Recent advances in the diagnosis and management of migraine
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7532.25 (Published 05 January 2006) Cite this as: BMJ 2006;332:25All rapid responses
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Feb 20, 2006
Dear Editors:
I am writing to compliment Dr. Goadsby on his truly outstanding
article on diagnosis and management of migraine. (1). His recent article
comes much closer to describing the reality of what I see in my large
headache practice than do most authors writing review articles today. I
had become so frustrated by the direction of the headache literature over
the last 10 years that I had virtually stopped reading it until I stumbled
across Dr. Goadsby’s articles about a year ago. I agree with several
points that he makes that I have been waiting for several years to see in
the headache literature. 1) Daily headache is usually daily migraine, 2)
Migraine is an ionopathy, or a channelopathy; an increased tendency to
make a headache because of an ion channel or ion pump mutation. 3)
Migraine is almost always accompanied by a change in mental status that
cannot have to do with the blood vessels or just the trigeminal nerve. 4)
Dr. Goadsby starts with the clinical presentation and asks, “where in the
brain could all of these symptoms arise in unison?” then explains, in
brie, his group’s theories about the posterior brain stem as the migraine
generator.
There were also, importantly, two recent “theories” that were
missing. ”Medication overuse headache” and “Rebound headache” as cause of
daily headache. A contrasting article is Dr. Dodick’s recent article in
NEJM on “Chronic Daily Headache” wherein the concepts of medication
overuse headache and rebound headache get all of the attention, and recent
advances in the genetics of migraine are completely ignored. “Rebound
headache” or “medication overuse headache” is an idea that was created by
an unnamed headache expert. It was then repeated so many times that it
became “truth” despite having absolutely no basis in any sort of
scientific study, and now almost everyone, (with the prominent exception
of Drs.Goadsby and Welch) is afraid to question its validity. (1, 3)
The overwhelming majority of daily headache in my practice is
migraine. Most of the patients I see have daily headache and they have
headaches that have all of the features of migraine. A mild migraine
becomes a severe migraine, but they are both the same underlying
chemistry. There is no reason to call daily headache “transformed
migraine”, it is true that it starts episodically then becomes daily, but
it is just daily migraine. It seems more appropriate to change our
definition of what a “migraine” can be than to add modifiers. Apparently
the International Headache Society (IHS) has recently begun to turn this
direction as well. (1) The migrainer has a lowered threshold for making a
headache due to a genetic mutation. Migrainers also have an increased risk
of lapsing into a daily headache syndrome. They can do so after mild head
trauma, or when exposed to increased levels of gonadotropin releasing
hormone during menopause, or when sleep deprived from a sleep disorder.
When the triptans came out over 10 years ago we told our patients
that they should use them only for their “migraines”. But our patients
found that if they used the triptans earlier in the headache, i.e. on a
milder headache, they had more consistent success in aborting them. When
the milder headaches; the “tension”, or “muscle contraction”, or “sinus”
headaches, are easily aborted by the triptans it means that the chemistry
of those headaches are the same as “migraine” and the detailed nosology
recommended by the IHS in the past is unnecessarily complex; some of the
headaches are small migraine, some are big migraine.
In the late 1990’s a colleague who was treating patients with
Familial Hemiplegic Migraine (FHM), right after the Ca++ channel (CACN)
mutation reports came out, taught me two very important things; one,
verapamil worked well for those patients but it took a month before they
noticed improvement and two, they had to go up to very high doses of
verapamil; 360-720mg. Up until that time I, like many Neurologists, had
had very patchy success using Ca++ channel blockers (CCB’s) as
preventatives. However, once I started using higher doses I had about a
60% success rate with verapamil. Many of my patients with severe daily
headache (whether they are taking daily pain medications or not) are cured
by verapamil. Once they get to the correct dose their headaches decrease
to 1-2 per month and are easily aborted with the same triptans that did
not work for them before. The effect of verapamil does not wear off, there
are no severe side effects and it works equally well in children,
teenagers and adults. There is no reason to blame these daily headache
sufferers for their own disease. Their headaches are not caused by taking
medication daily. Teenagers with daily headache (who generally do not like
taking medication) grow up to be adults with daily headache. Both groups
respond in the same way to the right medication
There is an odd disconnect currently, especially in the U.S. headache
literature, between the basic science and clinical science of migraine.
The basic science of migraine has advanced dramatically in the last 10
years but it is as though we are so resistant to changing our thinking
that most authors tend to ignore the basic science because it does not fit
with the current trigemino-inflammatory theory. There are many reported
Ca++ channel mutations linked to migraine.( 4-7 ) There are Ca++ pump
mutations linked to migraine. There are mouse models that show that when
Ca++ channel mutations are caused in mouse astrocytes they cause a lowered
threshold for spreading depression .( 8 ) Also, the basic scientists
writing about their ion channel discoveries are forced by the current
trigemino-inflammatory dogma (which absolutely does not have room for Ca++
channels) to add the caveat that familial hemiplegic migraine is rare, as
though their findings are not applicable to migraine patients in general.
