THE FUTURE OF THERAPY IN HEADACHE

Surgical treatment of primary headaches

Angelo Franzini • Giuseppe Messina •

Roberto Cordella • Alberto Proietti Cecchini •

Massimo Leone • Gennaro Bussone

� Springer-Verlag 2012

Abstract Neuromodulation for the treatment of drug-

refractory cranial neuralgias constitutes an exciting field of

research for physicians; in the last decade, several meth-

odologies have been described which could help many

patients to exit such desperate conditions; although the

exact mechanisms of action of these techniques are still

matter of debate, several experimental and neuroradiolog-

ical modalities can help us to get near the concept of

understanding them. In this paper, the authors summarize

the most recent surgical procedures used to treat severe and

pharmaco-resistant cranial painful conditions, along with

brief descriptions of the results obtained in the several

published so far.

Keywords Neuromodulation � Deep brain stimulation �Cluster headache

Introduction

Chronic cluster headache (CCH) is the only primary

headache in which a clear indication to surgical neuro-

modulation has been established in the last decade [1].

After the preliminary favourable results of pHyp DBS in

CCH patients [2], a new interest developed in neuromod-

ulation applied to the treatment of primary headaches and

less invasive procedures have been suggested and tested.

The neuromodulation procedures tested in the treatment of

primary headache include vagal nerve stimulation (VNS),

occipital nerve stimulation (ONS), sphenopalatine ganglion

stimulation (SPGs) and stimulation of distal trigeminal

terminations in the face subcutaneous layer [3–6]. Our aim

is to report the results of DBS and ONS in CCH patients

suggesting the guidelines for the treatment of patients

refractory to the drug and conservative treatment.

Results of posterior hypothalamus deep brain

stimulation (DBS)

The first attempt to treat CCH by neuromodulation proce-

dures was based on neuroimaging and particularly on the

observation that a discrete volume of the posterior hypo-

thalamus was activated during the pain bouts in CCH

patients [7]. The target of the procedure was the alleged

hyperactive posterior hypothalamus (pHyp) and its inhibi-

tion was obtained delivering ‘‘in situ’’ high frequency

current (180 Hz, 1–3 V, 60–90 ls pulse width) trough

deep implanted electrodes. Really, the treated patients

underwent a full DBS procedure as in the treatment of

Parkinson disease; the only difference was the site of the

deep target which is the subthalamic nucleus in Parkinso-

nian patients and within posterior hypothalamus (pHyp) in

CCH patients.

Hypothalamic DBS was first tried in 2002 in a patient in

desperate conditions due to the dramatic autonomic

involvement and pain [8]. Subsequently, we reported on 16

drug-resistant CCH patients who received hypothalamic

implants after a mean follow-up of over 4 years [9]. After

the first 2 years, pain abolition or major pain reduction was

obtained in 13 patients (83.3 % responders). After 4 years

A. Franzini � G. Messina (&) � R. Cordella

Department of Neurosurgery, Fondazione Istituto Nazionale

Neurologico ‘‘Carlo Besta’’, Via Celoria 11, 20133 Milan, Italy

e-mail: giusmex@gmail.com

A. Proietti Cecchini � M. Leone � G. Bussone

Department of Neurology, Fondazione Istituto Nazionale

Neurologico ‘‘Carlo Besta’’, Milan, Italy

123

Neurol Sci (2012) 33 (Suppl 1):S131–S135

DOI 10.1007/s10072-012-1057-2

a persistent pain-free state was still present in 10 patients

(62 % responders) although four of these also required

medical prophylaxis as an add on to control the attacks.

