Download Deep brain stimulation for medically intractable cluster headache

Neurobiology of Disease 38 (2010) 361–368
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Neurobiology of Disease
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n b d i
Review
Deep brain stimulation for medically intractable cluster headache
Karl A. Sillay a,⁎, Sepehr Sani b, Philip A. Starr c
a
b
c
Department of Neurosurgery, University of Wisconsin, Madison, USA
Department of Neurosurgery, Rush University Medical Center, Chicago, USA
Department of Neurosurgery, University of California, San Francisco, USA
a r t i c l e
i n f o
Article history:
Received 3 February 2009
Revised 27 April 2009
Accepted 25 May 2009
Available online 6 June 2009
Keywords:
Cluster headache
Deep brain stimulation
Posterior hypothalamic area
Stereotactic neurosurgery
a b s t r a c t
Cluster headache is the most severe primary headache disorder known. Ten to 20% of cases are medically
intractable. DBS of the posterior hypothalamic area has shown effectiveness for alleviation of cluster headache
in many but not all of the 46 reported cases from European centers and the eight cases studied at the University
of California, San Francisco. This surgical strategy was based on the finding of increased blood flow in the
posterior hypothalamic area on H15
2 O PET scanning during spontaneous and nitroglycerin-induced cluster
headache attacks. The target point used, 4–5 mm posterior to the mamillothalamic tract, is in the border zone
between posterior hypothalamus, anterior periventricular gray matter, and inferior thalamus. Recently,
occipital nerve stimulation has shown efficacy, calling in question the use of DBS as a first line surgical therapy.
In this report, we review the indications, techniques, and outcomes of DBS for cluster headache.
© 2009 Elsevier Inc. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . .
Overview of cluster headache . . . . . . . . . . . . .
Evidence for hypothalamic area involvement in CH. . .
Indications for DBS . . . . . . . . . . . . . . . . . .
Inclusion criteria . . . . . . . . . . . . . . . . .
Exclusion criteria. . . . . . . . . . . . . . . . .
Pre- and postoperative evaluation . . . . . . . . . . .
Surgical technique . . . . . . . . . . . . . . . . . .
Defining the brain target by brain atlas and by MRI
Single unit recording . . . . . . . . . . . . . . .
Lead placement and intra-operative test stimulation
Lead anchoring and IPG placement . . . . . . . .
Documentation of electrode locations . . . . . . . . .
Device programming . . . . . . . . . . . . . . . . .
Clinical outcomes . . . . . . . . . . . . . . . . . .
Time course for stimulation-induced relief. . . . . . .
Complications . . . . . . . . . . . . . . . . . . . .
Perioperative complications . . . . . . . . . . . .
Stimulation-induced adverse events . . . . . . . .
Potential mechanism of action . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author. Department of Neurosurgery, University of Wisconsin, Madison, K4/842 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. Fax: +1
608 263 1728.
E-mail address: [email protected] (K.A. Sillay).
Available online on ScienceDirect (www.sciencedirect.com).
0969-9961/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.nbd.2009.05.020
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K.A. Sillay et al. / Neurobiology of Disease 38 (2010) 361–368
Introduction
Cluster headache (CH) is the most severe of the primary headache
disorders. It affects approximately 1 in 1000 persons, and 20% of
patients are significantly disabled in spite of optimal medical therapy
(Russell 2004). Peripheral nerve ablation procedures have been
performed for CH, with little benefit. Positron emission tomography
(PET) using 15-O-H2O as the tracer has shown a focal increase in
cerebral blood flow in the ipsilateral posterior hypothalamic region
during a CH attack in addition to areas with increased cerebral blood
flow with other pain syndromes (May et al., 1998, 2000). Based on this
finding, in 2000 a promising new surgical procedure for severe CH was
introduced in Milan, Italy: chronic deep brain stimulation (DBS) of the
posterior hypothalamic region (Leone et al., 2001). To date, four openlabel case series have been published, three from European centers
and fourth from our own (Schoenen et al., 2005; Leone et al., 2006;
Starr et al., 2007; Bartsch et al., 2008). Additional centers have
published case reports bringing the number of reported cases above
50 (Wilkinson et al., 2004; Benabid et al., 2006; D'Andrea et al., 2006;
Rasche et al., 2006; Mateos et al., 2007; Owen et al., 2007). In the four
case series, most patients received major benefit, but approximately
25% of patients were nonresponders.
