep brain stimulation target selection
in the context of the indications for treatment. Two major areas have evolved to become the
Additionally, consideration should be given to primary targets in contemporary DBS treatment of
leaving the intermittent pulse generator external- chronic pain. These are the paresthesia-producing
ized in the setting of terminal cancer pain. Cogni- areas (somatosensory thalamus, medial lemniscus,
tive status should be adequate to permit the or thalamic radiations) for the treatment of neu-
patients cooperation during intraoperative testing. ropathic pain and the medial areas (PAG/PVG)
Pain is a subjective complaint that is directly for the treatment of nociceptive pain [54].
assessable only by the patient. Socioeconomic
factors, interindividual variability in pain toler- Paresthesia-producing stimulation
ance, psychologic factors, and the possibility of
secondary gain must all be considered. As a result, Theoretic basis and supporting evidence
numerous attempts have been made to quantify or The origin of paresthesia-producing stimula-
classify pain. Although pain patients commonly tion lies in the Melzack-Wall gate control theory
suer from minor psychiatric problems, such as of pain, which states that threshold stimulation
anxiety and mild depression, the patient should be applied to large peripheral nerve bers causes
free of any major psychiatric illnesses, including suppression of conduction in small nociceptive
severe untreated depression. Tests such as the bers through opioid-dependent mechanisms in-
Minnesota Multiphasic Personality Inventory volving activation of met-enkephalinergic inter-
(MMPI) should be used to screen for certain neurons in the dorsal horn of the spinal cord [55].
personality traits that are associated with less Wall and Sweet [56] conrmed that nociceptive
favorable outcomes. Patients identied as having ber inputs could be suppressed through such
strong psychologic components to their pain a mechanism, and the neurosurgical community
should be treated appropriately before surgical began to apply the principle. This rst included
decision making. For the purpose of assessing stimulating the dorsal columns of the spinal cord,
DBS outcomes, clinical pain scales, such as the later moving rostrally to the brains lemniscal
McGill Pain Questionnaire [52] and a visual pathways (ventrocaudal nucleus, medial lemnis-
analog scale [53], should be used before and after cus, or thalamic radiations) in an attempt to
surgery. Although pain patients may have un- induce paresthesias chronically in the distribution
dergone numerous surgical procedures to alleviate of the patients pain. With experience, it became
their pain, a history of overly excessive or un- evident that such stimulation was eective pri-
necessary surgeries should raise suspicion. Finally, marily for neuropathic pain versus nociceptive
the patient should be able and willing to give pain. Investigation revealed abnormal neuronal
informed consent with realistic expectations of the activity of the somatosensory thalamus in the set-
potential risks, benets, and shortcomings of DBS ting of neuropathic pain [39,40]. Hypothetically,
treatment for pain. electrical stimulation of the brains lemniscal
pathways may alter the brains complex process-
ing of such signals rather than simply blocking
The team transmission of pain along pathways. Animal
The decision to perform DBS for the treatment studies have supported this theory. VPL stimula-
of pain should always be made in the setting of tion in primates may inhibit spinothalamic tract
a multidisciplinary pain team. In addition to the neurons of the dorsal horn of the spinal cord [57
neurosurgeon, the team should include a pain 59]. In rats, VPL stimulation has been shown to
specialist to conrm that the patient is truly inhibit neuronal activity in the centromedian-
refractory to maximal conservative pain manage- parafascicular (CM-Pf) complex [60].
ment and to assist with continued postimplanta-
tion pharmacologic treatment if necessary. Specic paresthesia producing deep brain targets
Psychiatrists and psychologists are necessary to The primary deep brain targets for neuropathic
identify contraindicated psychologic issues and to pain lie in the somatosensory thalamus. They are
B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357 347

the VPL for bodily pain and the VPM nucleus for PAG is targeted, because dorsal PAG stimulation
facial pain. There are two situations in which almost universally induces unpleasant sensations,
stimulation of the thalamic radiations in the IC even at low amplitudes [36], but ventral PAG
may be more ecacious than direct stimulation of stimulation induces visual side eects, such as
the VPL/VPM, however. The rst is when pares- oscillopsia.