This, despite the fact that the reports about FHM clearly show that most
of the family members with the mutation have migraines that are not
accompanied by paralysis, the family members with paralysis have headaches
frequently and paralysis rarely, and a significant number of general
headache patients have also been found to have Ca++ channel mutations. (9-
12)
Migraine, if you ask any migrainer, is not just a disorder of head
pain, but a disorder of head pain and altered level of thought and
consciousness. This additional symptom is present in almost all migraine
suffers as the headache becomes severe, and is present in many daily
headache patients even when their head pain is mild. The migrainer often
goes to bed, not just because of pain, but because of the inability to
think. The trigeminal nerve does not govern global intellectual
functioning therefore it cannot explain this most important effect of
migraine. This is an aspect of migraine which has been relatively ignored
in the headache literature, and must be explained by any theory of the
pathophysiology of migraine. This symptom could be explained by widespread
inhibitory input of astrocytes on neurons, which may be what happens in
spreading depression, as suggested by Dr. Welch’s group. (13) It could
also be explained by malfunction of the Serotonergic Raphe Nuclei (SRN),
as suggested by Dr. Goadsby’s group in London. (14-17)
Once the CACN mutations of FHM were published and the physicians
treating them found that verapamil prevented their headaches, there was an
appropriate scientific basis for large, case-controlled trials of CCB’s in
headache patients. Unfortunately, to the best of my knowledge, large
trials with verapamil still haven’t been published, even though
flunerazine (a calcium channel blocker not available in the U.S.) is used
in many clinics in Europe as first line therapy for migraine prevention,
and high dose verapamil has been successful in preventing cluster
headache. (18) Verapamil may be used for migraine prevention more widely
than is represented in the current migraine review articles, but
unfortunately most reviews mention it last, if at all. (1, 14, 19)
There appear to be some distinctive features about verapamil that
make it different from the other calcium channel blockers (CCB’s). (20-22)
Verapamil works on L type calcium channels but all the CACN mutations
reported in migraine have been P/Q type channels. (4-7 ) All of the known
P/Q type blockers are poisons, which is presumably why the ion channel
biochemists have not been suggesting CCB’s to treat FHM or Familial
Episodic Ataxia (FEA). However, there is literature to suggest that some
of the L type blockers can be P/Q type blockers at very high doses.(20-22)
My experience with verapamil, as well as some of the smaller trials that
have been successful, probably suggest that verapamil is chemically
distinctive. Verapamil is a benzothiazepine, all of the other calcium
channel blockers currently available are either dihydropyridines or
phenylalkylamines. It may be that verapamil, among these three categories,
is the only L type CCB that can cross over to act on the P/Q type channels
at higher doses. Also there are specific issues about the state of the Ca
++ channel and the binding of the CCB’s which may explain the long delay
in its action. (20-23) It is my thought that the prior clinical trials
were not designed with these specifics in mind therefore the results were
inconsistent. I have also had excellent success with verapamil in treating
FEA, another episodic disorder of neurologic dysfunction caused by P/Q
type, voltage-gated, Ca++ channel mutations. (24) I have also observed
that, once controlled, they can have break through episodes of vertigo
when exposed to monosodium glutamate.
Migraine is clearly an episodic disorder caused by altered brain
excitability. The blood flow observations in migraine were real but they
are an epiphenomenon. At last, most of the European literature and several
U.S. authors have disposed of the “vascular” theory of migraine and it is
now mentioned only as an historical point. (25-27) Now the “trigeminal
inflammatory” part of the theory deserves a similar fate. For the past
decade, migraine researchers have directed their attention to the distal
trigeminal nerves where they end on the vessels and the meninges, instead
of the trigeminal caudal nucleus (TCN). (28) Just because the parenchyma
of the brain does not have pain fibers does not mean that our experience
of spontaneous headache occurs in the organs of the brain that do have
pain fibers. It’s as illogical to look at the blood vessels and meninges
for the cause of migraine as it would be to look at the nerve endings in
the skin for the source of pain in a post stroke pain syndrome. The pain
is being sent to consciousness from the TCN, just as the pain of thalamic
stroke is sent to consciousness from the injured thalamus, not from the
painful arm or leg. Multiple studies directed at inhibiting these
inflammatory chemicals have failed to make a dent in migraine. (15) The
release of inflammatory neurochemicals in the meninges are indeed real
observations but the only role they play in migraine is that they make the
scalp and meninges hurt after the headache has been present long enough,
producing the allodynia of migraine that is receiving so much attention
recently.