Many aspects of this novel therapy remain to be elucidated,
including the actual proportion of patients who respond favorably, the
degree and duration of response, presurgical predictors of outcome,
the mechanism of action, the time course of onset and washout of the
therapeutic effect, optimal programming parameters, and the the
safety of the procedure. Currently, no commercial DBS device has US
or European regulatory approval for this emerging indication. This
report reviews the relevant features of CH, surgical indications for
DBS, surgical techniques, clinical outcomes, and possible mechanism
of action.
disappointing, with a low rate of persistent headache relief and a high
rate of facial anesthesia. In addition, there are case reports of patients
with CH who had no relief of pain with complete interruption of the
trigeminal nerve, despite having complete facial anesthesia, indicating
that peripheral nociception is not necessary to the experience of pain
in CH (Matharu and Goadsby, 2002; Leone 2004).
Evidence for hypothalamic area involvement in CH
May and colleagues referenced the striking circadian pattern of
cluster attacks and suggested involvement of hypothalamic centers
(May et al., 1998). Hypothalamic centers including the supraoptic and
lateral hypothalamic areas have been associated with circadian
rhythms (Saper et al., 2005). Recently, both functional and structural
imaging have provided evidence for specific abnormalities within the
hypothalamic area in CH. Positron Emission Tomography (PET) using
H15
2 O has shown increased regional cerebral blood flow (rCBF) in the
ipsilateral posterior “hypothalamic grey matter” in nine CH patients
during nitroglycerin-induced CH attacks, in comparison with eight
control CH patients who were not having headache (May et al., 1998,
2000). Voxel-based MRI morphometry has shown an increase in the
size of the same area showing PET activation in 25 patients with CH,
compared with 29 healthy controls (May et al., 1999). Significant
increases in rCBF in this region have also been shown in an individual
CH patient during a spontaneous headache, in comparison with the
same individual without headache (Sprenger et al., 2004). The results
of SPECT imaging in CH have been inconsistent (May and Leone,
2003). Functional MRI (fMRI) has been used to study isolated cases of
headache disorders closely related to cluster headache, included
under the broader heading of trigeminal autonomic cephalgia (May et
al., 1999; Sprenger et al., 2004, 2005). fMRI has shown blood oxygen
level dependent (BOLD) contrast changes in the ipsilateral hypothalamic area during spontaneous pain attacks in these disorders.
Overview of cluster headache
Indications for DBS
The international headache society defines cluster headache as a
primary headache disorder characterized by recurrent attacks of
excruciating unilateral periorbital pain, usually with evidence of
ipsilateral cranial autonomic hyperactivity, including lacrimation,
conjunctival injection, ptosis, or meiosis (2004). Attacks may occur
from once every other day to eight times a day and last 15–180 min.
Attacks tend to occur at regular times of the day. The prevalence of
CH is approximately 0.2% (Russell 2004). In the episodic form of CH,
affecting 80–90% of patients, attacks occur seasonally, with periods
of complete remission. In the chronic form, affecting 10–20% of
patients, remissions do not occur or last less than 1 month (May and
Leone, 2003). During the active period of headache attacks, a CH
attack may be triggered by sublingual nitroglycerin, and has been
used to experimentally trigger attacks (May 2005). Alcohol consumption is also a common trigger and this history is considered
useful diagnostically.
Prophylactic medical therapy of CH includes verapamil, ergot
derivatives such as methysergide, lithium carbonate, divalproic acid,
melatonin, and corticosteriods (May and Leone, 2003). Abortive
medical therapy includes the use of 100% oxygen, injectable
sumatriptan, ergotomines, indomethacin, intranasal lidocaine or
capsaicin, corticosteroids and opiate medications (May and Leone,
2003). Among those patients who fail medical therapy, the chronic
form is disproportionately represented, and those who have had
chronic CH for at least one year are unlikely to have a spontaneous
remission in the following year (Manzoni et al., 1991).
Prior to 2000, surgical therapy for CH was directed at interruption
of the trigeminal nerve by chemical ablation, balloon compression,
partial or complete surgical sectioning of the trigeminal root (Jarrar et
al., 2003), or radiosurgical ablation of the trigeminal dorsal root entry
zone (Donnet et al., 2005). The results of these procedures have been
The European group who developed this procedure has published
guidelines for surgical treatment (Leone et al., 2004). These criteria
emphasize the need for the accurate diagnosis of the disorder, the
failure of standard medical therapy at maximally tolerated doses, and
the exclusion of those in whom the natural course of spontaneous or
episodic remissions would be mistaken for a DBS treatment response.
Patients who fail to respond to preventative treatments such as
verapamil, lithium, methysergide, melatonin, and prednisolone may
still respond to abortive agents such as sumatriptan, zolmitriptan,
oxygen, dihydroergotamine, or octreotide (Goadsby 2007). The time
course for CH symptom onset as compared to relief from abortive
medications may leave the patient in sufficient distress to continue
consideration for surgical intervention, however.
