Initial experience Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches:

Cephalalgia


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Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches:
Initial experience
KL Reed, SB Black, CJ Banta II and KR Will
2010 30: 260 originally published online 15 February 2010
Cephalalgia
DOI: 10.1111/j.1468-2982.2009.01996.x

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Original Article
Cephalalgia
30(3) 260–271
Combined occipital and supraorbital
! International Headache Society 2010
Reprints and permissions:
neurostimulation for the treatment
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1111/j.1468-2982.2009.01996.x
of chronic migraine headaches:
cep.sagepub.com
Initial experience
KL Reed1, SB Black2, CJ Banta II3 and KR Will1
Abstract
A novel approach to the treatment of chronic migraine headaches based on neurostimulation of both occipital and
supraorbital nerves was developed and reduced to clinical practice in a series of patients with headaches unresponsive to
currently available therapies. Following positive trials, seven patients with chronic migraine and refractory chronic
migraine headaches had permanent combined occipital nerve–supraorbital nerve neurostimulation systems implanted.
The relative responses to two stimulation programs were evaluated: one that stimulated only the occipital leads and one
that stimulated both the occipital and supraorbital leads together. With follow-up ranging from 1 to 35 months all
patients reported a full therapeutic response but only to combined supraorbital–occipital neurostimulation. Occipital
nerve stimulation alone provided a markedly inferior and inadequate response. Combined occipital nerve–supraorbital
nerve neurostimulation systems may provide effective treatment for patients with chronic migraine and refractory
chronic migraine headaches. For patients with chronic migraine headaches the response to combined systems appears
to be substantially better than occipital nerve stimulation alone.
Keywords
Migraine, chronic migraine, refractory migraine, peripheral nerve stimulation, occipital nerve stimulation, supraorbital
nerve stimulation
Date received: 24 March 2009; accepted: 26 July 2009
Introduction
As the evidence base for PNS in the treatment of
Following our initial report in 1999 on occipital nerve
cephalic neuralgias has increased, attention has shifted
stimulation (ONS) treatment for refractory occipital
to its potential in treating primary and secondary head-
neuralgia (1), the development of peripheral nerve stim-
aches. In 2003, Popeney and Alo observed strongly pos-
ulation (PNS) for head pain has proceeded along two
itive responses in a series of patients with headaches with
general diagnostic avenues: certain cephalic neuralgias
migrainous symptoms (11), and Dodick observed a sim-
(occipital neuralgia and certain trigeminal neuralgias)
ilar response in a patient with cluster headaches (12).
and the distinct, more general primary headache syn-
Subsequent investigations have reported that various
dromes. Regarding the cephalic neuralgias, numerous
headache syndromes responded variably to ONS, with
subsequent investigators have supported our initial
the majority of studies involving three general diagnostic
findings for occipital neuralgia (2–6), whereas others
have successfully extended this treatment methodology
1
to the frontal region and various trigeminal neuralgias
Department of Anesthesiology, Presbyterian Hospital of Dallas, TX,
USA.
(7–9). Importantly, the results of studies on cephalic
2Medical Director of Neurology, Baylor University Medical Center of
neuralgias were consistent with the well-documented
Dallas, TX, USA.
effectiveness of implanted neurostimulation for neuro-
3Department of Orthopedic Surgery, Presbyterian Hospital of Dallas,
pathic pain syndromes over the rest of the body, includ-
Dallas, TX, USA.
ing the torso and limbs. Indeed, neuropathic pain
Corresponding author:
remains possibly the best documented indication for
Kenneth L. Reed MD, 8220 Walnut Hill Lane, Suite 202, Dallas, TX 75231,
implantable neurostimulators, regardless of anatomical
USA.
location (10).
Email: klreed1@swbell.net
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Reed et al.
261
categories: occipito-cervical headaches (3,7,13,14), cluster
the distribution of the stimulated nerve, is therefore
headaches (15–21) and chronic migraines (22–25).
novel; however, as the clinical results are persuasive,
Although summaries of these studies reveal a consistently
it needs to be explained. Otherwise, the traditional clin-
high (average 88%) response rate for occipital neuralgia
ical approach of seeking a concordant paraesthesia sug-
and cervicogenic headaches, they indicate only roughly a
gests that combining SONS with ONS may provide for
40–50% rate for primary migraines and cluster head-
a better treatment response in patients with hemicra-
aches (Tables 3–5), which suggests that a substantial
nial/holocephalic primary migraines than would be
subset of patients with these types of primary headache
seen with ONS alone, where the paraesthesia would
may indeed not respond to ONS.
cover only the occipital portion of the pain. Or, more
Importantly, the historical trajectory of PNS treat-
generally, it suggests that ONS may be best for occipital
ment has evolved differently over the frontal and occi-
pain, SONS for frontal pain and combined ONS–
pital regions. Over the occipital region the indications
SONS for holocephalic pain.