thesia-producing stimulation over a wide area of
Hypothalamic stimulation
the body is needed to treat a large pain distribu-
tion. The second is in the setting of postthalamic Stimulation of the posterior hypothalamus
infarct pain in which the remaining thalamic sub- exclusively for the treatment of intractable CH
strate may be insucient for eective thalamic was recently reported [27,28]. This target was
stimulation. Even IC (or attempted thalamic) selected based on reports of posteroinferior hypo-
stimulation in the setting of thalamic pain syn- thalamic hyperactivity seen on PET scans, func-
drome has produced poor outcomes [50], however, tional MRI, and electrophysiologic recordings of
and more promising therapies, such as precentral the area [2527,69]. The posteroinferior hypothal-
cortical stimulation, should be considered. amus is believed to be the source of CH. HFS may
inhibit hyperactive hypothalamic neurons. An
Medial stimulation alternative explanation is stimulation-induced ac-
tivation of pain-modulating pathways [27]. CH is
In 1969, Reynolds [23] observed that electrical
the only pain condition currently treated with
stimulation of PAG/PVG produced analgesia in
posteroinferior hypothalamic stimulation. The
rats. Based on this work, stimulation of the PAG/
original and characteristic feature of this target
PVG in human patients as a treatment for pain
is that DBS is meant to inhibit its hyperactivity by
was rst performed in 1977 by two groups:
HFS, whereas all the other above-mentioned
Richardson and Akil [20,21] and Hosobuchi
targets were meant to be activated through low-
et al [22]. In addition to demonstrating eective
frequency stimulation.
pain relief, both groups demonstrated a rise in cere-
brospinal uid (CSF) endogenous opioid levels. Multitarget implantation
This rise in CSF b-endorphin and met-enkephalin
levels was later conrmed by several groups In some cases, patients may present with pain
[21,51,6163] The underlying mechanism is be- that legitimately involves neuropathic and noci-
lieved to involve activation of opioid pathways ceptive components, or denitive classication of
that interact with serotonergic neurons descending the pain is not possible. Such mixed presentations
from the nucleus raphe magnus (NRM) to the are commonly encountered in patients with low
dorsal horn of the spinal cord [6266]. This theory back pain or failed back syndrome in which
is supported by the existence of cross-tolerance clinicians often classify the midline component
between PAG/PVG stimulation and opioids as as nociceptive and the radicular component as
well as the suppression of PAG/PVGs eect by neuropathic. Patients presenting with combined
the administration of naloxone [22,67]. More or ambiguous pain types may be best treated with
recently, Nandi et al [68] implicated a thalamic combined implantations of the PAG/PVG and
role in PVG stimulation by describing a reduction VPL/VPM targets.
in pain-related thalamic eld potentials in re-
sponse to low-frequency (535 Hz) PVG stimula- When to consider deep brain stimulation:
tion. Medial stimulation is primarily used for consideration of alternative neurosurgical pain
nociceptive pain. Although some believe it is also interventions
eective for selected cases of neuropathic pain, The goal of neurosurgical pain management is
this is controversial. to provide the patient with maximum pain relief
Specic targets for medial stimulation using the least invasive and safest technique
The primary targets for medial stimulation are available. The following are examples of alterna-
the PAG and the PVG. Although low-frequency tive neurosurgical pain interventions that should
stimulation of either the PAG or PVG is capable be considered in specied cases.