Two recent publications on occipital nerve stimulation (ONS) for
CH show similar efficacy overall to the world experience with
hypothalamic DBS, with approximately 60% of patients as responders
based on N50% reduction in headache severity or frequency (Burns et
al., 2007; Magis et al., 2007). Since the publication of these two
papers, we have changed our algorithm for surgery: patients with
medically intractable chronic CH are offered ONS, with the possibility
of proceeding to DBS after 1 year if the ONS fails.
Our own criteria (⁎), modified and expanded from the published
guidelines (Leone et al., 2004), are as follows:
Inclusion criteria
1) Patients must meet the International Headache Society (IHS)
diagnostic criteria for CH (2004).
⁎2) At least 6 debilitating headaches per week which should be rated
by the patient at least 6 on a visual-analog scale of 1–10.
K.A. Sillay et al. / Neurobiology of Disease 38 (2010) 361–368
3) Inadequate relief from prophylactic therapy, to include: verapamil, lithium, divalproex sodium, methysergide, topiramate,
gabapentin, nonsteroidal anti-inflammatory agents including
indomethacin, and short-term use of corticosteroids.
⁎4) Inadequate relief from abortive therapy, to include: oxygen,
sumatriptan, opiates.
5) Chronic form of CH for at least two years, with headache always
lateralizing to the same side.
⁎6) Successful completion of daily headache diaries over a onemonth period prior to surgery, to measure pre-operative headache characteristics.
⁎7) Failure of occipital nerve stimulation therapy for at least one year.
Exclusion criteria
1.) Serious untreated psychiatric comorbidity.
2.) Any medical condition that increases the risk of stereotactic
neurosurgery, including untreated hypertension, coagulopathy,
severe diabetes, serious cardiac or pulmonary disease, or medical
need for chronic anticoagulation with coumadin.
3.) Any medical condition that greatly limits the life expectancy of
the patient.
⁎4.) A concomitant headache disorder distinct from CH, such as
migraine, which affects the patient greater than twice per month.
5.) Any other serious chronic neurologic disorder (such as epilepsy,
multiple sclerosis, degenerative brain disease).
6.) Inability to undergo screening brain MRI.
7.) Screening MRI showing a brain mass, prior stroke, brain atrophy
out of proportion to age, small vessel ischemic disease, or ectatic
blood vessels near the stereotactic target.
⁎8.) Age b18 or N75.
9.) Pregnancy.
Pre- and postoperative evaluation
Patients undergo a screening visit with a headache neurologist
as well as the neurosurgeon to check inclusion and exclusion
criteria for surgical therapy. Prior to surgery, patients are required to
complete headache diaries daily for four consecutive weeks in the
month prior to surgery, during the first 3 months after surgery, and
during the 6th and 12th months following surgery. Patients were
carefully instructed on how to score their daily headache diary: 1)
the time of day each headache episode occurred, 2) the duration of
the headache, 3) the intensity on a visual-analog scale of 1–10 of
the headache (1— slight pain, 10— worst imaginable pain), and 4)
the use of abortive and prophylactic medications. Patients were
also instructed to make note of headaches that were not characteristic of their usual cluster attacks, in order to screen for the
presence of other concurrent primary headache disorders. Headache characteristics are averaged from headache diaries over a onemonth period. In our practice, patients are considered “responders”
to DBS therapy if at the one year time point, there is a N50%
reduction in headache frequency, intensity, or both, compared to
the pre-operative baseline.
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Defining the brain target by brain atlas and by MRI
Following placement of the stereotactic headframe (Leksell series
G, Elekta, Inc.), MRI is performed on a 1.5 T scanner (Phillips Intera,
Best, the Netherlands). Two MR image sets are obtained: 1.) A
volumetric gadolinium-enhanced gradient echo (3D-GRE) MRI covering the whole brain in 1.5 mm axial slices, which is mainly for
trajectory planning and visualization of the anterior and posterior
commissures (parameters: TR = 20, TE = 2.9, matrix = 256 × 192, flip
angle = 30°, NEX = 1). 2.) a T2-weighted fast spin echo (T2FSE)
sequence, limited to the diencephalon and midbrain, in the axial plane
at 2 mm slice thickness. The T2FSE scan is mainly for visualizing
structural detail in the immediate vicinity of the brain target, the
mammillothalamic tract and the red nucleus. (parameters: TR = 3000,
TE = 90, matrix = 268 × 512, NEX = 6, bandwidth = 183 Hz/pixel,
interleaved). Both image sets are imported into a stereotactic surgical
planning software package (Framelink version 5.1, Medtronic-SNT,
Boulder, CO), computationally fused, and reformatted to produce
images orthogonal to the anterior commissure–posterior commissure
(AC–PC) line and midsagittal planes.
