ANIRCEF - HCNE JOINT MEETING

Neuromodulation in drug-resistant primary headaches:what have we learned?

Massimo Leone • Alberto Proietti Cecchini •

Angelo Franzini • Gennaro Bussone

� Springer-Verlag 2011

Abstract In the last years neurostimulation procedures

have been introduced to treat primary neurovascular

headaches, namely cluster headache and migraine. Hypo-

thalamic stimulation is now accepted as therapeutic

procedure to treat drug-resistant chronic cluster headache

when patients suffer from daily multiple attacks. The

inadequacy of the definition of the term ‘‘chronic’’

according to the International Headache Society criteria for

both cluster headache and migraine when it is used to select

patients for neurostimulation procedures is now evident.

On the same side, there is no agreement about the use of

the term ‘‘drug-resistant’’ again when it is used to select

patients for neurostimulation procedures. We have pro-

posed that only patients suffering from daily neurovascular

headaches in the last 1–2 years, with complete drug-

resistance should be proposed for invasive procedures.

Keywords Cluster headache � Migraine �Neurostimulation � Occipital nerve stimulation �Deep brain stimulation

Introduction

In this paper, we will shortly review some aspects that we

have been learning in 11 years after neurostimulation

procedures have been introduced to treat primary neuro-

vascular headaches, namely cluster headache and migraine.

Cluster headache

Patient selection for neurostimulation procedures

The International Classification of Headache Disorders

defines chronic cluster headache when attacks occur for

more than 1 year without remission or with remissions of

less than 1 month [1]. These criteria allow a diagnosis of

chronic CH when the patient suffers from only three to four

attacks per month or per week over 1 year. At our insti-

tution we propose patients for an invasive surgical proce-

dure such as ONS or DBS only if they experience more

than two attacks per day. It is evident that the IHS defi-

nition of chronic CH is necessary but not enough for sur-

gical purposes. In particular we recommended that

posterior hypothalamic stimulation be considered only for

cluster headache patients who suffer from daily—or almost

attacks—for least 1–2 years [2].

And what about the term drug-resistant? The term drug-

resistant has been used to refer to patients who do not

respond to one or more types of drug [3], as well as to those

who do not respond to any of the known medications [2].

Patients unresponsive to one or more preventatives can

improve under untried pharmacological treatments.

Accordingly, they should be reported as partially drug-

resistant, while the term completely drug-resistant should

indicate patients who do not obtain benefit with any med-

ication [4]. The condition of complete drug resistance is

much more serious than that of partial resistance. Com-

pletely drug-resistant patients often resort to numerous

medications (e.g., analgesics, triptans, nonsteroidal anti-

inflammatory agents, opioids, ergot-derivatives, steroids)

M. Leone (&) � A. P. Cecchini � G. Bussone

Headache Centre Neurology Department,

National Neurological Institute (IRCCS) Foundation ‘‘C.Besta’’,

via Celoria 11, 20133 Milan, Italy

e-mail: leone@istituto-besta.it

A. Franzini

Neurosurgery Department, National Neurological Institute

(IRCCS) Foundation ‘‘C.Besta’’, via Celoria 11,

20133 Milan, Italy

123

Neurol Sci (2011) 32 (Suppl 1):S23–S26

DOI 10.1007/s10072-011-0554-z

in increasingly desperate attempts to relieve their daily

headaches. For these reasons we have proposed that

patients are eligible for neurostimulation procedure only

when they are completely drug-resistant, i.e unresponsive

to all indicated drugs in the guidelines or in the literature

(unless contraindicated) [2, 4].

Primary endpoints

Occipital nerve stimulation (ONS) was firstly employed in

chronic migraine [5]. Seven out of the eight chronic

migraine patients initially had the headache resolved

5–25 min soon after starting stimulation. Unfortunately

these results were not observed in other studies and acute

pain resolution should not be one of the criteria for

assessing ONS efficacy [6]. The situation is similar for

drug-resistant chronic cluster headache (CCH) in which

neither acute ONS nor acute hypothalamic stimulation

usually provokes headache disappearance [7]. In a recent

study on eight drug-resistant CCH patients, ONS decreased

attack frequency after a median follow-up of 20 months in

three patients (by 95, 90 and 60%); in a fourth patient

reduction ranged between 20 and 80%; in two other patients

attack frequency reduction was 25 and 40%; the remaining

two patients had no improvement. Notwithstanding these

results patients reported they were satisfied with the treat-

ment and would recommend it to other CH patients [8]. One

may argue that patient satisfaction is not an appropriate tool

to measure the efficacy of the procedure since a number of

factors, independent of an effect on pain, can affect patient

satisfaction. IHS recommends that headache frequency

reported on a diary card be the primary endpoint when

evaluating efficacy of preventive treatment in CH [9].