studied for ONS treatment progressed, as noted, from
Noting a subset of patients with primary migraine
solely occipital neuralgia to the more general primary
headaches that may be non-responsive to ONS, and
headaches, whereas over the frontal region the indica-
based upon the historical clinical approach of covering
tions remained largely limited to various trigeminal
the painful area as best as possible with the paraesthe-
neuralgias. While a report by Slavin in 2006 included
sia, as well as the potential neuroanatomical substrate
headache patients treated with supraorbital nerve stim-
of the TCC with its final common pathway for both
ulation (SONS) along with ONS (7), a corresponding
trigeminal and occipital nociceptive afferents, we
effort to evaluate specifically the potential effectiveness
hypothesized that patients with hemicranial/holocepha-
of SONS for primary headaches was not made until
lic, primary migraine headaches would respond better
2007, when Narouze described a positive response in
when both occipital and supraorbital stimulation
a patient with cluster headaches (26). This is interesting,
were applied together as opposed to occipital stimula-
as a consideration of the final common neuroanatomi-
tion alone. We report on seven patients with severe,
cal pathway for all cephalic afferents suggests potential
chronic migraine headaches (three had refractory head-
for a salutary effect from SONS. Specifically, both the
aches) that benefited from combined ONS and SONS.
trigeminal and greater occipital nociceptive afferents
This is the first report on the use of combined fron-
converge on the same second-order sensory neurons
tal
and
occipital
neurostimulation
for
primary
in the trigeminocervical complex (TCC), and thus on
headaches.
a final common pathway to the higher structures,
including nuclei felt to be important in pain modulation
(27–29). Acknowledging this common neurosubstrate
Materials and methods
begs the question as to the potential effectiveness of
Patient population
SONS as a treatment for frontal headaches analogous
to ONS and occipital headaches.
Patients were referred by experienced neurology head-
Another rationale for considering the potential for
ache specialists. Diagnoses conformed to criteria of the
SONS in the treatment of headaches is based on the
International Classification of Headache Disorders,
generally accepted clinical approach to treating pain
2nd edn, of the International Headache Society (IHS)
with neurostimulation, whereby the goal is to produce
(31) and satisfied appendix criteria for chronic migraine
a concordant paraesthesia, i.e. to cover the painful
(32). All patients had well-documented histories
region as best as possible with the stimulator-induced
of severe (disabling), chronic migraine headaches
paraesthesia. This is the clinical indicator that the
(Table 1). Additionally, three patients (cases 1, 2 and
appropriate portion of the nervous system is being sti-
6) satisfied Schulman’s proposed criteria for refractory
mulated and is the recognized approach to neurostimu-
headaches (33). The other four had headaches unre-
lation and pain over the torso and limbs (30). For
sponsive to extended courses of medical management
example, one would not generally consider treating
but did not strictly meet the Schulman criteria. The
chronic abdominal wall pain by an induced paraesthe-
headaches were either hemicranial or holocephalic in
sia localized to the lumbar region. However, that is
extent, having specifically no history suggesting a pri-
indeed what is being suggested for certain headache
mary occipital focus (it cannot have initiated from or be
types and is thus a relevant concern, as several studies
localized to the occiput). For the three patients with
have reported improvements in patients with holoce-
refractory headaches, the medications listed were pro-
phalic/hemicranial migraine and cluster headaches
vided at optimal dosages and over sufficient periods
(thus a fronto-temporal distribution of pain) by stimu-
(over 2 months) to be consistent with the criteria for
lating the anatomically distant occiput (3,11,12,15–25).
refractory headache. Several patients were taking small
This methodology of treating distant pain, outside of
doses of opiates at presentation; however, these were of
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262
Cephalalgia 30(3)
the order of only a few pills a week and were initiated
ding
only after the headaches became refractory and the
ed
accor
patients were awaiting evaluation for neurostimulation.
S
c
,
scotoma.
This was carefully taken into consideration to ensure
Functional
status
Impair
Incapacitated
Incapacitated
Limited
Limited
Incapacitated
Homebound
that there were no associated rebound headaches.
specialist
migraine;
Furthermore, based upon the clear clinical presenta-
onic
tions, the diagnostic clinicians were confident that
c
hr
none of the patients had hemicrania continua, so that
headache
y
amitriptyline)
an indomethacin trial was not considered necessary.
sumatriptan)
ology
r
a
ctor
Although some patients had severe, daily headaches
oex,
opranolol,
(nadolol,
r
ef
ofen,
ofen,
neur
that often began unilaterally, ultimately they all devel-
(pr
the
CM,
oped holocephalic pain and none had autonomic fea-
(divalpr
R
ibupr
egabalin,
ibupr
tions.
pr
Fioricet
by
tures. Those agreeing were provided full and detailed
en,
aura;
x
information on the procedure, and informed consent
o
en,
x
medica
o
ofen,
was obtained.