As reported by the Milan group, the anatomic target in commissural
coordinates is 2 mm lateral to the midline, 5 mm inferior to the axial
plane containing anterior and posterior commissures, and 3 mm
posterior to the midcommissural point (Franzini et al., 2003). This
target was selected to correspond to the brain region that has increased
rCBF on H15
2 O PET during CH attacks in the study of May et al. (2000).
The target is plotted in Fig. 1 with respect to the appropriate axial slice
from the Schaltenbrand et al. human brain atlas (Schaltenbrand et al.,
1977). This brain slice (which is slightly oblique with respect to the
commissural plane) shows the continuous rim of grey matter lining
the inferior wall of the third ventricle and the upper Sylvian aqueduct.
This continuum includes the hypothalamus proper, the periventricular
grey (PVG),and the periaqueductal grey, bordering the parafascicular
and subparafasicular nuclei of the thalamus. The asterisk in Fig. 1
indicates the Milan DBS target, which has been the surgical target in all
published series. Some anatomists consider the mammillothalamic
tract as the posterior border of the hypothalamus (Schaltenbrand et al.,
1977; Swaab 2003), but some human brain atlases depict the
Surgical technique
The surgical technique is similar to that used for placement of
DBS electrodes into the basal ganglia for movement disorders:
MRI based stereotaxy, microelectrode recording in the region of
the MRI-defined target, and intra-operative test stimulation using
an external pulse generator, to define voltage thresholds for
stimulation-induced adverse effects (Starr 2002). Intravenous
sedation is used during the initial exposure of the surgery.
Sedation is not normally used for microelectrode recording or test
stimulation.
Fig. 1. Anatomy of the hypothalamus, periventricular gray (PVG) and periaqueductal
gray (PAG), from the Schaltenbrand and Warren human brain atlas (Schaltenbrand et
al., 1977, Starr et al., 2007), reprinted with permissions. MTT = mammillothalamic tract,
RN = red nucleus. The asterisk marks the target point for DBS in cluster headache, based
on the work of Franzini et al. (2003).
364
K.A. Sillay et al. / Neurobiology of Disease 38 (2010) 361–368
Lead placement and intra-operative test stimulation
Fig. 2. Two second segment of single unit microelectrode recordings 6 mm dorsal, 1 mm
dorsal, and 0.5 mm beyond the stereotactic target. From Starr et al. (2008), reprinted
with kind permission of Springer Science + Business Media.
hypothalamus as extending several mm posterior to the mammillothalamic tract (Talairach and Tournoux 1988). There is no consensus
among anatomists regarding the precise border between the hypothalamus and the PVG (Swaab 2003). Therefore, the “hypothalamic” DBS
target published by the Milan group could be considered to be in the
hypothalamic area including the posterior hypothalamus, anterior
PVG, and superiorly bordered by the parafascicular and subparafascicular nuclei are seen on another atlas (Mai et al., 2004).
To account for possible variations in diencephalic anatomy that
may affect target coordinates as measured from the commissures, we
utilize the T2FSE sequence to confirm that the intended target point is
located 3–5 mm posterior to the mammillothalamic tract and is
medial to the anterior border of the red nucleus, on the axial plane
5 mm inferior to the intercommissural line. The AC–PC based
coordinates are modified, if needed, to ensure that the anatomic
target lies in a consistent relationship to the mammillothalamic tract
and red nucleus.
A “default” trajectory through the brain is set at 60° from the AC–
PC line in the sagittal projection and 10° lateral from the vertical in the
coronal projection. This trajectory is visualized on the Gadoliniumenhanced volumetric MRI. Small adjustments in the arc and ring
angles are then made to avoid traversing sulci, lateral ventricle,
cortical veins, and dural venous lakes.
Following confirmation of target depth with microelectrode
recording, the permanent lead is placed. We have used the Medtronic
model 3387 lead (contacts spaced over 10.5 mm) while others have
used the model 3389 lead (contacts spaced over 7.5 mm). Test
stimulation is performed in bipolar mode using contacts 0−, 3+,
185 Hz, and 60 μs pulse width (model 3625 external tester, Medtronic,
Inc., Minneapolis MN). After cautioning the patient about potential
stimulation-induced sensations (double vision, dizziness, vertigo,
mood changes) voltage is increased at 0.5 V/sec up to 6 V, during
continuous examination of the patient's cranial nerve function.
Voltage threshold for oculomotor disturbance, or subjective phenomena such as mood change, are noted. The patient's blood pressure and
pulse are carefully monitored during test stimulation, although no
changes in vital signs have been noted during our preliminary studies.