The triptans are known to work on Serotonin 1B and 1D receptors which
are feedback inhibitors of the release of Serotonin. Currently we are
being taught that these medications are acting on the Serotonin receptors
in cerebral blood vessels. Importantly, however, all of the symptoms of
migraine; the inability to think, the mild nausea, the mild neck tension,
and mild photophobia, all go away in unison when the triptans are used
early in the headache. This means that either the triptans work at several
different places simultaneously or there is a central generator where
migraine starts, and if caught soon enough, can be turned off. (14-17,29)
The SRN, in the periaquiductal grey of the dorsal brain stem is where most
of the Serotonin released in the brain originates. The SRN are also one of
the central volume controls for vigilance, the nausea center, the
chemotrigger zone, is in the floor of the 4th ventricle, right next door,
the TCN, causing headache pain, is just anterior, and just in front of the
TCN is the salavatory nucleus that gives facial congestion to all of the
migrainers who think they have “sinus headache”. It seems obvious that
for all of these disparate symptoms to resolve in synchrony the triptans
must act in an area that can produce all of them. Unfortunately, the daily
headache patients are unsuccessful with the triptans because they are
always too far into the headache to use them in the “brainstem phase”.
However, as soon as the correct preventative converts the daily headache
into an episodic headache the triptans become successful again. Sadly,
most of the headache experts in the U. S. are not yet teaching this model
despite the fact that the PET Scan studies showing the posterior brain
stem “lit up” in migrainers are over 10 years old. (30)
Once the altered excitability of the brain stem is understood many
other clinical observations follow quite logically. The excitability of
the brainstem and its tendency to make a migraine will be affected by
other neurotransmitters like glutamate in monosodium glutamate or the
Gonadotropin Releasing hormones (GRH). The effects of GRH as a
neurotransmitter explain why migraine begins in boys and girls at puberty,
why the headaches are less frequent in men after age 18, as they have
constant levels of testosterone suppressing spikes of GRH in the brain. It
explains why there is a monthly pattern in menstruating women following
the GRH spikes, why migraine gets better in pregnancy while GRH is
suppressed by progesterone, why very severe menstrual migraine can be
stopped by leuprolide, ( 31 ) why the headaches get worse during
menopause when the GRH is very elevated, and why migraine goes away after
menopause. Altered excitability of the brainstem caused by an ion channel
mutation also fits well with the last 7-8 years of experience using
epilepsy medications for prevention of migraine. Depakote, Zonegran and
Topamax have all been used very successfully as migraine preventatives
and, not surprisingly, they are all channel stabilizers. (13)
Any theory about the pathophysiology of migraine should also explain
many long standing clinical observations in migraine such as the link
between sleep deprivation and migraine. Many migraine sufferers with
severe migraine since their teens have also had trouble sleeping since
teen years. The periaquiductal grey is heavily involved in putting us to
sleep; those patients with the inability to turn their brain off to go to
sleep may have hyperactivity in the same area causing their increased
incidence of migraine. Also, I have recently observed that in my patients
with daily headache who fail two or three preventatives the incidence of
an untreated sleep disorder such as sleep apnea is very high, even in
young female patients who are not obese.
My experience with verapamil has dramatically changed my level of
success with treating daily headache patients, which is now a very
rewarding part of my practice. I would like to encourage physicians who do
clinical trials in daily headache to design large, case-controlled
clinical trials of verapamil in higher doses. I would also like to
challenge our clinicians who treat daily headache to take on the
responsibility of finding the right preventative agent for the daily
headache patient instead of blaming them for their disease.
Migraine is one of the most common, disabling disorders of young,
healthy people and it can be effectively cured in most patients using the
medications we have today. The fact that it is so common will probably
mean that there are many genes that can lower the threshold for making a
headache, (34) but the underlying concept of hyperexcitability is a
unifying one that combines our clinical observations with the newer
scientific studies and gives us new directions for successful treatment.
Stasha Gominak, M.D.
East Texas Medical Center Neurologic Institute
700 Olympic Plaza, Suite 904
Tyler, Texas 75701
SGominak@Yahoo.com
References:
1. Goadsby PJ Recent advances in the diagnosis and management of migraine.
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2. Dodick DW. Chronic Daily Headache. NEJM 2006;354:158-165
3. Welch KMA, Goadsby PJ. Chronic daily headache:nosology and
pathophysiology Curr Opin Neurol 2002;15:287-295.
4. Joutel A, Bousser MG, Biousse V, et al A gene for familial
hemiplegic migraine maps to chromosome 19. Nat Genet 1993;5:40-45.
5. Gardner K, Barmada MM, Ptacek LJ, Hoffman E. A new locus for
hemiplegic migraine maps to chromosome 1q31. Neurology 1997;49:1231-1238.
6. Ducros A, Joutel A, Vahedi K, Cecillon M, et al. Mapping of a
second locus for familial hemiplegic migraine to 1q21-q23 and evidence of
further heterogeneity. Ann Neurol 1997;42:885-890.
7. Kraus RL, Sinnegger MJ, Koschak A, Glossmann H, Stenirri S,
Carrera P, Striessnig J. Three new familial hemiplegic migraine mutants
affect P/Q type Ca++ channel kinetics. Jour Biol Chem, 2000;275:9239-43.
8. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos
LA, et al. A CACNA1a knockin migraine mouse model with increased
susceptibility to cortical spreading depression. Neuron. 2004 Mar
4;41(5):701-10.
9. Ducros A, Denier C, Joutel A, Cecillon M, et al. The clinical
spectrum of familial hemiplegic migraine associated with mutations in a
neuronal calcium channel. NEJM 2001;345:17-24.
10. Nyholt DR, Lea RA, Goadsby PJ, Brimage PJ, Griffiths LR. Familial
typical migraine. Neurology 1998;50:1428-32.
11. Terwindt GM, Ophoff RA, Haan J, Vergouwe MN, et al. Variable
clinical expression of mutations in the P/Q-type calcium channel gene in
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12. Joutel A, Ducros A, Vahedi D, et al. Genetic heterogeneity of
familial hemiplegic migraine. Am J. Hum Genet 1994;22:21-26.
13. Welch KM. Brain hyperexcitability: the basis for antiepileptic
drugs in migraine prevention. Headache 2005;45:S25-S32.
14. Goadsby PJ, Lipton RB, Ferrari MD. Migraine – Current
understanding and treatment. NEJM 2002;346:257-270.
15.Goadsby PJ. Migraine pathophysiology. Headache 2005;45:S14-S24.
16. Knight E, Goadsby PJ. The periaquiductal grey matter modulates
trigemino-vascular input: A role in migraine? Neuroscience 2001;106:793-
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17. Knight YE, Bartsch T, Kaube H, Goadsby PJ.P/Q-type calcium-
channel blockade in the periaquiductal gray facilitates trigeminal
nociception: A functional genetic link for migraine? J Neurosci
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18. Leone M, D’Amico D, Attanasio A. Verapamil is an effective
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19.Silberstein SD Preventive treatment of headaches. 2005,Curr Opin
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20. Doering CJ, Zamponi GW. Molecular pharmacology of non –L-type
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type Ca++ channels Cell Physiol Biochem 1999;9:242-169.
23. Kraus RL, Sinnegger MJ, Glossmann H, Hering S, Striessnig J.
Familial hemiplegic migraine mutations change alpha 1A Ca++ channel
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24. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic
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26. Silberstein SD. Migraine. Lancet 2004;363:381-91
27.Welch KMA. Research developments in the physiopathology of primary
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Competing interests:
I have accepted lecture stipends from Glaxo Smith Kline and Pfizer for Headache lectures.
Competing interests: No competing interests
Anne Macgregor and colleagues consider that it is prudent not to
contribute to the increased risk of ischaemic stroke in women with
migraine with use of progestogen/oestrogen combination contraception,
given that effective contraception without oestrogen is available.1
Do they mean that women with migraine should use progestagen-only
contraception which can cause breast cancer and has a high first year
discontinuation rate, because of irregular bleeding, weight gain and
depression, and also causes osteoporosis in young women?
Migraine occurs as a result of upset amine metabolism and is
therefore a disorder of both blood vessels and brain function.2
Kato and colleagues write that progesterone in hormonal preparations
increases the incidence of breast cancer and that tissue factor (TF), the
initiator of the extrinsic coagulation pathway, is associated with
metastasis in a wide variety of cancers. They demonstrated that TF mRNA
and protein are up-regulated by progesterone in the breast cancer cell
line ZR-75. The increase in TF was rapid and reached a maximum at 24
hours. An increase in TF corresponded to an increase in procoagulant
activity. Furthermore, progesterone increased the invasion of ZR-75 cells
through a matrigel, an effect that was blocked by an antibody against TF.
Because TF expression is associated with an enhanced risk of metastasis,
Kato postulates that the progesterone-dependent up-regulation of TF
provides a survival advantage to burgeoning breast cancer cells and may
contribute to the increased risk of cancer associated with combined
hormones.3
Also Mirkin and colleagues found that progesterone and progestins
increased vascular endothelial growth factor (VEGF) mRNA in T47-D breast
cancer cells and concludes that effect of progesterones on the angiogenic
gene in the T-47 D cells may relate to breast cancer growth.4
High single doses of progestins or long-acting progestin implants may
be available for use for emergency or continuous contraception but the
reasons for the disastrous consequences of such use are becoming more
clearly understood than ever.
1 MacGregor EA, Steiner TJ, Davies PT. Advances in managing
migraine in women. http://bmj.com/cgi/eletters/332/7532/25#127693, 6 Feb
2006
2 Grant ECG. The influence of hormones on headache and mood in women.
Hemicrania 1975;6:2-10.
3 Kato S, Pinto M, Carajal A. Progesterone Increases Tissue Factor
Gene Expression, Procoagulant Activity, and Invasion in the Breast Cancer
Cell Line ZR-75-1. J Clin Endocrinol Metab 2005; 90: 1181–1188.
4 Mirkin S, Wong BC, Archer DF. Effect of 17 beta-estradiol,
progesterone, synthetic progestins, tibolone, and tibolone metabolites on
vascular endothelial growth factor mRNA in breast cancer cells. Fertil
Steril. 2005; 84: 485-91.