Hypothalamic stimulation: efficacy results

We have reported on 16 drug-resistant chronic cluster head-

ache patients who received hypothalamic implants after a

mean follow-up of more than 4 years [10, 11]. In the first

2 years, a pain-free state or almost pain-free state was

observed in 13 of the 16 patients. After 4 years, a persistent

pain-free state was present in 10 patients (62%). This showed

a ‘‘tolerance’’ to the hypothalamic stimulation in three of the

ten patients, notwithstanding the many changes in stimulation

settings. It is very interesting to note that the illness shifted

from chronic to episodic in three patients. Similar improve-

ments have been reported from other studies: 62% of 58

patients obtained such improvement (for a review see [11]).

Hypothalamic stimulation: tolerability and adverse events

Hypothalamic implantation is associated with a small risk

of intracerebral hemorrhage as with any cerebral electrode

implantation procedure. At one centre, one patient died

soon after the operation, because of implantation-induced

intracerebral hemorrhage; in another patient, the implan-

tation was stopped because of panic attack [12]. We

reported a small transient non-symptomatic hemorrhage

into the third ventricle in on case; follow-up revealed

complete resolution [10].This operation must be performed

by an expert neurosurgical team. No untoward intraoper-

ative modifications in EEG, blood pressure, temperature,

breathing, affective state, or state of consciousness are

reported [10].

Hypothalamic stimulation often induces visual distur-

bances, mainly diplopia and this occurs in most patients

when the amplitude is increased too rapidly; however, it is

self-limiting. No changes in electrolyte balance, body

temperature, blood pressure, sleep–wake cycle, appetite or

thirst, or EEG findings have been observed on prolonged

hypothalamic stimulation. Levels of cortisol, prolactin,

thyroid hormones, thyroid-stimulating hormone, and tes-

tosterone also remain unchanged. Weight loss may occur in

the first 3–6 postoperative months, related to steroid

withdrawal. One patient ceased menstruating as a result of

excessive drug/analgesic use; about 1 month after hypo-

thalamic implantation 38 her cycles returned to normal. No

depressive or behavioral changes have been observed. (for

a review see [11]).

Hypothalamic stimulation: pathophysiological

implications

Recently, the relation between the hypothalamus and the

trigeminal system in human beings has been further elu-

cidated. In a PET study performed on chronic CH patients

successfully treated by hypothalamic neurostimulation, the

hypothalamic stimulation induced increased blood flow

(activation) in both the ipsilateral posterior inferior hypo-

thalamic grey matter (at the stimulator tip) and the ipsi-

lateral trigeminal system [13]. For the first time a

functional connection between the hypothalamus and the

trigeminal system in humans has been clearly documented.

It is very interesting, however, that in these patients, acti-

vation of the trigeminal system was neither accompanied

by headache attacks, nor by other facial signs or symptoms

attributable to trigeminal function, nor autonomic cranio-

facial phenomena. According to these observations one can

speculate that the trigeminal system activation is necessary

for a CH attack, but it is not sufficient on its own to

precipitate CH. The leading hypothesis that prompted

stimulation of posterior hypothalamus in CH was that high-

frequency hypothalamic stimulation might inhibit hyper-

activity of this brain area. So far more than 50 patients with

drug-resistant chronic CH who have received implantation

benefit notable clinical improvement in about 60% of cases

S24 Neurol Sci (2011) 32 (Suppl 1):S23–S26

123

(for review see [11]). Hypothalamic stimulation has to

continue for weeks or months before the headache reduc-

tion is reached. On the other side, it is noteworthy that

acute stimulation is unable to prevent ongoing CH attacks

[7]. Continuous hypothalamic stimulation has also proved

successful in SUNCT [14, 15], and in PH [16]. The

mechanism of hypothalamic stimulation appears to be

complex as indicated by the latency of chronic stimulation

and inefficacy of acute stimulation: efficacy of hypotha-

lamic DBS is not the result of simple inhibition of hypo-

thalamic neurons, as initially supposed. It has been

hypothesized that at least part of the effect of hypothalamic

stimulation could be due by neuromodulation of the an-

tinociceptive system. This hypothesis is supported by a

recent finding of an increased threshold for cold pain at the

first trigeminal branch on the stimulated side [17].