sumatriptan
egabalin,
ocodone,
ithout
napr
triptyline)
w
,
pr
DHE)
vious
ibupr
categorized
ydr
nor
(napr
h
re
pre
a
ine
topiramate)
e
gr
er
of
nadolol,
w
y
mi
,
etine,
oex,
A,
Trial stimulation; procedure technique
ocodone
x
Mo
ydr
alprazolam,
egabalin,
zolmitriptan,
Utilizing C-arm fluoroscopy, Axxess or Quatrode [St Jude
h
pr
dulo
summar
elitriptan)
,
amitriptyline,
divalpr
rizatriptan,
diagnoses
a
ura;
Medical (St Jude), Dallas, TX, USA] wire lead arrays
tizanidine
,
i
t
h
the
w
were placed subcutaneously across the supraorbital
ofen,
y
nerves just over the eyebrow and across the greater occi-
vious)
opranolol,
sumatriptan)
ibupr
butorphanol,
topiramate
v
erapamil,
sumatriptan,
accumulated
igraine
pital nerves just above the occipital ridge. Following
e
,
pr
(gabapentin,
e
m
sertraline
,
(zolmitriptan,
submission
er
placement, patients were provided with two programs
summar
(pr
(sumatriptan,
w
&
acid,
to
MA,
for the unit: one that stimulated only the occipital
e;
ent
oic
ocodone,
ocodone,
ocodone,
nerves and another that stimulated both the occipital
meds
Prior
igrain
ergotamine
amitriptyline,
Fioricet
topiramate
ntheses
m
and supraorbital nerves. Extensive instructions on the
opiramate,
alpr
HA
Curr
T
V
Hydr
Oxycarbazine
Hydr
Hydr
Sumatriptan
c
ferral.
pare
e
gi
use of the equipment and how to monitor and document
re
in
the response appropriately were provided. Following a 3–
emipl
smell
,
h
5-day trial period, the leads were removed and the patient
patient
HM
interviewed as to the response. During approximately half
foul
loss,
numb
medications
of the trial period, the unit was programmed to stimulate
o
initial
vis
at
igraine;
only the occipital nerves, and for the other half both the
limb
m
set
supraorbital and greater occipital nerves were stimulated.
Neur
Symp
None
Sc,
None
None
Tinnitus,
None
None
nic
sentation;
r
o
A minimum criterion for a positive trial was at least 50%
those
c
h
e
pre
of
overall improvement in pain, The relative response to
y
ears
er
criteria.
at
w
occipital stimulation alone and combined occipital–
y
ears
y
ears
y
ears
y
ear
y
ear
months
tion
Dur
CM
5
2
1.5
4
1
1
6
edn
ent
supraorbital stimulation was determined and, based
dura
curr
2nd
M,
upon the results, the final system configuration for the
e
diagnoses
er
C
permanent implant was accordingly planned. Based
Dx
Recat
ders,
w
Dur
upon the patient’s usage pattern during the trial, as
HA
HA
RCM
RCM
CM
CM
CM
RCM
CM
initial
reflected in the total energy required as determined by
Disor
r
a
ine;
entheses
ig
the St Jude programming computer, a determination
Dx
m
par
nic
was made as to which specific implantable pulse generator
HA
Init
MoA
HM
MoA
CDH
CDH
MA
MA
of
o
Headache
(IPG) would be best. Options included rechargeable Eon
chr
er
.
of
out
M,
or Eon Mini (St Jude; life expectancy of 10 years) and
ec
y
ed
C
Ex
non-rechargeable Eon-C (St Jude; life expectancy of
.
visor
ed
5 years) units (Table 2).
demographics
Occupation
Homemak
Corp
Super
Retir
Underwriter
Student
Unemplo
(Initial/Recategorized)—the
headache;
Classification
y—medications
a
i
ly
d
Patient
nic
o
Permanent implant: operative technique
1.
Init/Recat
Age/sex
36/F
49/F
50/F
71/F
57M
20/F
24/F
Summar
chr
DX
H,
Following positioning, prep and general anaesthesia
International
able
D
T
No
1
2
3
4
5
6
7
HA
to
Meds
C
(patients were not intubated), small incisions were
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Reed et al.
263
made over the patient’s forehead and upper cervi-
ersity
cal region to accept introducer needles, which
ork
ork
were advanced subcutaneously across the bases of
status
w
w
univ
the
supraorbital
and
greater
occipital
nerves.
to
to
to
Quatrode (St Jude) wire lead arrays were then placed
Ret
Ret
Ret
per the frontal introducers and passed to an incision
Functional
Normal
Full;
Full;
Normal
Normal
Full;
Normal
over the right ear, where they were anchored, looped
and further advanced to the occipital incision. In a
similar fashion quatrode leads were also placed
across the occipital nerves and anchored, whereby
strain relief loops were fashioned in all leads. Prior
to anchoring, the patient was awakened to confirm
sumatriptan
appropriate placement by their description of the
stimulator-induced paraesthesia pattern and, as neces-
sary, the leads were adjusted to optimize this pattern.
opiramate,
Following re-induction of anaesthesia, an incision was
HA
Meds
T
None
None
None
NSAIA
None
None
made over the upper outer gluteal region, where a
pocket was fashioned to accept an IPG. The leads
.
ed
ed
o
.
were tunnelled to the pocket and connected to the
stimulation.
IPG. Following closure, a sterile dressing was applied.