of eective pain relief, the threshold for evoking
Ablative techniques
unpleasant sensations (eg, fear, nervousness,
doom) is lower with PVG stimulation than with Although ablative techniques have largely been
PAG stimulation. Additionally, only the ventral replaced with neuromodulation, some continue to
348 B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357

be used. Tasker and Filho [54] reported that years, a large number of studies have reported
although the steady pain component associated a benet from the use of IDD in nonmalignant
with spinal cord injury may benet from VPL pain, primarily in failed back syndrome. Roberts
DBS, the lancinating and evoked elements may be et al [75] reported a mean reduction in pain of
better treated with ablative techniques. Addition- 60% at 3 years of follow-up. A prior prospective
ally, bilateral cordotomy provides immediate but study assessing IDD in nonmalignant pain re-
short-lived (less than 2 years) pain relief and may ported less dramatic results, however, with 36%
be a safer and more cost-eective alternative in of patients having 50% or greater pain reduction
the setting of intractable cancer pain. Other at 2 years [76].
ablative techniques still used for the treatment of
cancer pain include mesencephalotomy, myelot-
Motor cortex simulation (precentral simulation)
omy, and cingulotomy. As discussed later in this
article, however, intrathecal drug delivery is more MCS, also known as precentral stimulation,
commonly used for cancer pain because it is was rst reported by Tsubokawa et al [77] in 1991.
nondestructive and potentially more ecacious. Although lacking controlled studies, precentral
Finally, endoscopically performed sympathecto- stimulation seems to be as ecacious as thalamic
mies provide pain relief in approximately one DBS in the treatment of a wide variety of
third of those with complex regional pain syn- neuropathic pain types, with successful outcomes
drome (CRPS) type I or II [70]. typically in 50% to 75% of cases [7781].
It has been suggested as a potentially superior
Spinal cord stimulation treatment relative to all other forms of chronic
stimulation used to treat poststroke pain. This
SCS is the caudal analogue of VPL stimulation
may be explained by the fact that thalamic
for the treatment of bodily neuropathic pain. Its
stimulation has been reported to yield painful
mechanism of action is also putatively based on
eects in the setting of poststroke pain. Katayama
Melzack and Walls gate control theory of pain.
et al [80] performed the only comparison between
SCS should be considered as a less invasive but
thalamic DBS and precentral stimulation for
equally ecacious alternative to thalamic/IC DBS
poststroke pain. Although this was not a pro-
for the treatment of neuropathic pain secondary
spective study, these investigators reported that
to peripheral nerve or nerve root injury. SCS is
precentral stimulation achieved excellent pain
contraindicated by obliteration of the spinal
control in 50% of cases, whereas thalamic or IC
epidural space or previous SCS failure. Note,
DBS actually increased the pain. Conversely,
however, that regarding previous SCS failure,
another group reported poor outcomes in the
a correlation is believed to exist between the
treatment of thalamic pain syndromes using
results of SCS and thalamic/IC DBS. Thus, if
precentral stimulation [79]. Nevertheless, numer-
SCS does not alleviate peripheral nerve or nerve
ous subsequent studies have reported good to
root pain, it is likely that DBS of the sensory
excellent outcomes using precentral stimulation
thalamus will also fail [54]. The success rate for
for thalamic pain syndrome [78,82,83].
CRPS types I and II is around 80% to 90% and is
MCS also seems to be particularly ecacious
around 60% to 70% for persistent radicular pain
for facial central pain, with outcomes as high as
after spinal surgery [71]. Notably, the ecacy of
an 83% reduction achieved in 77% of patients
contemporary SCS may be greater than previ-
[78]. Finally, from a safety perspective, although
ously reported because of recent improvements
electrode grid placement requires a craniotomy,
in technique and hardware [72,73].
the procedure is often entirely extradural and thus
less invasive than DBS. To date, there has been no
Intrathecal/intraventricular drug delivery
published report of neurologic injury occurring
The most common use of intraventricular drug secondary to MCS placement [84]. This may be
delivery (IDD) systems (usually infusing opioids) explained by the easily accessible and proportion-
is in the treatment of terminal cancer pain and ately large area of facial representation on the
should be strongly considered when life expec- cortical convexity.