Hypothalamic stimulation also increases blood flow in

brain pain matrix [13]: activation of the thalamus,

somatosensory cortex, precuneus, anterior cingulate cortex,

and deactivation in the middle temporal gyrus, posterior

cingulate cortex, and insula. Hypothalamic stimulation

could exert its therapeutic effect in CH by gradually

restoring normal function and metabolism in hypometa-

bolic areas in patients with CH. Even if the idea that the

hypothalamus is the so-called CH generator is appealing,

the recent neuroimaging and neurostimulation findings

discussed above indicate other hypothesis. If the hypo-

thalamus were the CH generator, hypothalamic stimulation

would be expected to precipitate CH pain attacks, but this

is not the case [18]. We hypothesize that this brain area

plays a major role in terminating, rather than inducing

single CH attacks [18]. In other terms one can argue that

the hypothalamus regulates the duration of a single CH.

Occipital nerve stimulation

The success of occipital nerve blockade in cluster headache

[19], prompted the use of occipital nerve stimulation to

treat drug-resistant chronic cluster headache. In one study

on eight patients, after a median follow-up of 20 months

attack frequency was reduced in three patients (by 95, 90

and 60%), in 2 patients improvement did not reach the 50%

reduction of headache attack frequency and in the

remaining efficacy was poor or absent [8]. Nevertheless,

these patients declared that they were satisfied with the

treatment and would recommend it to other patients with

cluster headache. Authors did not fully explain the dis-

crepancy; it seems that factors other than pain have a role

in patients’ evaluation of the therapy. The lesson is that

conclusions on efficacy have to be primarily based on

headache frequency as suggested by IHS [9].

In another ONS study on eight DR CCH patients [20]

result are hampered by different selection criteria compared

to other neurostimulation studies. Two are the main

differences compared to other studies. In this study the

majority of the patients had less than 9 headache attacks

per week, while in the other neurostimulation studies on

DR CCH selected patients suffered at least 2–8 attacks

per day. The second difference is that three of the eight

patients had a follow-up of less than 5 months: such a

short follow is a huge obstacle to have firm conclusion on

the effect of the procedure [20].

The lesson is that a long term follow-up is required in

order to establish efficacy of this procedure; another key

message is to keep in mind headache frequency in each

patients: it is evident that the higher the headache attack

frequency the more difficult is the headache treatment.

Migraine

At the beginning of neurostimulation in migraine it was

reported that GON stimulation induced headache disap-

pearance in chronic migraine patients [5]. In that study,

authors reported that once the simulator was off headache

reappeared in few minutes and disappeared as soon as

stimulation re-started [5]. So far, this observation has never

been reported in other studies on chronic migraine [6]. The

discrepancy could be due to differences in selected popu-

lation. It is not easy to compare population in the various

studies, mainly because there is no agreement on the term

‘‘chronic migraine’’, ‘‘transformed migraine’’, ‘‘intracta-

ble’’, ‘‘resistant’’, drug-resistant’’. In addition the psycho-

logical profile of these patients is incompletely described.

In this regard, in the last years the question if the current

definition of the International Headache Society of chronic

migraine is adequate for surgical purposes has emerged.

The International Headache Society defines chronic as a

migraine patients whose headaches are present for 15 days

or more per month for at least 3 months [1]. We think that

3 months is too short as observation period to select

‘‘chronic’’ migraine patient for a surgical operation (whose

results are not guaranteed in terms of efficacy).

Another matter of discussion is that there is no com-

monly accepted definition of the term ‘‘drug-resistance’’

again for surgical purposes [21]. In fact there is no agree-

ment on the use of the terms ‘‘intractable’’, ‘‘resistant’’,

‘‘drug-resistant’’ etc. [4]. We proposed that before con-

sidering any neurostimulation procedure, an adequate trial

with recommended effective prophylactic drugs need to be

done [4]. Special attention is required to both duration and

dosage of drug treatment. Before considering any neur-

ostimulation procedure, treatment of medication overuse

and treatment of comorbidities have to be undertaken:

about 50% of chronic migraine with medication overuse do

better after specific detoxication treatments. At the same

time, chronic migraine patients may experience huge

Neurol Sci (2011) 32 (Suppl 1):S23–S26 S25

123

improvements when the coexisting psychiatric disorder is

properly treated.

Conflict of interest The authors declare that there is no actual or

potential conflict of interest in relation to this article.