Competing interests:
None declared
Competing interests: No competing interests
As a medical mystery that has persisted well over two millennia and
defied modern technology in particular advanced neuroimaging, the maze or
catacomb (replete with cul-de-sacs) that migraine represents would have
done Sherlock Holmes proud – to grapple with its intricacies and
uncertainties is one of the pleasures afforded to any mind that takes
Doyle’s delight to heart.
Professor Goadsby’s recent overview of migraine [1] addresses none of
the burning issues that confound theory and therapy in primary headache
research and practice. Since research and clinical practice cannot be
dissociated, the generally well-masked despair of the therapist managing
migraine and other primary headache syndromes is a genuine concern with
substantial ethical overtones. If we as therapists are ourselves uncertain
about the pathogenesis of migraine, what we communicate to the patient
will be, at best, nothing but a half-truth or a perceived truth.
A leading researcher in primary headaches recently claimed in a
rebuttal (Diener HC. Reply to "Topiramate for migraine prophylaxis: addressing the blood brain barrier related pharmacokinetic-pathophysiological disconnect". Int J Clin Pract, 2006—in press) that it is no longer correct to
maintain that use of propranolol is empirical, as the role of this agent
has been substantiated in randomised controlled trials (RCTs). RCTs in
primary headaches compare one empirically used agent with another
empirically used agent – but unless the scientific basis of action of
therapeutic agent(s) and the pathophysiology of migraine is clearly
understood, all such agents will continue to be labelled as empirical.
Also, recruiting patients into RCTs for migraine preventive therapies at a
time when the range of potential therapies – and the underlying scientific
suppositions -- varies enormously from pharmacological agents to
biological toxin (botulinum) to closure of patent foramen ovale or atrial
septal defect is a clinical practice that is balanced precariously on the
razor’s edge of science and ethics and is one that misuses an important
clinical research tool. The critical mass of understanding that justifies
RCTs has not yet been achieved in primary headache research. Finally, most
consensus statements about migraine therapy are based on statistical-
mathematical validity rather than biological validity.
Current migraine research enterprise steadfastly refuses to
countenance the following critical issues [2][3][4][5][6][7][8][9]:
1. Is migraine a pan-trigeminal disorder or an ophthalmic nerve disorder?
2. Is brain penetrability of migraine prophylactic agents
pharmacokinetically inconsequential? If atenolol can prevent migraine as
well as propranolol, can brain dysfunction including the putative ion
channelopathy or ionopathy [1] be central to migraine pathogenesis?
3. Are there any adaptive mechanisms that delay onset of migraine aura or
headache for many hours or a few days (post-stress, post-alcohol
consumption, post-catastrophic psychical distress) or maintain migraine
patients in prolonged remissions or prevent occurrence of migraine in
approximately four-fifths of the general population that is as exposed to
common daily stresses of living as are migraine patients?
4. Does migraine begin with the aura or headache or with the prodrome or
(more strictly and appropriately) with the pre-prodromal phase?
5. Do migraine aura-aborting agents cross the blood-brain barrier?
6. Are tricyclic antidepressants (including the prototype, amitriptyline)
overall anti-serotonergic or serotonomimetic agents? Does amitriptyline
increase or decrease brain intrinsic noradrenergic function? If
amitriptyline is potentially epileptogenic, how can we reconcile its
fairly established migraine preventive effect with that of new anti-
convulsants?
7. If brain neuronal dysfunction indeed underlies migraine, why does
caffeine- or cocaine-withdrawal rather than consumption precipitate
migraine?
8. Is the scintillating scotoma of migraine a monocular or a binocular
phenomenon? As a monocular positive functional phenomenon, the
scintillating scotoma cannot arise from the occipital visual cortex,
thereby introducing a conceptual distinction in the site of origin of the
scintillating scotoma and other visual auras (e.g., homonymous
hemianopia).
9. Does advanced neuroimaging after onset of aura or headache reflect the
“what” or the “why” of migraine?
10. Why is vomiting not a feature of cluster headache or tension-type
headache?
11. Why and how does vomiting commonly remit migraine headache?
12. Is there evidence for a neuroprotective role for cortical spreading
spreading depression (CSD)?
13. Can retinal spreading depression explain clinical features of the
migrainous scintillating scotoma?
14. How might blood pressure be linked to migraine and to theories that
maintain brain dysfunction at their core?
15. Does biology of an illness reflect (simplistic ictal arousal-related
“markers”) measurements in sophisticated laboratories or the elucidation
of the physiological forces that push an individual towards disease or
health?