tancy is limited. A recent randomized trial found Two situations in which precentral stimulation
intrathecal drug delivery to be superior (52% is relatively contraindicated are large cortical
decrease) to comprehensive medical management strokes with signicant encephalomalacia in the
in pain control (39% reduction) [74]. In recent intended region of stimulation and the presence of
B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357 349

signicant weakness in the distribution of the pain. Once the optimal placement site is found, the
The treatment of leg pain has been dicult using microelectrode is replaced with the permanent
precentral stimulation simply because of the inter- electrode, which is then secured in place. Al-
hemispheric location of the corresponding cortex. though many groups secure the electrode using
Recently, however, Saitoh et al [85] have reported commercially available plates or caps, the authors
eective treatment of leg pain by placing electrodes prefer using suture tied in serial knots to attach
subdurally in the interhemispheric ssure. the electrode to the perimeter of the burr hole,
which is then embedded in a low-prole layer of
Surgical technique methyl methacrylate. The electrode is then at-
tached to an extension cable, which is externalized
General stereotactic technique
through a second stab incision for trial stimula-
The general stereotactic technique used for the tion. Postoperative MRI or CT allows for assess-
DBS treatment of pain is the same used in the ment of postoperative perielectrode edema or
DBS treatment of other indications. First, stereo- hematoma. Once these resolve, if present, and
tactic imaging is performed using one of several trial stimulation proves ecacious, the intermit-
imaging modalities: MRI, CT, ventriculography, tent pulse generator (IPG) is implanted. The IPG
or some combination of the three. The advantages is implanted through an infraclavicular incision
and disadvantages of each remain topics of debate and should be secured directly to the surface of
[86]. Regardless of imaging modality, almost all the pectoralis fascia. Cables are passed subcuta-
groups use indirect targeting for initial localiza- neously to connect the generator and electrodes,
tion. Indirect imaging involves dening the target resulting in a permanent fully enclosed system that
in relation to third ventricular landmarks, primar- is transcutaneously programmable via telemetry.
ily the anterior commissure (AC) and posterior
commissure (PC), as opposed to direct visualiza-
Paresthesia-producing targets
tion of the target itself. Additionally, these targets
are always incompletely dened; even MRI fails to Ventroposterolateral nucleus, ventralis
identify the thalamic subdivisions clearly. The posteromedialis, and internal capsule
patient is then taken to the operating room with Electrodes implanted in the somatosensory
a stereotactic frame xed to the head maintaining thalamic nuclei are placed in the somatotopic
the identical stereotactic relations present during area corresponding to the location of the pain in
image acquisition. Electrophysiologic renement the contralateral body near the entry site of the
of the target, followed by denitive electrode medial lemniscus. Electrodes implanted in the IC
implantation, is then performed via a precoronal are placed in its posterior limb. The VPM is
parasagittal burr hole using local anesthesia. It is targeted for facial pain, the VPL for bodily pain,
important that the patient remains coherent and the IC when inadequate tissue remains after
during the procedure so as to provide valuable thalamic infarction. For these targets, pain relief
feedback regarding the eects of intraoperative is produced only on the side contralateral to
stimulation. A plethora of electrophysiology sys- implantation. Therefore, implantations can either
tems are commercially available. be unilateral (contralateral to the side of unilateral
Electrophysiologic localization comprises re- pain) or bilateral (for bilateral pain). Stereotactic
cording (detection of neuronal activity) and stim- coordinates for each target are shown in Table 1.
ulation. Electrophysiology involves recording Physiologic localization for all three should be
cellular activity along the potential track of performed from 10 mm above to 6 mm below the
implantation to map the borders of the target AC-PC plane in 2-mm steps [15]. Final electrode
and dene surrounding structures. Stimulation is position along the dorsoventral plane is deter-
performed using either micro- or macrostimula- mined by the location of optimal stimulation
tion. The goal is twofold: to assess for the positive results, specically, the area where the voltage
eects of stimulation (reduction in pain or other threshold for producing paresthesias in the distri-
known prognostically positive signs) and to assess bution of pain is lowest and the threshold for
for adverse stimulation eects (eg, undesirable producing adverse eects is highest. Stimulation-
sensations, muscular contractions). Note that the induced muscle contractions are usually caused by
parameters of intraoperative stimulation should involvement of the corticospinal tract in the
be compatible with those used for chronic stimu- posterior limb of the IC [86]. Although electro-
lation specic to the type of pain being treated. physiology may help to identify entry into the
350 B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357

Table 1 Electrophysiology is valuable for PVG implanta-


Stereotactic coordinates of deep brain stimulation tion by helping to place the electrode in close
targets for the treatment of pain proximity to several adjacent nuclei that some
Target Stereotactic coordinates believe to be correlated with superior outcomes.