A threshold for oculomotor disturbance (typically gaze paralysis, skew
deviation, nystagmus or subjective double vision) of 2–6 V is
consistent with lead placement at the intended target. Some patients
experience dysphoria at N3 V.
Lead anchoring and IPG placement
Leads are anchored to the skull with a lead anchoring device (Stimlock, Medtronic Inc.). After scalp closure and headframe removal,
general anesthesia is induced for placement of the lead extender and
pulse generator (Soletra, Medtronic Inc. Minneapolis MN).
Documentation of electrode locations
Postoperative MRI to demonstrate the location of the electrode tip
is performed in all cases, according to the published safety guidelines
for performing brain MRI in patients with implanted DBS systems
(Medtronic ; Rezai et al., 2004). Fig. 3 shows the typical location of the
electrode tip on axial MRI, 5 mm inferior to the intercommissural line,
from our series. In this axial plane, the mean (+/− standard
deviation) distance of the lead posterior to the mammillothalamic
tract is 4.8 +/− 0.9 mm (N = 7 cases).
Device programming
Programming parameters in our patients were based on the two
previously published case series (Franzini et al., 2003; Schoenen et al.,
Single unit recording
A single microelectrode penetration is made to the steretotactic
target, allowing monitoring of the implant trajectory and potentially
guiding DBS electrode implant depth. Only two recent publications
explore single unit recordings in the posterior hypothalamic region
(Cordella et al., 2007; Sani et al., 2009). Examples of spontaneous
single unit discharge in the target region are shown in Fig. 2. In
twenty-four neurons analyzed from our limited series, the target area
is characterized by sparse, low amplitude, wide action potentials in a
regular pattern at a low frequency (13.2 ± 12.2 Hz; mean ± SD). The
inferior boundary of the target is marked either by the interpeduncular cistern or the red nucleus, depending on the angulation of the
lead and the patient's individual anatomy (Sani et al., 2009). If the
most distal segment of the recording shows electrical silence
(characteristic of cisternal entry) or dense neuronal units with narrow
action potentials and high-frequency discharge 30–50 Hz (characteristic of the red nucleus), the recording is stopped and the lead depth
accordingly adjusted slightly more superiorly. Continued advancement of a microelectrode into a region of electrical silence beyond the
target is not recommended due to proximity to the basilar artery
bifurcation and associated perforating branches.
Fig. 3. DBS electrode location on postoperative MRI (axial T2 weighted fast spin echo).
The white arrows indicate the locations of the mammillothalamic tract (MTT) and the
tip of the DBS electrode. From Starr et al. (2007), reprinted with permission.
K.A. Sillay et al. / Neurobiology of Disease 38 (2010) 361–368
365
Table 1
Outcome of hypothalamic DBS for CH in five patients.
Case #
1
2
3
4
5
Averages
Age (yrs) /
sex
Disease
duration (yrs)
Follow-up
(months)
Pre-operative status
Most recent status with (% change)
# HA per week
Mean HA intensity (VAS 1–10)
# HA per week
Mean HA intensity (VAS 1–10)
Responder
58 / M
42 / M
41 / M
66 / F
38 / M
49 / 4M:1F
30
9
12
16
8
15
12
12
12
12
6
10.8
13
22
16
51
6
21.6
6.7
4.9
7.5
6.4
7.8
6.66
12 (− 8%)
4 (− 82%)
16 0%
56 (+ 10%)
1 (− 83%)
17.8 (− 17.6%)
2.6 (− 61%)
2.5 (− 49%)
7.5 0%
4 (− 37.5%)
6.5 (− 17%)
4.62 (− 30.6%)
YES
YES
NO
NO
YES
60%
Responders
The percentage change in headache parameters compared to the baseline preoperative status is given in parentheses. Headache intensity is rated on a 1–10 visual analog scale with
10 equal to the most severe possible pain, and 1 equal to mildest perceivable pain. The mean values are averaged from all headaches in a one-week period as reported on headache
diaries completed daily at home. Cases 1, 2, and 5 are considered “responders” to DBS based on a N 50% reduction in headache intensity or frequency. Averages appear below in each
column. Adapted from Starr et al. (2008), with kind permission of Springer Science+Business Media.
Abbreviations: M = male, F = female, HA = headache, VAS = visual analog scale.
2005): Monopolar stimulation, pulse width of 60 μs, frequency 185 Hz,
and voltage 1–3 V (stopping short of the threshold for acute persistent
stimulation-induced adverse effects). Devices were kept activated at
all times postoperatively. Our detailed postoperative programming
protocol is as follows:
Week 0 (one week post surgery):
1.) Activate the device in monopolar mode using pw = 60 μs,
frequency = 185 Hz. Record voltage threshold for stimulationinduced adverse effects (typically dizziness or visual disturbance),
at all contacts in monopolar mode.
