Hed_4198.tex

Preventing Disturbing Migraine Aura With Lamotrigine:
An Open Study
Julio Pascual, MD; Ana B. Caminero, MD; Valent´ın Mateos, MD; Carlos Roig, MD; Rogelio Leira, MD; Carlos Garc´ıa-Monc ´o, MD; Miguel J. La´ınez, MD Background.—Lamotrigine has been suggested as possibly effective for preventing migraine aura.
Objective.—To describe our experience with a series of patients with disturbing migraine aura treated with
lamotrigine.
Methods.—The members of the Headache Group of the Spanish Society of Neurology were sent an ad hoc
questionnaire to collect patients treated with lamotrigine due to disturbing migraine aura. The main outcome
parameter (“response”) was a >50% reduction in the mean frequency of migraine auras at 3 to 6 months of
treatment.
Results.—A total of 47 patients had been treated with lamotrigine due to severe migraine aura. Three could not
complete the protocol as a result of developing skin rashes. Thirty (68%) patients responded. These were 21 females
and 9 males whose ages ranged from 19 to 71 years. Eight suffered from migraine with “prolonged” aura, 8 typical
aura with migraine headache (but had frequent episodes including speech symptoms), 6 basilar-type migraine, 6
typical aura without headache, and 2 hemiplegic migraine. Fifteen had been previously treated, without response,
with other preventatives. The mean monthly frequency of migraine auras in these 30 patients changed from 4.2
(range: 1 to 15) to 0.7 (range: 0 to 6). Response was considered as excellent (>75% reduction) in 21 cases (70% of
responders). Auras reappeared in 2 months in 9 out of 13 patients where lamotrigine was stopped, and ceased as
soon as this drug was reintroduced.
Conclusions.—Lamotrigine should be considered in clinical practice for the preventive treatment of selected
patients with disturbing migraine auras. Lamotrigine seems worthy of a controlled trial as prophylaxis of migraine
aura.
Key words: lamotrigine, migraine aura, migraine prophylaxis
Migraine auras occur in about 15% of migraineurs, migraine auras usually require no pharmacological usually develop over 5 to 20 minutes, and last less treatment but only diagnostic reassurance. There are a than 60 minutes.1 Patients with short and infrequent few migraine patients, however, for whom treatment ofmigraine aura would be welcomed. Those include pa-tients with prolonged (>60 minutes) and/or frequent From the University Hospital. M. de Valdecilla, Neurology,
Santander, Cantabria, Spain (Dr. Pascual); Hospital Ntra. Sra.
migraine auras, especially if the aura contains speech Sonsoles, Neurology, Avila, Spain (Dr. Caminero); Hospi-
disturbances, posterior fossa symptoms, or profound tal General de Asturias, Neurology, Oviedo, Asturias, Spain
hemiparesis. None of the current acute migraine med- (Dr. Mateos); Hospital Santa Cruz y San Pablo, Neurology,
ications are useful in the specific treatment of migraine Barcelona, Spain (Dr. Roig); University Hospital, Neurol-
ogy, Santiago de Compostela, Spain (Dr. Leira); and Hos-
aura. In fact, triptans have been reported to be inef- pital de Gald ´acano, Neurology, Gald ´acano, Vizcaya, Spain
ficacious when given during migraine aura, both fail- (Dr. Garcia-Monc ´o).
ing to abort the aura, and to prevent the subsequent Address all correspondence to J. Pascual, University Hospital
pain2 and ergotamine-containing medications should M. de Valdecilla, Neurology, Santander, Cantabria, Spain.
be administered with caution during the aura phase Accepted for publication May 20, 2004.
due to their potent vascular effects.3 There have been several scattered reports showing some benefit with i.v.
aura symptomatology, due to its high frequency or/and verapamil,4,5 i.v. furosemide,6 and intranasal ke- severity. Therefore, only patients meeting criteria for tamine7 in the specific treatment of migraine with typical aura without headache, hemiplegic migraine, prolonged aura. In the biggest trial, intranasal ke- basilar-type migraine, persistent aura without infarc- tamine reduced the duration and severity of neuro- tion, and migraine-triggered seizure were included in logic deficits in only 5 out of 11 patients and induced this analysis.1 Without exception, all had normal exten- sive laboratory determinations, including work up for Experience in the prevention of migraine aura is an underlying coagulopathy, and neuroimaging (CT also either scarce or negative. Beta-blockers remain and usually MRI brain scans). Patients fulfilling crite- the preventive treatment of choice for the most stan- ria for typical aura with migraine headache were only dard migraine patients. These drugs, however, have included if, usually, the aura was prolonged, contained been incriminated as a potential contributor to mi- reversible aphasia and/or the episodes were frequent.
grainous stroke and are not recommended in disturb- All the patients had to have suffered from these mi- ing migraine aura.8-11 To our knowledge, there is no graine variants for at least 1 year and presented at published specific experience for flunarizine with this least one attack per month in the last 3 months. Exclu- indication. Regarding the two antiepileptic drugs with sion criteria included any prophylactic treatment of demonstrated antimigraine efficacy, valproic acid was headache within the last 2 weeks prior to the begin- reported as being useful in two patients with persistent ning of the trial and previous treatment or contraindi- migraine aura,12 while in a recent open trial topiramate cations to lamotrigine. There was no fixed dosing pro- was not effective in preventing aura in 12 migraine tocol, even though most investigators had begun with 25 mg at night and increased 25 mg per week usu- Lamotrigine has been tested in the prophylaxis of ally until reaching a minimum dose of 100 mg. The migraine headache in a placebo-controlled trial and main outcome parameter (“response”) was a >50% proved to be of little value in reducing the frequency reduction in the mean frequency of migraine auras at of migraine attacks.14 This sodium channel blocker, 3 to 6 months of treatment as compared to that of the however, was shown to be efficacious in preventing 3 months prior to treatment. We considered response migraine aura in three different open trials including a as “excellent” if reduction in the frequency of migraine total of 38 patients.15-17 The aim of this open trial has auras >75%. Patients with a reduction in aura fre- been to explore further the possible efficacy of lamot- quency <50% were considered as nonresponders.
rigine in the prevention of migraine aura in patientswith disturbing migraine aura.