VPM X: 810 mm lateral to midline These nuclei are the dorsomedial nucleus (DM),
Y: 810 mm posterior to the Pf nucleus, and the endymalis nucleus [33,86].
AC-PCmidpoint Stimulation eects that are positive prognostica-
Z: 10 mm above AC-PC to 6 mm tors include a feeling of warmth or cold either
below AC-PC in 2-mm steps contralateral or globally, pleasure, and relaxation.
VPL X: 1416 mm lateral to midline These sensations are usually achieved at threshold
Y: 1012 mm posterior to amplitude using a frequency of 50 Hz and pulse
AC-PCmidpoint durations between 0.2 and 1.0 milliseconds [36].
Z: 10 mm above AC-PC to 6 mm
Pain reduction is commonly reported but typically
below AC-PC in 2-mm steps
with a delay of 10 minutes after the onset of
IC X: 25 mm lateral to midline
Y: 1214 mm posterior to stimulation [50]. Hosobuchi [87] reported that the
AC-PCmidpoint single best predictor of correct electrode placement
Z: 10 mm above AC-PC to 6 mm is stimulation-induced inhibition of conjugate
below AC-PC in 2-mm steps upgaze; however, this is potentially associated with
PVG X: 23 mm lateral to wall of 3V oscillopsia, making the setting range narrow.
Y: 2 mm anterior to PC Young and Rinaldi [86] and Young [92] reported
Z: start 2 mm above target characteristic changes of baseline vital signs in
Hypothalamus X: 2 mm lateral to midline response to stimulation when the appropriate
Y: 2 mm posterior to AC-PCmidpoint
target is encountered. These include an increase
Z: 5 mm below AC-PCmidpoint
of heart rate by 32  12, beats per minute, an
Abbreviations: AC, anterior commissure; IC, internal increase in mean systolic blood pressure by 72  21
Capsule; PC, posterior commissure; PVG, periventricu- mm Hg, and an increase in mean diastolic blood
lar gray mutter; VPL, ventropostero latteral nucleus;
pressure by 47  10 mm Hg. Eighty-seven percent
VPM, ventralis posteromedialis; 3V, .
of patients with these changes ultimately had pain
relief versus 26% of patients who did not have these
somatosensory thalamus, the area of stimulation-
cardiovascular changes [86,92] Negative eects of
produced paresthesias and cellular receptive elds
stimulation include the following: blurred vision,
do not always match [36]. Because stimulation
oscillopsia, and nystagmus caused by involvement
delivery is the sole clinically eective component
of the nearby Edinger-Westphal and third cranial
in the end, stimulation results should always take
nerve nuclei; sympathetic responses, such as fear
precedence over electrophysiology results in de-
and anxiety, when placed too anterior; and sensa-
termining the nal electrode position. Typical
tions of vertigo, nausea, and suocation when
long-term stimulation parameters for the VPL
placed too posterior or deep [50,89,93,94]. Un-
and VPM are an amplitude (Amp) of 2 to 8 V,
desirable sensations of fear, anxiety, and burning
a frequency (Freq) of 50 to 100 Hz, and a pulse
are encountered with progressively higher ampli-
width (PW) of 0.2 to 0.8 milliseconds [50].