Neur
Symp
NA
Resolv
NA
NA
Resolv
NA
NA
v
e
Following recovery from anaesthesia, the neurostimu-
ner
lator was programmed by a representative of the man-
ufacturer. While fully implanted, the IPG was capable
90
Imp
of responding to an external, programming computer
HA
%
90–100
90–100
90–100
60
90–100
90–100
through a radiofrequency couple. The goal of pro-
alone.
v
e–supraorbital
gramming was to provide the patient with the most
ner
e
effective paraesthesia pattern possible, which was
ONS
v
er
accomplished
by
optimizing
various
parameters
eq/Mo
vs.
3/0
0/0
0/0
0/0
0/0
0/0
including signal amplitude, pulse width and frequency,
Fr
30/0
occipital
temporal signal variation, negative/positive terminal
HA
Mild/Se
settings, and active lead combinations. The patient
ON–SONS
received and was fully instructed in the use of a por-
ON–SONS,
table handheld programmer, which provided the
patient the continuous option of adjusting signal
combined
agent;
y
strength, frequency and location. Disposition included
combined
75
full
100
100
100
100
100
100
prophylactic antibiotics and instructions on tempo-
time
the
ON–SONS
rary activity restrictions.
of
use
For the first 2 months the patients were re-evaluated
stimulation
%
at frequent intervals and ongoing responses were doc-
ently
anti-inflammator
umented. A representative of the manufacturer was
curr
Bil
oidal
available at each visit and, as necessary, would repro-
ON–SON
v
Bil
Bil
Bil
Bil
Bil
Bil
Bil
gram the neurostimulator to re-optimize the settings.
Uni
System
patients
Importantly, each patient was continually provided
non-ster
the
with at least two specific programs: one that would
combined
stimulate only the occipital leads and another that
time
NSAIA,
to
of
would stimulate both the occipital and supraorbital
(ANS)
Eon
Eon
EM
Eon
Eon
Eon
EM
leads. The patients were repeatedly instructed to evalu-
cent
IPG
ate both programs intermittently to determine which
applicable;
one worked best, and their relative preferences were
r
esponses
not
reported. Following this initial 2-month stabilization
1
NA,
period, the patients returned every 2–3 months thereaf-
Patient
F/U
35
29
19
15
12
10
Months
ON–SONS—per
ter for general re-evaluations, including assessments
2.
Mini;
both of their ongoing clinical response and of which
time
Eon
programs (ONS vs. combined ONS–SONS) they pre-
able
of
T
No
1
2
3
4
5
6
7
%
EM,
ferentially used.
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264
Cephalalgia 30(3)
Results
unremarkable, and a diagnosis of migraine without
aura was made. The headaches came under control
Trial stimulator
with topiramate, sertraline and sumatriptan. A year
Using a subjective criterion of 50% improvement in the
later, when the pain became refractory (failed extended
pain as the standard for a positive trial, seven of eight
trials of ergotamine, propranolol, ibuprofen, naproxen
patients had positive trials as all reported 80–100%
and other triptans), transdermal fentanyl was added,
improvement in pain and neurological symptoms.
and she was referred to our facility with a diagnosis of
These positive results came only with the combined
chronic migraine headaches. Supraorbital and greater
frontal–occipital lead combination, as all had markedly
occipital nerve blocks provided temporary relief. In
inferior responses (much less than 50%), when only
April 2006 a bilateral combined ON–SON stimulation
occipital neurostimulation was applied. All seven
system was implanted with immediate, near-complete res-
patients who reported a positive response ultimately
olution of the headaches. In June 2006 signs of infection
had the full system implanted.
developed in one supraorbital lead, but remarkably
cleared with local debridement and prolonged antibiotics.
Thereafter, the headaches remained under excellent con-
Permanent stimulator
trol with the stimulator and topiramate as a prophylactic
All patients received bilateral combined occipital nerve–
agent. At her last evaluation in January 2009 she reported
supraorbital nerve (ON–SON) combined systems. Even
being largely headache free, indicating about three mild
the patients with primarily unilateral pain would often
headaches per month, which respond to sumatriptan.
ultimately have the pain globalize, and all thus preferred
the bilateral system. Based upon the energy requirements
Case 2
observed during the trial period, all patients had
rechargeable Eon or Eon Mini IPG units (St Jude) rec-
In September 2006 a 49-year-old White woman pre-
ommended and implanted, which was not surprising due
sented with daily incapacitating headaches. They had
to the multi-lead systems. The seven patients with per-
begun as a teenager and were controlled well with var-
manent implants had a median follow-up of 15 months
ious prophylactic and abortive agents. Over the 2 years
(range 1–35 months) following placement of the perma-
prior to presentation they had progressed to severe
nent neurostimulator system (Table 2). All seven con-
daily, unilateral throbbing headaches interspersed
tinue to use their stimulators, with each continuing to
with fleeting, knifelike pains in her eye and jaw.
describe almost identical results to those achieved during
Flashing lights and transient paresis of her left arm
the trial. Five were able to discontinue their medications
were a common prodrome approximately 2 h before
completely, and the other two noted marked reductions.
headache onset. Significant visual loss occurred with
All returned to fully functional lifestyles including col-
50% of the headaches, and photophobia and phono-
lege and work. As indicated and on an ongoing basis, the
phobia were common. These ultimately became refrac-
patients would intermittently evaluate and report the
tory to extended courses of various prophylactic
results of the relative efficacy of the two programs (occi-
(topiramate,
valproate,
propranolol,
amitriptyline)
pital stimulation alone vs. combined supraorbital and
and abortive (multiple triptans, naproxen) medications.