The current classification of primary headache disorders is an
elaborate exercise in phenomenology that has no pathophysiological or
biologic basis but has rendered the creation of a unifying hypothesis for
primary headaches virtually impossible. The second seemingly
unsurmountable conceptual roadblock is the implication of intrinsic
noradrenergic activation in the pathogenesis of migraine, as underscored
in the biobehavioral model of migraine. Since noradrenergic activation is
a prominent component of the stress response, the biobehavioral model of
migraine does not lend an explanation either for the characteristic delay
in onset of headache in a wide variety of clinical circumstances or for
disappearance of prolonged headache with a step up in central autonomic
activation, as is documented with General Grant’s headache [10] with the
news of surrender of the Confederates in the American Civil War.
Just as the atheromatous plaque underlies angina, Prinzmetal’s
angina, and the several myocardial infarction-related coronary syndromes,
I predict that a common idiosyncratic ocular haemo-hydrodynamic
disturbance underlies migraine, cluster headache and other trigeminal
autonomic cephalalgias (TACs), and tension-type / chronic daily headache,
the clinical variations being an expression of ocular handling of sudden
or sustained ocular choroidal congestion. To maintain that a distinct
physiological basis will eventually be discovered for each of the many
primary headache variants delineated in the Headache Classification of the
International Headache Society is a classic example of irrational
scepticism that requires complete suspension of clinical disbelief [5].
The ocular compression manœuvre will find clinical application in benign-
cough induced headache [6][7] and, eventually, also in TACs.
Any comprehensive theory for migraine must address all the issues
discussed herein. Till then, the science of migraine will remain at its
infancy and all “biological” advances will be illusionary. The hyper-focus
on neuropeptides, magnesium, sex hormones, platelets, or deep white matter
lesions is simply diversionary in nature [11]. No biologic meaning can yet
be given to genetic linkages detected at this level of comprehension.
References
1. Goadsby PJ. Recent advances in the diagnosis and management of
migraine. BMJ 2006;332:25-29.
2. Gupta VK. Migrainous scintillating scotoma and headache is ocular in
origin: a new hypothesis. Med Hypotheses 2006; 66:454-460. Available
online 13 December 2005.
3. Gupta VK. Migraine, cortical excitability, and evoked potentials:
a clinico-pharmacological perspective. Brain 2005;128:E36.
4. Gupta VK. MRI imaging in primary headaches. Radiology
2006:238:754-755.
5. Gupta VK. Classification of primary headaches: pathophysiology versus
nosology? BMJ 2004; published online Jan 22. Available at:
http://bmj.bmjjournals.com/cgi/eletters/328/7432/119
6. Gupta VK. Is benign cough headache caused by intraocular
haemodynamic aberration? Med Hypotheses 2004;62:45-48.
7. Gupta VK. Ocular compression manœuvre aborts benign cough-induced
headache. Headache 2005;45:612-614.
8. Gupta VK. Lamotrigine, migraine aura and headache: tightening the
Gordian knot of primary headache? J Neurol Neurosurg Psychiatry (28
November 2005). Available at:
http://jnnp.bmjjournals.com/cgi/eletters/76/12/1730#764
9. Gupta VK. Intraocular pressure, systemic blood pressure, and
headache: occult pathophysiological link? Br J Ophthalmol (21 December
2005). Available at: http://bjo.bmjjournals.com/cgi/eletters/89/3/2848.
10. Jarcho S. General Grant’s headache. Bull N Y Acad Med 1967;43:1224-
1226.
11. Gupta V. Silent or non-clinical infarct-like lesions in the posterior
circulation territory in migraine: brain hypoperfusion or hyperperfusion?
Brain 2006;129:E39.
Competing interests:
None declared
Competing interests: No competing interests
Editor,
The peripheral circulation in migraine
The review paper on migraine by Goadsby (1) did not contain any
reference to
studies which reported a relationship between migraine and the peripheral
circulation. Evidence of an association between migraine and chronic
venous
insufficiency was first documented in two studies that identified a severe
haemorheological disturbance in the microcirculation in continuity with
varicose veins (2), and long term relief of migraine after surgical
treatment of
coexisting varicose veins (3). Impaired blood rheology in venous disease
is
associated with increased red cell aggregation and limited blood fluidity
(4
-6).
Long-term relief of migraine in association with persistent foramen ovale
followed closure of right-to-left cardiac shunts (7,8). Migraine in
patients
with antiphospholipid syndrome was relieved by anticoagulant therapy
(9,10)
. In these studies the possible roles of microemboli or other substances
in
the peripheral circulation (7,8) and thrombosis or sludging (9,10) are
considered.
1. Goadsby PJ. Recent advances in the diagnosis and management of
migraine. BMJ 2006;332:25-9 (10 January)
2. Glass GM. Measurement of the suspension stability of blood in vivo in
large blood vessels of the upper limb and in varicose veins. Clin
Hemorheol
1986; 6: 413-15.
3. Glass GM, Glass GB. Relief of migraine and other headache following
surgical treatment of varicose veins. Vasc Surg 1991;12:654-60.
4. Lowe GDO. Blood rheology and venous thrombosis. Clin Hemorheol
1984;4:571-88.