tudes in the PVG and anterior PAG and are easily
evoked during dorsal PAG stimulation, making it
Medial targets
a less desirable target. Additionally, PAG or PVG
Periaqueductal gray matter and periventricular stimulation below the AC-PC plane has been noted
gray matter to induce such eects commonly [54]. Typical long-
Electrodes implanted in the PAG and PVG are term stimulation parameters for PVG stimulation
placed at the level of the diencephalic-mesence- are an Amp of 1 to 5 V, a Freq of 25 to 50 Hz, and
phalic transition. Although some advocate bilater- a PW of 0.1 to 0.5 milliseconds [50]. Furthermore,
al implantation [87,88], numerous reports indicate higher frequency PVG stimulation (frequency of
that unilateral implantation is sucient to relieve 50100 Hz) has been reported to actually worsen
even bilateral pain [49,8991]. The topic remains pain [68].
controversial. Stereotactic coordinates for each
target are shown in Table 1. Physiologic localiza- Posteroinferior hypothalamic target
tion should start 2 mm above the target and Electrodes are implanted in the posteroinferior
continue until the optimal location is found [89]. hypothalamus ipsilateral to the symptoms of the
B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357 351

CH. Stereotactic coordinates are shown in Table 1. patients. The rate of success in stimulation trials
Physiologic localization begins 10 mm above the is correlated with the quality of patient selection.
target and continues until the optimal location is
found. Electrophysiology may demonstrate hy-
peractive hypothalamic neuronal ring. Notably, Complications
stimulation-induced pain relief has a lag time Overall, complications of DBS for pain are no
between several hours and several weeks after dierent than those seen in DBS for movement
initiation of stimulation [69]. As a result, nal disorders. Although complications do vary ac-
electrode placement is largely guided by stimula- cording to target, implanting the VPL nucleus for
tion-induced side eects. At the optimal site, pain is likely comparable to implanting the
stimulation greater than 4 V elicited conjugate nucleus ventralis intermedius for tremor. DBS
ocular deviation in all cases and was often complications can be divided into two categories:
accompanied by undesirable feelings of near perioperative and long term. The most common
death, whereas no additional side eects were perioperative complication is hemorrhage. Terao
present at routine stimulation parameters: an et al [104] recently reported that hemorrhages
Amp of 0.7 to 3 V, a Freq of 180 Hz, and a PW were seen on the CT scans of 3.4% of 59 patients
of 60 milliseconds [27,28,69]. who received subthalamic nucleus implantations
for the treatment of Parkinsons disease. This is in
Putative new targets agreement with the hemorrhage rates reported by
To date, DBS for pain has not been one of the Bendok and Levy [105]: 1.6% to 4.1% in their
most successful areas of functional neurosurgery. meta-analysis of the literature. The rate of hem-
As a result, pharmacologic, psychotherapeutic, orrhage resulting in neurologic decits, however,
and palliative approaches are taking an increas- was only 0.02%. Regarding overall complication
ingly important place. Not all deep brain targets rates, Beric et al [106] reported that 26 of 86
have been fully explored, however. In the past patients undergoing electrode implantation for
three decades, the properties of a descending movement disorders had an untoward event re-
inhibitory system that originates in the PAG and lated to their procedure. Of these, 6% had
rostral ventral medulla, an area that includes the persistent neurologic sequelae.
NRM and paragigantocellularis, have been well Excluding the development of tolerance, most
documented [9597]. Furthermore, it has been long-term or delayed complications are related to
demonstrated that electrical and chemical stimu- hardware. In the multicenter United States and
lation of these sites produces analgesia and in- European Tremor Trials (n = 197 patients),
hibition of spinal cord nociceptive neurons [98 adverse events related to the device included lead
101]. Revival of DBS for pain might arise from migration or dislodgment (1.0%), lead fracture
the development or use of new targets, such as the (0.5%), infection (1.5%), erosion (2.5%), electri-
NRM [64,65] or the lateral habenula [102,103]. cal short circuit or open circuit (1.0%), and
component malfunction (1.5%) [107]. Oh et al
Trial stimulation and implantation of [108] reported the hardware complications of 79
intermittent pulse generator patients implanted with 124 electrodes during
a mean follow-up period of 33 months. Overall,
Regardless of the pain type or target, a period 20 patients (25.3%) had 26 hardware-related
of trial stimulation beginning several days after complications involving 23 (18.5%) of the electro-
implantation and lasting approximately 1 week is des. A signicant nding was a high number of
used by virtually all groups. The purpose of trial complications involving erosions or infections,
stimulation is to determine if ecacy is possible, which occurred in 7 of 12 instances as a late
and if so, at what stimulation parameters. Stim- complication (beyond 12 months).