occipital stimulation). The results remained consistent
The headaches were incapacitating to the point of full
in that all continue to greatly prefer the combined pro-
disability, as she was forced to resign her corporate
gram, and indeed most use it exclusively.
executive position. In early 2006 she came under the
care of a local neurology headache specialty group,
who diagnosed hemiplegic migraine and referred her
Case reports
to our office in July 2006. In September 2006 bilateral
occipital leads were placed with moderate but, on the
Case 1
whole, inadequate relief. With the addition of supraor-
A 36-year-old White woman presented in June 2005 with
bital leads in October 2006, the headaches and all neu-
a history of migraine headaches since childhood, which
rological symptoms (visual loss, paresis) resolved. In
5 years previously had progressed to daily severe, throb-
March 2007 an occipital lead migrated and was reposi-
bing headaches, associated with nausea, vomiting and
tioned. Thereafter, she remained headache free off med-
photophobia. Often heralded by blurred vision, they usu-
ications and back to full functional status.
ally began on the left side and progressed to a holocepha-
lic distribution. In 2004, when they began to seriously
Case 3
affect her activities, an extensive neurological evaluation,
including magnetic resonance imaging (MRI) and vascu-
A 50-year-old White woman presented with a 30-year
lar studies, by a neurology headache specialist was
history of progressively severe migraine headaches.
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Reed et al.
265
Various regimens including anti-inflammatory medica-
headaches that were associated with tinnitus and a
tions, triptans, topiramate and botulinum toxin injections
foul taste and smell. After a period of ineffective
initially helped; however, in 2005 the situation had pro-
dental and chiropractic treatment, he had come under
gressed to severe, daily headaches, unresponsive to all
the care of an experienced neurology headache special-
measures, at which point an occipital nerve decompres-
ist. A full radiographic and laboratory evaluation was
sion was performed with no response. Rendered comple-
unremarkable, and a diagnosis of chronic daily head-
tely disabled, she was forced to resign her supervisory
aches was established. When the problem was unabated
position at work. She had then come under the care of
by an extensive course of medical management, includ-
an experienced neurology headache specialist, whose
ing naproxen, sumatriptan, hydrocodone, topiramate
diagnostic evaluation was unremarkable. When the pain
and duloxetine, a bilateral combined ON–SON stimu-
proved unresponsive to botulinum toxin injections and
lation
system
was
implanted
in
March
2008.
medication management (hydrocodone, butorphanol,
Subsequently, the headaches and neurological symp-
alprazolam, and pregabalin), she was referred to our
toms completely resolved off medications. Months
clinic with a diagnosis of migraine without aura head-
later he developed some recurrent daily head pain, but
aches. She was found to be suffering from daily, severe,
this stabilized to a current low daily pain level that was
throbbing right hemicranial headaches, noting occasional
60% improved over presentation. The frequency of
left supraorbital pain. Nausea and vomiting were com-
severe headaches decreased to once every 3 months.
monly associated. Greater occipital and supraorbital
nerve blocks provided only temporary relief. In August
Case 6
2007 a bilateral combined ON–SON stimulation system
was implanted, and the headaches promptly and comple-
A 20-year-old White woman noted the onset of
tely resolved. In early 2008 she presented with local swell-
migraine headaches at age 12 years and until age 15
ing and tenderness at the IPG site. Studies ruled out
years experienced migraines with aura two to three
infection, and a diagnosis of allergy to titanium was deter-
times a week. In 2003 the headaches had escalated in
mined by skin testing. The pulse generator was ultimately
severity and responded well to dihydroergotamine. In
replaced with an Eon Mini (St Jude), around which a
March 2005 the headaches again escalated, and she was
surgical mesh wrap provided a successful safeguard to
admitted to an in-patient headache specialty hospital,
the allergy. Thereafter, she remained completely headache
where she underwent an extensive diagnostic evaluation
free off medications and returned to a full activity sched-
and treatment protocol. The headaches responded to
ule, including work. She uses the stimulator about 50% of
zolmitriptan, and in September 2006 she enrolled in
each day and occasionally can go a day completely with-
college. A year later, however, they progressed to the
out it. If a headache does start, it promptly resolves with
point that she had to withdraw from college and return
resumption of the stimulation. She uses the full frontal
home. She was experiencing severe daily, throbbing
and occipital system about 75% of the time and just the
hemicranial headaches, associated with nausea, vomit-
occipital leads 25% of the time.
ing and photophobia that became refractory to all ther-
apeutic measures. Over the year prior to presentation
various medication regimens, including combinations
Case 4
of nadolol, topiramate, various triptans, dihydroergo-
A 71-year-old White woman presented in November 2007
tamine, mixed analgesics and hydrocodone, were tried
with a 4-year history of daily holocephalic headaches for
without benefit. At the time of referral she was comple-
which she had variously tried gabapentin, pregabalin,
tely disabled (homebound and unable to participate in
nortriptyline, oxycarbazine and butalbital. She was eval-
even brief family outings) and was taking only hydro-
uated by an experienced neurologist, who obtained a full
codone twice weekly. In May 2008 a bilateral combined
imaging panel and diagnosed chronic daily headaches.