References

1. Headache Classification Committee of the International Head-

ache Society (2004) The International Classification of Headache

Disorders, 2nd edn. Cephalalgia 24(Suppl 1):1–160

2. Leone M, May A, Franzini A et al (2004) Deep brain stimulation

for intractable chronic cluster headache: proposals for patient

selection. Cephalalgia 24(11):934–937

3. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D

(2006) Towards a definition of intractable headache for use in

clinical practice and trials. Cephalalgia 26:1168–1170

4. Leone M, Proietti A, Mea E, D’Amico D, Tullo V, Grazzi L,

Bussone G (2008) Therapeutic neurostimulation in chronic

headaches: problems of patient selection. Neurol Sci 29:S59–S61

5. Matharu MS, Bartsch T, Ward N, Frackowiak RSJ, Weiner R,

Goadsby PJ (2004) Central neuromodulation in chronic migraine

patients with suboccipital stimulators: a PET study. Brain

127:220–230

6. Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M,

Goadsby PJ (2004) Occipital nerve stimulation for the treatment

of intractable chronic migraine headache: ONSTIM feasibility

study. Cephalalgia 31(3):271–285

7. Leone M, Franzini A, Broggi G, Mea E, Proietti Cecchini A,

Bussone G (2006) Acute hypothalamic stimulation and ongoing

cluster headache attacks. Neurology 67(10):1844–1845

8. Burns B, Watkins L, Goadsby PJ (2009) Treatment of intractable

chronic cluster headache by occipital nerve stimulation in 14

patients. Neurology 72(4):341–345

9. Lipton RB, Micieli G, Russell D, Solomon S, Tfelt-Hansen P,

Waldenlind E (1995) Guidelines for controlled clinical trials of

drugs in cluster headache. Cephalalgia 14:452–462

10. Leone M, Franzini A, Broggi G, Bussone G (2006) Hypothalamic

stimulation for intractable cluster headache: long-term experi-

ence. Neurology 67:150–152

11. Leone M, Proietti Cecchini A, Franzini A, Broggi G, Cortelli P,

Montagna P, May A, Juergens T, Cordella R, Carella F, Bussone

G (2008) Lessons from 8 years’ experience of hypothalamic

stimulation in cluster headache. Cephalalgia 28:789–797

12. Schoenen J, Di Clemente L, Vandenheede M et al (2005)

Hypothalamic stimulation in chronic cluster headache: a pilot

study of efficacy and mode of action. Brain 128:940–947

13. May A, Leone M, Boecker H, Sprenger T, Juergens T, Bussone G

et al (2006) Hypothalamic deep brain stimulation in positron

emission tomography. J Neurosci 26:3589–3593

14. Leone M, Franzini A, D’Andrea G, Broggi G, Casucci G, Bus-

sone G (2005) Deep brain stimulation to relieve severe drug-

resistant SUNCT. Ann Neurol 57:924–927

15. Lyons MK, Dodick DW, Evidente VGH (2008) Responsiveness

of short-lasting unilateral neuralgiform headache with conjunc-

tival injection and tearing to hypothalamic deep brain stimula-

tion. J Neurosurg 26:1–3

16. Walcott BP, Bamber NI, Anderson DE (2009) Successful treat-

ment of chronic paroxysmal hemicrania with posterior hypotha-

lamic stimulation: technical case report. Neurosurgery 65:E997

17. Jurgens T, Leone M, Proietti-Cecchini A, Busch V, Mea E,

Bussone G et al (2009) Hypothalamic deep-brain stimulation

modulates thermal sensitivity and pain thresholds in cluster

headache. Pain 146(1–2):84–90

18. Leone M, Bussone G (2009) Pathophysiology of trigeminal

autonomic cephalgias. Lancet Neurol 8:755–764

19. Ambrosini A et al (2005) Suboccipital injection with a mixture of

rapid- and long-acting steroids in cluster headache: a double-

blind placebo controlled study. Pain 118(1–2):92–96

20. Magis D, Allena M, Bolla M, De Pasqua V, Remacle JM,

Schoenen J (2007) Occipital nerve stimulation for drug-resistant

chronic cluster headache: a prospective pilot study. Lancet

Neurol 6:314–321

21. D’Amico D, Leone M, Grazzi L, Bussone G (2008) When should

‘‘chronic migraine’’ patients be considered ‘‘refractory’’ to

pharmacological prophylaxis? Neurol Sci 29:S55–S58

S26 Neurol Sci (2011) 32 (Suppl 1):S23–S26

123