ulation is usually deemed successful if it can
improve the patients pain by 50% or greater. If
the trial period demonstrates eective pain relief Outcomes
from stimulation, the IPG is implanted. If stimu-
Outcomes by pain type and target
lation is not ecacious, the IPG is not implanted
and the electrodes may be removed. Kumar et al The general consensus regarding target selec-
[50] reported satisfactory trial stimulation and tion is that neuropathic pain should be treated
subsequent IPG implantation in 78% of 68 with VPM/VPL stimulation, nociceptive pain with
352 B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357

PAG/PVG stimulation, and mixed pain with sumed. No adverse eects were noted in any of the
implantation of both target areas. Although there patients, all had intact trigeminal sensation, and
was previously considerable debate concerning the the benet of stimulation was universally revers-
importance of target-pain type matching in pre- ible [27,28,69].
dicting outcomes, Levys recent meta-analysis of
all reported cases in the literature concluded that Tolerance
it is indeed extremely important [36]. In summary,
Tolerance is the term used to describe the loss
Levy normalized the long-term outcomes of 13
of stimulation-induced benet over time. The
studies in which 1114 patients were treated with
pathophysiology underlying tolerance remains un-
DBS for pain [19,48,49,86,109115]. Long-term
known but is often attributed to a cross-tolerance
success criteria included greater than 50% pain
to opioids. Exhaustion of the serotonergic pathway
reduction, greater than 1 year of stimulator use,
has been considered in both situations, and high-
and an outcome description of good, excellent,
dose l-tryptophan administration has been used to
total, moderate, or complete. Failure criteria
reverse it, with mixed results. High-dose l-trypto-
included less than 50% pain reduction, discontin-
phan is no longer used, however, because it may
uation of the stimulator, and an outcome de-
present a risk of adverse side eects [116]. What
scription of fair, poor, none, slight, or partial.
degree of loss and over what period of time are
He found a long-term success rate of 50% (range:
variable. Although tolerance often develops during
19%79%) for all cases, 47% for neuropathic
the rst year, Kumar et al [50] reported a mean
pain cases, and 61% for nociceptive pain cases.
onset of tolerance for PVG stimulation at 7.1 years
Additionally, the success rates for each pain type
and for thalamic stimulation at 3.8 years. Several
were evaluated according to whether the VPL/
methods have been used to remedy the problem of
VPM or the PAG/PVG was targeted. For neuro-
tolerance. They include altering stimulation pa-
pathic pain, the long-term success rate was 56%
rameters, stimulation holidays, stimulation ramp-
using VPL/VPM and 23% using PAG/PVG. For
ing (gradual augmentation of stimulation intensity
nociceptive pain, the long-term success rate was
in a cyclic manner), and implanting a second
0% using VPL/VPM and 59% using PAG/PVG.
electrode in an alternative target or in the same
In interpreting these results, two opposing
target contralaterally if not already done [50]. Of
factors must be considered. First, a large percent-
these remedies, implantation of a second electrode
age of the reported outcomes represent patients
proved most eective. As stated previously, toler-
operated on during the early stages of DBS for
ance of hypothalamic stimulation was observed in
pain. Assuming that improvements in outcomes
only one of seven cases [28].