2.) Review postoperative MRI to determine which contact is closest to
the intended target (usually contact 0 or 1), and select this
contact. Slowly increase the voltage up to 2.0 V, or to 0.1 V less
than the threshold for persistent side effects, whichever is higher.
3.) Verify normal impedances and battery life using the programmer.
Weeks 4,8,12,26:
1.) Review headache diaries. If debilitating headaches have persisted
in the prior month, increase voltage by 0.5 V, or to 0.1 V less than
the threshold for persistent side effects whichever is greater.
2.) If the patient has reached 3.0 V without headache relief, switch
contact choice to the next most superior contact. Slowly increase
the voltage up to 3.0 V, or to 0.1 V less than the threshold for
persistent side effects, whichever is greater. Verify normal
impedances and battery life using the programmer.
Clinical outcomes
The short-term clinical outcomes of DBS for CH appear promising
in many but not all patients. The Milan group has published the
largest series with sixteen patients and mean follow-up time of
4 years (Leone et al., 2006, 2008). Patients were not followed using
headache diaries, quality of life measures, or other standardized tools.
They report “major improvements” in pain during the first two years
in 13 patients. They report a persistent “pain-free state” in 10 patients
(62%) at four-year follow-up. Efficacy has been lost in three patients
during the last two years of follow-up. They do report a change in
illness from chronic to episodic in these three patients. Formal blinded
trials with DBS on and off were not performed. Several patients had
inadvertent inactivation of the device (due to electrical malfunction of
the device) with recurrence of attacks, indicating that the benefit of
stimulation was unlikely to be due to placebo. A detailed four-year
follow-up on their initial patient was published, showing that the
headache attacks have been consistently eliminated with the stimulator on (Leone 2004).
A German multi-center group recently reported six patients with
mean follow-up of 17 months. Four of six patients showed a “profound”
decrease of their attack frequency and pain intensity during the first
6 months. One patient returned to baseline after 6 months of response.
Two patients had experienced only a marginal, non-significant
decrease within the first weeks under neurostimulation before
returning to their former attack frequency. At 17 months, three
patients were “almost completely attack free,” with three treatment
failures (Bartsch et al., 2008).
A group in Liege, Belgium reported on four of their six implanted
patients with a mean clinical follow-up of 14.5 months (Schoenen et
al., 2005). Two of the four are free of headache attacks; a third had the
frequency of attacks reduced to less than 3/month, while the fourth
has had only transient benefit with each reprogramming.
Our own series includes eight patients, with follow-up on five
(Table 1). Patients were followed using headache diaries in which the
frequency, intensity, and duration of headaches were recorded daily
for one month prior to surgery and for one month at the 6 month and
12 month follow-up times. The length of follow-up is 12 months for
the first four patients and 6 months for the final patient. Three of five
patients (cases 1, 2, and 5) may be considered “responders” based on a
N50% reduction in headache frequency, intensity, or both. One of the
three responders (case 2) had been using sumatripitan injections to
reduce the intensity and duration of each headache, and has not
required any abortive therapy postoperatively due to the much lower
intensity. Case 3 had transient complete suppression of headaches for
1–2 weeks following each re-programming session, but no persistent
benefit in headaches, or reduction in abortive therapy, in the intervals
Table 2
Outcomes published in the literature with at least one-year follow-up.
Publication(s)
Reported patients
Follow-up (years)
Responders (number)
Leone et al. (2006)
Rasche et al. (2006); Bartsch et al. (2008);
Rasche et al. (2008)
Starr et al. (2007, 2008) Starr and Ahn (2008)
Schoenen et al. (2005)
D'Andrea et al. (2006)
Mateos et al. (2007) (abstract)
Benabid et al. (2006) (abstract)
16
6
4
1.4
10
3
62%
50%
5
4
3
2
1
1
4
2.5
1
1
3
2
2
2
1
60%
50%
66%
100%
100%
Adapted from Leone et al. (2008), with permission.
Responders (percent)
366
K.A. Sillay et al. / Neurobiology of Disease 38 (2010) 361–368
between programming changes. He no longer uses the device. Case 4
has had a 30% reduction in headache intensity, which failed to meet
the 50% threshold to be considered a “responder”.
In sum, these open-label series indicate that 50–75% of CH patients
have substantial relief of headache symptoms 1–4 years postoperatively (Table 2). In those who benefit, headache episodes remain
present but are decreased in intensity and frequency. Prophylactic and
abortive medications are reduced in many cases. Improvements with
DBS appear durable over time, although Leone, et. al have reported a
decrease in efficacy in the last two years of follow-up. These early
findings should be confirmed with controlled blinded studies. Since a
proportion of patients with CH appear to not benefit in a significant
way from DBS, a method of prospectively predicting response to
therapy is needed.