5. Dormandy JA. Importance of blood rheology in venous thrombosis. Clin
Hemorheol 1987;7:119-22.
6. Ernst E, Matrai A, Marshall M. Limited blood fluidity as a contributory
factor in chronic venous insufficiency. Clin Hemorheol 1989;4;107-11.
7. Wilmshurst P, Nightingale S, Walsh KP, Morrison WL. Effect on migraine
of closure of cardiac right-to-left shunts to prevent recurrence of
decompression illness or stroke or for haemodynamic reasons. Lancet 2000;
356:1648-51.
8. Wilmshurst P, Nightingale S. Relationship between migraine and cardiac
and pulmonary right-to-left shunts. Clin Sci 2001;100:215-220.
9. Cuadrado MJ, Khamashda MA, Hughes GRV. Migraine and stroke in
young women. QJ Med 2000; 93:317-19.
10. Hughes GRV. Migraine, memory loss, and “multiple sclerosis”.
Neurological features of antiphospholipid (Hughes’) syndrome. Postgrad Med
J 2002;79:81-3.
Gerard M Glass, retired vascular surgeon,
Strangford
BT30 7LX, gmglass@btopenworld.com
Competing interests:
None declared
Competing interests: No competing interests
Editor,
Goadsby’s recent article is a timely update on the diagnosis and
management
of migraine.1 It is also appropriate to comment on recent developments in
the management of menstrual attacks of migraine, which affect 50% of
women with migraine.2 These attacks are typically more severe, of longer
duration and less responsive to treatment compared to attacks at other
times
of the cycle.2,3
In spite of the general belief that women’s periods are always
regular, the
natural variability of the menstrual cycle can make it difficult for women
with
pure menstrual or menstrually-related migraine to plan their lives around
unpredictable attacks.4 Trials using a fertility monitor to predict
menstruation, and hence predict menstrual attacks of migraine, have been
successful in improving management.4
When symptomatic treatment alone is inadequate, perimenstrual
prophylaxis
is indicated. Although there is little evidence for Goadsby’s
recommendation
of ergotamine taken at night, evidence does exist for perimenstrual
oestrogen. The most recent advance has been evidence from randomized
controlled clinical trials suggesting benefit of perimenstrual
triptans.5,6
A number of studies included in a recent meta-analysis confirm the
association between migraine and ischaemic stroke, which is strengthened
by
the oestrogen component of combined hormonal contraception (CHC).7
Cooling queries the rationale for contraindicating CHC in women with
migraine with aura if, as Goadsby states, migraine is “not a disorder of
blood
vessels but one of brain function”. This is not at odds with the
contraindication, as strokes at the time of migraine aura are rare.8 It is
most
likely that migraine with aura is a marker for increased risk of ischaemic
stroke, rather than causal. Hence, it is prudent not to contribute to this
risk,
given that effective contraception without oestrogen is available.
More specific information on diagnosis and management can be
found in the UK “Guidelines for all doctors in the management and
diagnosis
of migraine and tension-type headache” developed by the British
Association
for the Study of Headache.9 These also include a section on the management
of migraine in children.
1. Goadsby PJ. Recent advances in the diagnosis and management of
migraine. BMJ 2006;332(7532):25-29.
2. Couturier EGM, Bomhof MAM, Neven AK, van DNP. Menstrual migraine
in a
representative Dutch population sample: prevalence, disability and
treatment.
Cephalalgia 2003;23(4):302-308.
3. MacGregor EA, Hackshaw A. Prevalence of migraine on each day of
the
natural menstrual cycle. Neurology 2004;63(2):351-3.
4. MacGregor EA, Frith A, Ellis J, Aspinall L. Predicting menstrual
migraine
with a home-use fertility monitor. Neurology 2005;64(3):561-3.
5. Newman L, Mannix LK, Landy S, Silberstein S, Lipton RB, Putnam DG,
et al.
Naratriptan as short-term prophylaxis of menstrually associated migraine:
a
randomized, double-blind, placebo-controlled study. Headache 2001;41(3):
248-56.
6. Silberstein SD, Elkind AH, Schreiber C, Keywood C. A randomized
trial of
frovatriptan for the intermittent prevention of menstrual migraine.
Neurology
2004;63:261-9.
7. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic
stroke in
people with migraine: systematic review and meta-analysis of observational
studies. BMJ 2005;330(7482):63-65.
8. Tzourio C, Tehindrazanarivelo A, Iglesias S, Alperovitch A, Chedru
F,
d'Anglejan-Chatillon J, et al. Case-control study of migraine and risk of
ischaemic stroke in young women. BMJ 1995;310(6983):830-3.
9. Steiner TJ, MacGregor EA, Davies PT. Guidelines for all doctors in
the
management and diagnosis of migraine and tension-type headache 2nd ed,
2004. www.bash.org.uk.