Subsequently, hypothalamic DBS became ineffective in

three patients despite many changes in the stimulation

settings. However, in these patients the illness also changed

from chronic to episodic, and they now experience months

of complete remission punctuated by periods of brief but

typical attacks [10]. Overall about 62 % of patients have

obtained significative improvement. In a double-blind,

prospective, crossover study, 11 patients from centres

throughout France were recruited to assess the efficacy and

safety of unilateral hypothalamic stimulation for severe

chronic drug-resistant CH [11]. During the randomized

phase, there was no significant difference in primary or

secondary outcome measures between active and sham

stimulation. At the end of the open phase, chronic stimu-

lation had reduced the frequency of their attacks by over

50 % in six patients, three of whom were pain free. There

were three adverse events: subcutaneous infection, tran-

sient loss of consciousness and micturition syncope. There

were no significant changes in hormonal function or elec-

trolytic balance. Although the randomized phase showed

no efficacy of hypothalamic stimulation, the open phase

indicated long-term efficacy in over 50 % of patients

without high morbidity. Of eight CH patients implanted in

California [12, 13], five had obtained [50 % reduction in

headache intensity or frequency after at least a year,

although none were completely pain free. A multicentre

study on six CH patients implanted in Germany reported

that three patients were almost pain free with treatment

failure in the other three [14]. A Belgian centre reported

that in four successfully implanted patients, two were pain

free and one had improved substantially [15]. One patient

from the Belgian series had fatal haemorrhage during

surgery. The three patients implanted in Oxford, UK, were

Fig. 1 Post-operative three-dimensional reconstruction CT image

(upper part) of a patient comprised in our series, submitted to

occipital nerve stimulation for refractory cluster headache; as it is

shown, in this case, a single median eight-contact electrode was used.

Lower part Axial images at the level of the electrode

S132 Neurol Sci (2012) 33 (Suppl 1):S131–S135

123

reported as pain free with no side effects after a follow-up

of 6 months to 2 years [16, 17]. The latency of chronic

stimulation and inefficacy of acute stimulation suggest that

the mechanism of hypothalamic stimulation is complex and

not the result of simple inhibition of hypothalamic neurons,

as supposed initially. At least part of the effect exerted by

hypothalamic stimulation could be due to modulation of

the antinociceptive system, as suggested by the finding of

increased threshold for cold pain at the site of the first

trigeminal branch ipsilateral to the stimulated side in

chronically stimulated patients [18]. One possible expla-

nation of the role of the hypothalamus in CH and TACs,

consistent with the accumulated data on hypothalamic

activations, is that this cerebral area plays a major role in

terminating rather than triggering attacks. This idea

envisages the hypothalamus as regulating the duration of

an attack, and the extent to which it does so would give rise

to the different phenotypic expressions of the TACs which

are principally distinguished by attack duration.

Anyway, pHyp DBS is a powerful therapy in CCH

patients when drug treatments and less invasive neuro-

modulation procedures (ONS and subcutaneous nerve

stimulation) fail. The stereotactic coordinates of the pos-

terior hypothalamus referred to the commissural system

are: 3 mm lateral, 5 mm posterior to the AC PC midpoint

and 4 mm inferior to the commissural plane. The stimu-

lation parameters ranged between 130 and 185 Hz,

60–180 ls pulse duration and 1–4 V amplitude.

Other refractory conditions benefited by pHyp DBS

include short lasting unilateral neuralgiform headache with

conjunctive injection and tearing (SUNCT) [19], first

branch trigeminal neuralgia in multiple sclerosis patients

[20] and chronic paroxysmal haemicrania [21].

Results of ONS

Occipital nerve stimulation consists of the stimulation of the

greater occipital nerve with paddle- or lead-type electrodes

positioned in the suboccipital subcutaneous region and

above the splenius capitis’ fascial plane; the number of the

implanted electrodes (generally one in the midline or two,

one for each side) usually vary according to the physician’s

preference and on the clinical picture of the patient, as do

the configuration of the electrodes’ themselves, which can

have different inter-contact distance and different lengths.

Implantation of a single subcutaneous electrode is per-

formed in the midline of the suboccipital region, whereas in

the bilateral implants two symmetrical electrodes are

positioned 1 cm in the midline below the inion and

extending laterally for 4–6 cm, to ensure coverage of the

greater occipital nerve’s main trunks [22] (Fig. 1). The

surgical technique has been described by our group in a

previous manuscript [23] and briefly consists of anchoring

the plastic tip of each positioned electrode to the underlying

muscular fascia with non-adsorbable sutures and of tun-

nelling the connection cables to the subcostal region, where

the internal pulse generators (IPGs) are placed. Clinical

indications to ONS are: CCH [24], hemicrania continua

[25], transformed migraine [26, 27], cervicogenic head-

aches [28] and occipital neuralgia [29, 30]. Apart from the

latter two indications, the use of ONS for the different types

of cranial neuralgias is justified by the presence of a func-

tional unit known as the ‘‘trigemino-cervical complex’’,

which comprises the trigeminal nucleus caudalis and the

first two cervical spinal myelomeres and in which noci-

ceptive informations of both the suboccipital and trigeminal

territory converge, thus stimulation of the greater occipital

nerve could modulate the central nociceptive trigeminal

neurons through peripheral cervical afferents [31].