Time course for stimulation-induced relief
The time course for wash-in and wash-out of the stimulationinduced relief has been studied in detail in only one published case
(Leone 2004). This patient had the unusual occurrence of bilateral
attacks and was thus implanted bilaterally. The devices were turned
off several times over four years, and only turned on again when
headaches recurred. The mean time for onset of headache suppression
following DBS activation was 16 days (range 2–46 days) and the mean
time for headache recurrence following DBS inactivation was 73 days
(range 2–290 days). The longest time for headache recurrence,
290 days, occurred on the side of the head where headaches were
episodic, not chronic, and thus may reflect a temporary spontaneous
remission on that side rather than a true prolonged washout time.
Other patients in the Milan series, as well as those in the University of
California, San Francisco and Liege series were also noted to require
days to weeks for onset of benefit, but the exact time course was not
quantified.
Complications
Perioperative complications
The authors of the Milan series of 16 patients reported one
asymptomatic third ventricular hemorrhage. In the Liege series, there
were surgical complications in two of the six patients: one died of a
large intracerebral and intraventricular hemorrhage several hours
after surgery, and one could not complete the implantation due to a
panic attack during physiological mapping of the target site. In our
series of 8 patients, there was a single surgical complication: an
intra-operative transient ischemic attack (TIA) in the first case. This
occurred immediately following intra-operative test stimulation
using the deepest contact at 60 μs, 185 Hz, up to 10 V. The patient
was noted to be drowsy and hemiplegic on the side ipsilateral to the
implant, which resolved completely in 5 min. Pulse and blood
pressure were unchanged during the episode. Emergent head CT scan
showed no hemorrhage. However, the DBS tip was noted to be
slightly deep to the target, having exited the floor of the third
ventricle, in the interpeduncular cistern at the midline. It is possible
that test stimulation in the setting of the interpeduncular tip
placement may have induced spasm of a contralateral thalamoperforator, resulting in transient capsular ischemia and ipsilateral motor
deficit. Contact 0 was not used in subsequent programming. TIAs did
not recur in this patient and did not occur in the subsequent six
patients.
Stimulation-induced adverse events
In all three series, voltage-limiting stimulation-induced adverse
effects were reported to be oculomotor disturbance or dizziness
above 1.5–3 V. One patient developed stimulation-induced brady-
cardia at therapeutic stimulation parameters requiring temporary
cessation of therapy (Leone 2004). Long-term stimulation-induced
adverse effects of unilateral implantation have been minor: In the
Milan series, detailed blood pressure measurements showed that
chronically stimulated patients developed asymptomatic orthostatic
hypotension (Franzini et al., 2004). Persistent mood changes have
not been observed. In the Milan series, most patients experienced
a mild weight loss, attributed to cessation of corticosteroids (Leone
et al., 2006).
Potential mechanism of action
CH may be triggered by heat, is associated with ipsilateral autonomic
signs, has been associated with systemic autonomic and vascular
changes. Cyclic phenomenon in daily pattern and yearly pattern along
with symptoms have indirectly implicated involvement of the suprachiasmatic nucleus, hypothalamic area, thalamus, midbrain, and
trigeminovascular systems (Swaab 2003). Although metabolic studies
have suggested involvement in the bilateral anterior cingulate cortex,
contralateral posterior thalamus, ipsilateral basal ganglia, bilateral
insulae, and cerebellar hemispheres, anatomic and metabolic studies
have identified unique features of the ipsilateral hypothalamic area.
The anatomy of the target region immediately posterior to the
mammillothalamic tract is complex. An initial MRI tractography study
has documented cortical and subcortical connectivity (Owen et al.,
2007). Axons associated with the medial forebrain bundle, containing
fiber tracts involved in all major ascending catecholaminergic systems,
as well as hypothalamic efferent projections to brainstem and spinal
cord, probably traverse this area (Jones and Moore, 1977; Saper et al.,
1979; Swanson and Cowan 1979). The fasciculus retroflexus, a
pathway connecting the habenular nucleus with the serotonergic
interpeduncular nucleus, also travels within the target region.
The superior border of the target region contains the parafascicular
and subparafasicular nuclei. The subpafafasicular nucleus has been
implicated in pain medication via calcitonin gene-related peptide
(CGRP)-containing neurons (De Lacalle and Saper, 2000) and has
been shown to have hypothalamic (Wang et al., 2006) and posterior
insular connectivity (Shi and Cassell, 1998). Recently CGRP antagonists, which have a vasodillatory effect, have shown promise in
treating vascular headache including migraine (Olesen et al., 2004).