Competing interests:
Member of the British
Association for the Study of
Headache (BASH) writing
committee for
Guidelines for all doctors in the
management and diagnosis of
migraine and tension-type
headache
Competing interests: No competing interests
Your review states that migraine is “not a disorder of blood vessels
but one of brain function". This raises 2 questions:
1. why is migaine associated with increased risk of stroke in women using
the combined oral contraceptive pill (COC)?
2. is migraine with aura still seen as evidence of brain ischaemia? If
not, what is the rationale for advising women who have migaine with aura
to avoid the COC (in order to avoid extra risk of stroke)? (see clinical
guidance from the Faculty of Family Planning and Reproductive Health Care
“First prescription of combined oral contraception” available at
www.ffprhc.org.uk (pdf))
Competing interests:
None declared
Competing interests: No competing interests
sir,
the article was informative and stimulating but it would be better if
migraine in childern and it;s managment would be mentioned because it is
emerging as a very common problem.
Competing interests:
None declared
Competing interests: No competing interests
Editor
I was surprised that Professor Goadsby made no mention of dietary
factors in his otherwise comprehensive clinical review of migraine (1).
It has always been the first strand of my enquiry with migraine sufferers
and it is often raised by patients. Does this omission suggest there is no
supporting evidence and that we should abandom this line of questioning?
Dr James Hardy
1. Goadsby, P. Recent advances in the diagnosis and management of
migraine. BMJ 2006;332:25-29
Competing interests:
None declared
Competing interests: No competing interests
Professor Goadsby acknowledges financial support from 10
pharmaceutical companies in his review of the management of migraine.1 He
lists numerous pharmaceuticals with unpleasant side-effects in a table of
preventative treatments. Also both ergot and oestrogen are still being
listed as migraine treatments or preventatives.
The evidence is overwhelming that use of ergot, oestrogens and
progestogens are the main causes of severe and frequent migraines in women
and why more women attend acute migraine clinics than men.2,3 Why is this
clear cut evidence still being ignored after three decades?
Headaches and migraine attacks warn of disturbed biochemistry. Both
zinc and magnesium deficiencies commonly disrupt amine pathways and
interfere with normal reactions to stress which results in headaches.4
The avoidance of ergot medications, progestogens and oestrogens and
smoking gave a 10 -fold reduction in migraine attacks.3 Further avoidance
of common dietary migraine precipitants, including alcoholic drinks,
resulted in 85% of 60 migraine patients having no further attacks and no
patient needed so-called “preventative pharmaceuticals”.5
1 Goadsby PJ. Recent advances in the diagnosis and management of
migraine. BMJ 2006;332:25-29 (7 January), doi:10.1136/bmj.332.7532.25
2 Grant ECG, Albuquerque M, Steiner TJ, Rose FC. Oral contraceptives,
smoking and ergotamine in migraine. In Current Concepts in Migraine
Research. Ed. Greene R. Raven Press, New York 1978 pp 97-100.
3 Grant ECG. Oral contraceptives, smoking, migraine and food
allergies. Lancet 1978; 2: 581-2.
4 Grant ECG. The pill, hormone replacement therapy, vascular and
mood over-reactivity and mineral imbalance. J Nutr Environ Med 1998; 8:
105-116.
5 Grant ECG. Food allergies and migraine. Lancet 1979; 1: 966-69.
Competing interests:
None declared
Competing interests: No competing interests
Re: Jolly Good Show for Goadsby
I'm not an expert like you doctors, but I'm a victim of migraines since I was a baby, so I think my experience is valuable. First, I would like to apologize for any writing errors, for I'm not an english native speaker. I remember my ealy days of life only because of migraines. Every night at bed I used to see wonderful waterfalls made of multicoloured stars (that is how they looked like back then)even if my eyes were wide opened. I thought this was normal until I was a teen-ager and found out that I had migraines. My symptoms since then are: tinnitus, a bloated sensation in stomach, intestines and ear, nausea, tingling, numbness, briliant or black spots, neck and eye pain, photophobia, phonophobia, constant yawning, among other less common symptoms and, of course, the terrible left temporal pain. I have found out many different triggers like monosodium glutamate, sodium bisulfite, ethanol, menstruation, sleep disturbances, sudden changes in routine, etc, but none of these triggers alone is sufficient to cause migraine. I kept a daily record of my life for many years trying to figure out the main trigger and after 30 years I finally found it. Weather change, specifically low atmospheric pressures, associated with hot weather and storms. I can predict a storm 3 days before it happens, even contradicting meterological forecasts. I started taking flunarizine (it is available here in Brazil) only during the summer season and it worked, not preventing completely all the symptoms but the terrible headache. After more 10 years of personal research I found out the dark side of the moon... I have Ehlers-Danlos Syndrome, the vascular type, and many of the migraine symptoms are common among sufferers. A connective tissue defect could be one more candidate for migraine? Ehlers-Danlos Syndrome is far more common than once thought, many types being inherited as an autosomal dominant trait. Just a contribution of a non-expert, confused and intrigued sufferer.
Competing interests:
None declared
Competing interests: No competing interests