Slavin [30] reported a significant improvement of

occipital neuralgia in seven out of ten patients previously

submitted to trial stimulation, Matharu [32] obtained

‘‘good’’ results in eight patients submitted to ONS (pain

reduction ranging from 75 to 90 %); Popeney [26] reported

an average improvement of 88.7 % in the Migraine Dis-

ability Index (MIDAS) in his series of 25 patients affected

by transformed migraine after C1, C2 and C3 electric

stimulation; Rodrigo-Royo [28] reported a ‘‘good’’ out-

come in four patients submitted to such procedure (C1–C3

electric stimulation) for occipital neuralgia. Trentman [33]

reported that 7 out of 8 patients submitted to Greater ONS

obtained ‘‘fair’’ or ‘‘better’’ results in terms of reduction of

disability.

As far as CCH is concerned, Mueller [34] reported a

reduction of frequency, duration, and severity in 90 % of

ten patients, with subsequent improvement in quality of life

as assessed by SF-36 scale; 70 % of patients in this series

were able to reduce the posology of pharmacological

treatment, too. Magis [35] reported that seven out of ten

patients with drug-resistant cluster headache were

responders to ONS after a follow-up ranging from 6 to

30 months; interestingly, in this study, a positive correla-

tion between the responsiveness and the hyperactivity of

the perigenual anterior cingulate cortex (PACC) assessed

with 18FDG-PET was found. At 6 months, there was

a 56 % (range 25–95 %) reduction in the frequency, a

48.8 % (range 20–60 %) decrease in the intensity and a

63.8 % (range 0–88.8 %) reduction in the duration of the

attacks. Burns [4] reported that 10 out of 14 patients ben-

efited from the procedure (although in various degrees:

percentage of improvement ranged from 20 to 90 %); most

of the patients reported relapse of pain attacks after

switching off the IPG. de Quintana-Schmidt [36] reported a

range of improvement of 25–95 % (mean 56 %) in the

frequency and of 20–60 % (mean 48.8 %) in intensity of

Neurol Sci (2012) 33 (Suppl 1):S131–S135 S133

123

cluster headache attacks in four patients submitted to the

procedure; all of the patients were reported to ‘‘recommend

the procedure’’ in this paper.

Our series of patients submitted to ONS for drug-

refractory cluster headache consists of 25 subjects, of

which only 20 have a follow-up of more than 3 months.

The duration of the illness ranges from 4 to 36 years, and

the period of chronicity ranges from 2 to 27 years. 14 out

of 20 patients (70 %) responded to the procedure ([50 %

reduction in the frequency of pain attacks). Noticeably,

whereas all of the responders presented with a minimum of

percentage in frequency of the attacks of 90 %, non-

responders presented a maximum of percentage in fre-

quency of the attacks of 19 %; there seems to be a ‘‘clear’’

cutoff point between responders and non-responders in our

series.

Discussion, guidelines and perspectives of surgical

treatment of primary headaches

ONS is the first choice procedure in CCH patients refrac-

tory to drugs and conservative treatments. The expected

favourable outcome is high ([60 % in our series) and the

procedure is minimally invasive. Risks of definitive CNS

or PNS lesions are quite zero in ONS patients. DBS is the

second choice procedure and carries a certain amount of

risks including mortality (\1 %). Both the procedures are

based on a definitive neuroprosthesis implant, nevertheless

the cost–benefit ratio in CCH patients is clearly favourable

to neuromodulation which has been demonstrated to reduce

the global costs in term of drugs, hospital admittances,

caregivers and disability [37]. Neuromodulation (ONS and

DBS) extended more than 80 % the therapeutic possibili-

ties in CCH patients and inspired a huge amount of studies

and the development of new devices to treat other primary

headaches including migraine and tension type headache.

VNS has been used to treat CH patients by Mauskop [3]

and also to treat some patients affected by drug-resistant

migraine [38]. The recent introduction of transcutaneous

VNS which is a non-invasive procedure and can produce

neuroimaging alterations and clinical effects similar to

VNS [39] may contribute to a better understanding of the

indications to VNS in primary headaches. Patients affected

by primary headaches may be submitted to long lasting

transcutaneous VNS to select patients which could gain

stable benefits by surgical VNS. Recently, also the elec-

trical stimulation of the sphenopalatine ganglion has been

proposed to treat primary headaches and particularly

migraine and CH [6]. In conclusion, reported experiences

in CCH patients suggest that central (DBS) and peripheral

(ONS, VNS, SPGs and subcutaneous stimulation)

neuromodulation will represent an important treatment

modality in primary headaches.

Conflict of interest The authors declare no conflict of interest.

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