Indeed in our series, the most frequently activated contact was 3 mm
rostral to the distal electrode contact and closer to thalamic nuclei
than the distal contact.
Although this complex anatomy raises many possible mechanisms,
several physiologic studies have proven informative. In the four implanted
patients in the Liege series, (Schoenen et al., 2005), chronic DBS had no
effect on urinary excretion of cortisol or melatonin, and no effect on
plasma levels on oxytocin and vasopressin. There was no long-term effect
on pressure pain thresholds in the supraorbital area, indicating that a
general analgesic effect could not explain the headache benefit. Local field
potential recordings in one patient during surgical implantation showed a
significant 20 Hz power increase, during the attack indicating a potential
marker for headache onset (Brittain et al., 2009).
Magnetoencephalography has shown widespread cortical and
subcortical connectivity in patients undergoing high-frequency deep
brain stimulation of the hypothalamic area (Ray et al., 2007). Ten of
the patients implanted in Milan have undergone PET imaging during
acute activation and deactivation of the DBS device (May et al., 2006).
Acute activation was associated with increased activity in the
ipsilateral hypothalamus, ipsilateral thalamus, somatosensory cortex
and precuneous, anterior cingulate cortex, and trigeminal nucleus.
There was deactivation in the posterior cingulate and contralateral
insula, regions known to be associated with pain sensation
(Ostrowsky et al., 2002). Major structures of the descending
antinociceptive system, including periaqueductal gray and rostral
ventromedial medulla, were not affected, suggesting that the effect
K.A. Sillay et al. / Neurobiology of Disease 38 (2010) 361–368
does not work through these descending systems in spite of their
extensive hypothalamic connections. This PET study only examined
acute effects of DBS (within minutes of activation). These acute DBSinduced changes may not reflect chronic changes underlying the HA
suppression, given that the time course for onset of the anti-headache
effect appears to be days to weeks.
Although the treatment of CH with DBS of the posterior
hypothalamic region is a new approach, nearby brain targets have
been previously explored for the treatment of other chronic pain
disorders. A number of investigators, working mainly between 1975
and 1990, reported deep brain stimulation of the PVG for neuropathic
pain syndromes. Young et al. (1985) reported the PVG target to be
10 mm posterior to the midcommissural point and 3–4 mm lateral to
the midline. This target is 8.5 mm superior and posterior to the Milan
CH target. An autopsy study of 7 patients who had undergone DBS for
neuropathic pain confirmed that effective electrodes were located
near the posterior commissure, well posterior to the CH target (Baskin
et al., 1986). Based on anatomic considerations, the Milan procedure is
in a brain region that is distinct from prior attempts at neuromodulation for other chronic pain conditions. Likewise, previously explored
targets for ablative surgeries for pain were not identical to the CH
target. Sano et al. (1975) utilized hypothalamotomy for chronic
neuropathic pain, but his target was immediately lateral to the
mammillothalamic tract and thus 3–5 mm anterior to the CH target.
The thalamic centromedian and parafascicular nuclei have also been
lesioned for pain treatment, but this target is 6–8 mm superior and
lateral to the CH target (Jeanmonod et al., 1993; Whittle and
Jenkinson, 1995; Young et al., 1995). Stimulation of periaqueductal
gray, posterior hypothalamus, anterior hypothalamus, subcommissural structures, is now being attempted via implanted intraventricular electrodes (Benabid et al., 2006).
Summary
CH is the most severe primary headache disorder known. Ten to
20% of cases are medically intractable. DBS of the posterior
hypothalamic area has shown effectiveness for alleviation of CH in
many but not all of the 46 reported cases from European centers and
the eight cases studied at the University of California, San Francisco.
This surgical strategy was based on the finding of increased blood flow
in the posterior hypothalamic area on H15
2 O PET scanning during
spontaneous and nitroglycerin-induced CH attacks. The target point
used, 4–5 mm posterior to the mamillothalamic tract, is in the border
zone between posterior hypothalamus, anterior periventricular gray
matter, and subparafacicular nucleus within the inferomedial thalamus. Important questions remain to be answered, including evaluation of the role of occipital nerve stimulation prior to DBS, a
determination of the proportion of patients who respond to this
therapy in blinded studies, measurement of wash-in and wash-out
times, pre-operative predictors of clinical success, risks of hemorrhage
and stimulation-induced adverse effects, optimal location of the active
contact, and mechanism of action. Further characterization of this
stimulation procedure in humans and in experimental systems may
also yield important physiological insights into the pathogenesis of
this primary headache disorder.
Acknowledgments
Many thanks to Dr. Andrew Ahn for his contributions to a previous
publication (Starr and Ahn, 2008) from which this chapter was
adapted.
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