ON–SON stimulation system was implanted, which
Chiropractic care and regional injections were not bene-
provided prompt and complete resolution of the head-
ficial. The headaches became unresponsive to medical
aches. Thereafter, she remained headache free and
management, and she was referred to our centre, taking
returned to college that autumn. At her last evaluation
only oxycarbazine. In December 2007 she responded well
10 months post implantation she was completely head-
to a bilateral combined ON–SON stimulation system and
ache free off medications.
has remained headache free off medications thereafter.
Case 7
Case 5
A 24-year-old White woman developed headaches as a
A 57-year-old White man presented in January 2008
teenager, which were controlled with regimens includ-
with a 1-year history of severe, daily, holocephalic
ing various triptans, divalproex, amitriptyline and
at NORTHEASTERN UNIV LIBRARY on October 24, 2010
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266
Cephalalgia 30(3)
anti-inflammatory medications. Six months prior to
presentation they progressed to severe daily headaches.
r
elief
(also
Visual changes typically heralded the onset, whereupon
50%
Reed
a severe, throbbing right hemicranial (occasional holo-
months
transformed
>
cephalic) headache would rapidly develop and associate
3–6
months
TM,
had
Author
with nausea, vomiting and noise intolerance. It gener-
at
6
ally lasted the rest of the day and forced her to bed. She
r
elief
r
elief
excellent
at
AS
AS
AS
patients;
had ultimately come under the care of an experienced
to
V
V
V
ement
in
in
neuralgia.
r
elief
in
neurology headache specialist, when an MRI scan of
ov
implanted
good
the brain and spine were unremarkable, and a diagnosis
excellent
excellent
ease
ease
pain
ease
pts
impr
as
occipital
of migraine with aura was made. All treatment efforts
to
to
of
decr
decr
decr
of
sponses/total
ultimately failed, as she became completely disabled
75%
r
elief
re
good
good
>
and homebound. When there was no response to a
excellent
ect.
r
esponded
medication change to sumatriptan and tizanidine, she
magnitude
had
had
had
rated
a
v
erage
a
v
erage
a
v
erage
(139/158)
diagnosis
had
corr
positive
al
was referred to our centre. A set of occipital nerve
as
Resp
80%
80%
100%
90%
73%
70%
97%
All
73%
88%
ot,
ia
/T
blocks was not helpful. A bilateral combined ON–
origin
os
P
SON stimulation system was fully implanted in
the
neuralg
February 2009, whereupon the headaches promptly
resolved, and she remained headache free off medica-
r
etain
e
neuralgia;
tions thereafter.
pts)
w
occipital
(10)
(50)
(25)
(19)
(11)
(6)
(4)
(9)
(5)
Resp
of
(no
occipital
Discussion
stimulation
80%
80%
95%
90%
71%
erm:
100%
100%
100%
100%
v
e
P
Rate
migraines,
diagnoses
ONa,
All of the patients reported marked improvement in
ner
onic
headache frequency and severity, resolution of asso-
chr
ciated neurological symptoms, and return to a fully
to
original
headaches;
active lifestyle. Furthermore, all remained convinced
occipital
(11)
the
Imp
that combined ON–SON stimulation benefited their
with
6
4
7
13
62
25
20
11
10
study
headaches much more than ONS did alone. The 88%
erm
(2).
P
158
maintains
trial-to-permanent stimulator ratio suggests that a high
eated
initial
No
80%
s
percentage of patients with chronic migraines may
tr
and
to
respond to combined neurostimulation. Perhaps most
occipitally-focused
Reed’
impressive were the improvements in patient function,
&
patients
OFH,
particularly notable in the three patients who were func-
modified
headaches
einer
tionally incapacitated, yet responded so well that all
ot
later
W
original
in
returned to their full pre-morbid lifestyle including col-
os/T
(92%)
P
was
the
headaches;
lege or work. Problems included a single lead migration,
focused
(1)
for
an infected lead, and an allergic reaction to the IPG.
rial:
T
13/13
?
25/25
20/20
11/14
6/6
4/4
10/14
7/8
96/104
C-2
diagnoses
Furthermore, the study is clearly limited due the small
rate
the
ysician
sample size, with other weaknesses including the lack of
occipitally
ph
a diary and the open-label, non-randomized structure.
Intractable
r
esponse
pain
Given the structure of the report, a placebo effect cannot
with
y
be completely excluded; however, given the uniform con-
100%
IC2H,
r
ecategorized
primar
tinuation of such dramatic responses across all patients
of
patients
Dx
ONa
IC2H
TM
ONa/TM
ONa
CEH
ONa
ONa
ONa
OFH
v
e
and for the duration of their implants, we feel that there
ha
the
on
diagnosis;
is probably minimal placebo effect.
was
indication
When considering neurostimulation and headaches,
(47–49)
Dx,
in addition to diagnosis we suggest that it is particularly
r
eports
r
eport)
(5)
r
eport
helpful to classify headaches according to the anatom-
of
(13)
y
authors
ical location of the pain. Accordingly, we distinguish
(1)
al.