accompany the signicant technical advances
made in the eld, one would expect that the
outcomes reported here underestimate the reality
Discussion and summary
of the current state. Second, follow-up periods
were variable among the outcomes reported by Neuromodulation for pain has evolved enor-
various groups. Although Levys normalization mously over the past decade. The general tech-
criteria [36] included continued use of the stimu- nique of electrode implantation into the deep
lator for longer than 1 year, tolerance to DBS has brain has become widespread, in part, because
been reported to occur after the rst year of use. of its application in the eld of movement
Because patients developing tolerance after 1 year disorders. As is true for most aspects of neuro-
would have been considered to have successful surgery, one of the most dicult decisions is
outcomes, one would expect that the outcomes determining the right operation for the right
reported here might be better than reality. patient. Unfortunately, in the treatment of pain,
Outcomes of hypothalamic stimulation for patient and procedure selection are often clouded
intractable CH are presented separately because by multiple variables. As a result, implementation
they have only recently been reported by a single of DBS for pain should be limited to experienced
group and represent the treatment of a relatively multidisciplinary teams.
unique type of pain. Six of the seven patients The fact that pain is a subjective complaint,
treated maintained complete pain relief with directly accessible only by the patient himself and
follow-up periods as long as 3 years. The seventh subject to multiple factors, including socioeco-
patient had a recurrence of symptoms at 18 nomic background, psychological status, and
months for which medical management was re- potential for secondary gain, makes outcome
B.A. Wallace et al / Neurosurg Clin N Am 15 (2004) 343357 353

assessment particularly dicult. As a means to Medical Device Act regulating implantable med-
quantify outcomes, a variety of pain question- ical devices. In the mid-1970s, DBS for pain was
naires and visual analog scales, along with pro- ocially brought to the market just before the law
ductivity measures and quality of life assessments, was put into eect. The law allowed all market-
have been used. The tools employed vary among released devices to remain on the market through
groups, however. Furthermore, although typically a grandfather clause for a period of time. The law
described as 50% pain reduction for greater than also required the US Food and Drug Adminis-
1 year, the denition of long-term success is also tration (FDA) to call for a premarket approval
variable. The lack of clear denition in outcome application, which was eective in 1989. At that
measures, combined with the absence of con- time, there was not sucient FDA quality data, so
trolled studies, makes an accurate comparison the products were taken o the market and an
among pain interventions extremely dicult. investigational device exemption (IDE) was led
Over the past decade, the pain community has to study the therapy/systems. The study struggled
moved away from DBS and toward newer alter- along for a few years, not enrolling sucient
native therapies, namely, MCS for central neuro- patients to le a premarket approval, and even-
pathic pain and SCS for peripheral neuropathic tually was stopped, with the therapy eectively
pain. Although this may, in fact, prove to be removed from the market in the early 1990s. From
a justied move, it is currently a relatively un- that point until the Activa (Medtronic, Minneap-
founded one. There are several major potential olis, Minnesota) therapy was released for tremor,
reasons underlying this move. First and foremost no DBS system was available for pain in the
is a potential perception of superior ecacy United States. Presently, there is no commercially
associated with MCS and SCS. Although this available system specically for pain, meaning
may be true, because of the limitations in outcome that other systems must be used o-label for DBS
analysis, the only currently available information treatment of pain (Mullett K, PhD, Medtronic,
is the nonstandardized outcome data pieced personal communication, 2003).
together in literature reviews. Interestingly, the In summary, although neurostimulation oers
average outcomes for all three modalities (50% the signicant advantage of producing reversible
75%) fall within a range whose dierence is eects in all targets, one must also consider the
possibly attributable to the confounding variables relative disadvantages of cost, risk of hardware
introduced by nonuniform outcome measures and implantation, and specialized follow-up care re-
denitions of success. The second reason may be quired for IPG programming and replacement.
the perception of the relative degree of safety or This being said, however, neuromodulation oers
invasiveness associated with each procedure. MCS selected patients an eective and safe solution for
and SCS are typically extradural procedures, their legitimate quest of intractable pain relief.
whereas DBS, by nature, is not. Although all
have an associated risk for complications, none is
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