(11)
headaches;
et
initial
original
three groups of patients who historically have aroused
(2)
(4)
s
Alo
(14)
y
o
(6)
Sundaraq
the
most interest amongst researchers concerned with neu-
Summar
Reed
al.
al.
(3)
al.
of
&
Reed’
et
&
et
al.
y
subsequent
vicogenic
rostimulation—one group with headaches localized pri-
3.
y
al.
et
et
&
eas
cer
marily to the occipital region (occipitally focused
et
vin
able
einer
einer
einer
headaches; Table 3) and two groups with headaches
opene
T
Study
W
W
P
Oh
Melvin
Kapural
Rodrigo-Ro
Sla
J
ohnstone,
Summar
W
Wher
co-author
CEH,
migraine.
at NORTHEASTERN UNIV LIBRARY on October 24, 2010
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Reed et al.
267
Table 4. Summary of reports on patients with cluster head-
holocephalic
headaches.
Examples
of
occipitally
aches treated with occipital nerve stimulation (ONS)
focused headaches include occipital neuralgia and cer-
vicogenic headaches; however, headaches with migrai-
No
nous
Study
implants
Response rate and magnitude
features may also be occipitally focused (3, 11). The
Dodick (12)
1
> 90% improvement
clinical importance of distinguishing these from the
Magis et al. (15)
8
7/8 (63%) had > 50% improve-
fronto-temporal migraine and cluster headache groups
ment in frequency or severity
(Tables 4 and 5) relates to the fact that for migraine and
Schwedt et al. (16)
1
> 70%
improvement
in
fre-
cluster headaches pain is perceived most commonly in
quency and severity
the distribution of the trigeminal nerve, as opposed to
Schwedt et al. (23)
3
HA frequency: 0% improved; HA
occipitally focused headaches, where pain perception is
severity:
1/3
had
> 50%
primarily in the distribution of the greater occipital
improvement
nerve. Therefore, recognizing that these two neural
Burns et al. (17,18)
14
5/14 (36%) of patients had > 50%
distributions are anatomically distinct and that ONS
improvement
in
frequency,
stimulates only one of them allows for critical compar-
severity or duration
isons between the groups on the relative response rates
Lainez et al. (19)
5
4/5
(80%)
had
100%
to ONS.
improvement
Indeed, a review of the historical response rates for
Vargas et al. (20)
4
3/4 (75%) had an average of 65%
ONS and headaches as set forth in these three tables
improvement in frequency
provides perspective for analysis of our data. The high-
Leone et al. (21)
10
3/10 (30%) of patients responded
est patient response rate to ONS is seen with the occi-
Summary
46
54%
(25/46)
of
patients
pitally focused headache group, with 88% of patients
responded
to
ONS
with
overall reporting a positive response. In contrast, in the
> 50% improvement
two patient groups with pain classically focused over
the frontal-temporal regions (migraines and cluster
headaches) only 47 and 54%, respectively, responded.
Indeed, the largest migraine study to date, Saper’s
Table 5. Summary of reports of patients with chronic migraines
report
on
data
abstracted
from
Medtronic’s
treated with occipital nerve stimulation (ONS)
(Medtronic Inc., Minneapolis, MN, USA) ONSTIM
study, found that only 40% of patients responded to
No
ONS over the long-term (25). As Saper went directly to
Study
implants Response rate and magnitude
permanent implant without antecedent trials, the
Schwedt et al. (23, 24)
8
4/8
(50%)
had
> 50%
results may be skewed compared with the series on
improvement in severity
occipitally focused headaches, which all began with
or freqeuncy
stimulator trials (Table 3). However, even if the results
Saper et al. (25)
51
20/51
(40%)
had
> 50%
of the occipitally focused studies are extrapolated to
improvement in pain
determine a long-term response rate based upon the
Summary
59
47%
(24/59)
of
patients
initial pre-trial patient number, which more closely
responded to ONS with
approximates Saper’s protocol, a 77% long-term rate
> 50%
is still derived, which remains markedly higher than
improvement in severity or
Saper’s 40% response rate. Therefore, the data suggest
frequency
that although patients with classic fronto-temporal
As there was no trial for the Medtronic Study, the 40% response rate is
headaches (migraine and cluster headaches) may
the rate of responders to the full implant.
respond to ONS, the response rate is considerably
lower than that for occipitally focused head pain. The
question arises how best to understand why migraine
and cluster headaches should have such a substantially
classically localized to the fronto-temporal regions
lower response rate to ONS than occipitally focused
(migraine and cluster headaches; Tables 4 and 5).
headaches or, alternatively, why combined ON–SON
Occipitally focused headaches is not a term used by
stimulation may be more effective for these headache
the IHS, and we define it here to be any headache
types than ONS alone.
(regardless of specific headache diagnosis) that either
These questions and our data should be considered
is localized primarily to the occipito-cervical region or
in the context of the current understanding of the neu-
begins there and subsequently progresses to involve
roanatomy
and
neurophysiology
of
head
pain.
other
anatomical
regions,
e.g.
hemicranial
or
Neuroanatomical studies of the TCC and brainstem
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268
Cephalalgia 30(3)
suggest possible sites of action for neurostimulation
all to stimulation of the distant occipital nerves, and
and may provide a potential substrate for understand-
why that response may be less pronounced than that
ing the evidence base for ONS and headaches.
seen with occipital pain.
Migraines and cluster headaches are understood to
The brainstem and higher structures also play a key
be disorders of the brain, whereby pain is most com-
role in migraine pathogenesis (34, 40–43), as well as a
monly perceived in the distribution of the trigeminal
likely one in pain modulation from neurostimulation
nerve (34, 35). Occipital neuralgia, cervicogenic head-
(22, 44, 45). Matharu’s elegant positron emission tomo-
aches and other occipitally focused secondary head-
graphy (PET) studies documented specific areas of
aches (e.g. post-traumatic headaches) differ in that in
brainstem activation in patients with migraines treated
these groups pain is perceived primarily in the distri-
by ONS and provide the best evidence to date of
bution of the greater occipital nerve (36–38). The first
neurostimulation-induced activation of higher neural
division of the trigeminal nerve innervates the frontal
centres (22). Paraesthesia-correlated activation was
regions of the head, including the forehead and supra-
observed in the cuneus, pulvinar and anterior cingulate
tentorial meninges and vasculature (34). The greater
cortex. Activation of the rostral dorsal pons demon-
occipital nerve derives largely from the C2 root and
strated a covariable response with pain scores and
provides the primary innervation for the occiput and
may be particularly important in the genesis of chronic
upper posterior cervical region, including the skin, soft
migraines. Activation of the pulvinar has also been
tissue and the infratentorial dura (37). The nexus of
reported in a patient with a thalamic stimulator for
these two systems occurs at the TCC, which is formed
chronic pain (44) and another with a spinal cord stim-
by the caudal trigeminal nucleus and portions of the
ulator for angina (45). Matharu hypothesized that acti-
upper three cervical dorsal horns (27–29). The pivotal
vation of these structures may be important in pain
interface here is where nociceptive afferents from both
modulation, including the affective dimension of pain
the trigeminal nerve and the greater occipital nerve
(22). Taken together, the discovery of partial nocicep-
converge on the same second-order neurons in the
tive convergence at the TCC and the PET documenta-
TCC and thus to a final common pathway to higher
tion of neurostimulator-induced brainstem activation
centres for cephalic nociception and modulation.
provide an attractive model that may help explain
Bartsch and Goadsby’s meticulous animal studies con-
why migraine headaches apparently respond to stimu-
vincingly demonstrated both this discrete convergence
lation of the distant occipital nerves but in a less
as well as subsequent sensitization of second-order
marked fashion than the responses seen with occipitally
TCC neurons following a sensory barrage, findings
focused head pain.
that probably underlie the clinical observations of allo-
The clinical analogue to the thesis of stimulating the
dynia, hyperpathia and spreading pain seen with pri-
appropriate portion of the nervous system is the topo-
mary headaches (27, 28, 39). In 2003 Popeney and Alo
graphic coverage of the neurostimulator-induced para-
suggested that this nociceptive convergence at the TCC
esthesia. We feel that the location of the paraesthesia in
may be significant with respect to the mechanism of
relation to the pain is a central issue and suggest that
action for ONS and migraine headaches (11) and thus
during the course of the historical evolution of investi-
help explain the clinical puzzle of how paraesthesia
gations into ONS and headaches, a paradigm shift
limited to the occiput could affect pain over the distant
occurred from the traditional approach to neurostimu-
fronto-temporal regions, as is seen with migraine head-
lation and pain. Over the decades the vast bulk of inves-
aches. It is interesting to consider that the convergence
tigational work on neurostimulation and pain involved
was found to be partial (48% of both trigeminal and
spinal cord stimulation for back and extremity pain,
occipital neurons terminated unilaterally on TCC neu-
and throughout this period the clinical approach has
rons) (27) and speculate on the possibility that this
always been to produce a paraesthesia over the part
partial convergence may be mechanistically related to
of the body that hurt, which indicated that the correct
the apparent lower response rates of the headaches with
portion of the nervous system was being stimulated.
pain in the front-temporal region (migraine, cluster)
Even reports of salutary effects from spinal cord stim-
compared
with
occipitally
focused
headaches
ulation for such pain problems as intractable angina
(Tables 3–5). Whereas for occipitally focused headaches
and abdominal visceral pain still have the paraesthesia
the stimulation is applied directly to the nerves that are
covering the related anatomical areas of pain (e.g. a
transmitting the pain signals, for the fronto-temporal
precordial paraesthesia was found to be best for
pain of migraine headaches ONS only indirectly influ-
angina) (10, 45, 46). Indeed, prior to 2003 we can find
ences the nociceptive system (trigeminal afferents at the
no evidence, regardless of anatomical location, that
TCC). Therefore, the TCC may provide a potential
neurostimulation reliably eased pain that was signifi-
mechanism
for
both
questions—why
the
fronto-
cantly outside the area of paraesthesia. The departure
temporal pain of migraine headaches may respond at
thus came with head pain, where in 2003 investigators
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