A total of 47 patients had been treated with lam- PATIENTS AND METHODS
otrigine due to disturbing migraine aura. Three could After some neurologists had reported positive ex- not complete the protocol as a result of developing skin periences with lamotrigine in patients with migraine rashes. Thirty (68%) out of the 44 patients responded.
aura at our Annual Meeting held in November 2002, There was no clear difference in any available the 88 active members of the Headache Group of parameter (age, sex, diagnosis, dosage, etc.) between the Spanish Society of Neurology were sent an ad those responders and nonresponders; henceforth, we hoc questionnaire to collect those patients treated will focus on the analysis of the responders’ group.
with lamotrigine due to disturbing migraine aura. All They were 21 females and 9 males, whose ages ranged patients gave verbal informed consent. Neurologists from 19 to 71 years. Eight patients in fact met diag- could include patients both retrospectively or also nostic criteria for typical aura with migraine headache, those treated prospectively until November 2003. To but had frequent episodes including aphasia. Eight suf- be eligible for this study patients should refer to a his- fered from probable migraine with aura (all migraine tory of disturbing migraine aura, that is, the reason for with prolonged aura according to the previous IHS their preventive treatment should obligatorily be the Classification), six basilar-type migraine, six typical Summary of Clinical Data and Frequency of Migraine Aura at Baseline and During Treatment (Responders)
aura without headache, and two hemiplegic migraine In four cases the auras did not come back, but this was (one familial and one sporadic). There was a history followed by a recurrence of migraine auras within 2 of occasional migraine-triggered seizures in three pa- months in nine patients. Lamotrigine was reintroduced tients. Fifteen had been previously treated, without re- in these nine patients with immediate response in all sponse, with β-blockers (n = 3), amitriptyline (n = 6), of them. Regarding the 17 patients left, 7 decided to calcium antagonists (n = 10), valproic acid (n = 11), remain on lamotrigine for more than 1 year (up to topiramate (n = 1), or carbamacepine (n = 4). The 4 years) due to their excellent response and for the doses of lamotrigine ranged from 50 to 300 mg/day remaining 10 no follow-up information is available as (mean = 110 mg daily; mode = 100 mg daily).
they have just completed the sixth month of treatment.
The mean monthly frequency of migraine auras in Demonstrative Clinical Case.—This 45-year-old
these 30 patients changed from 4.2 (range: 1 to 15) to woman began 20 years ago with very infrequent 0.7 (range: 0 to 6) (Table). Response was considered as episodes of progressive hemianoptic visual distur- excellent in 21 cases (70% of the responders). Lamo- bances, accompanied by paresthesias in one arm last- trigine was stopped after 6 to 12 months in 13 patients.
ing 45 to 90 minutes. The episodes occurred on both sides and included dysphasia when the left hemi- Is there any explanation for a specific effect of sphere was involved. She denied posterior headache.
lamotrigine on migraine aura? Glutamate has been Complete laboratory determinations, including study involved as the key neurotransmitter in the develop- of prothrombotic conditions, EEG, echocardiogram, ment and propagation of the neurophysiological cor- carotid Doppler, transcranial Doppler, brain MRI, relate of the aura, the cortical spreading depression and MRI angiography were normal. During spring phenomenon.18 Plasma and cerebrospinal glutamate 2002, she experienced an increase in the frequency levels are higher in migraine with aura that in mi- of these episodes to 8/month. In July 2002, she began graine without aura.19-21 Lamotrigine acts by blocking taking valproic acid, 1 g/daily, with no response after voltage-sensitive sodium channels, leading to an inhi- 2 months. In October 2002, lamotrigine, up to a dose bition of the neural release of glutamate.22-24 There- of 50 mg/12 h, was initiated with total disappearance fore, if high glutamate levels were responsible for cor- of these episodes. Lamotrigine was tapered in August tical spreading depression and the clinical symptoms 2003. Fifteen days after lamotrigine had been stopped of migraine aura, lamotrigine might suppress this phe- she again began to experience two to three similar nomenon and thus prevent aura development. Lam- episodes/week. Lamotrigine was reintroduced with no otrigine also attenuates calcium influx via its effect on further episodes after a 6-month follow-up.
high-voltage-activated calcium channels and preventscalcium overload in neurons. The effective suppres-sion of aura symptoms of lamotrigine may be due to COMMENTS
the potent presynaptic and postsynaptic inhibition of The results of this trial concur with previous ob- glutamate, indicating that lamotrigine would act as a servations indicating a specific benefit of lamotrigine noncompetitive NMDA antagonist.25,26 in preventing migraine aura.15-17 Our data add further In conclusion, lamotrigine should be considered evidence to this potential beneficial effect of lamot- in clinical practice for the preventive treatment of se- rigine. First, this is the trial with the highest number lected patients with disturbing migraine auras. Lamo- of patients. Second, 36 out of the 38 reported patients trigine seems worthy of a controlled trial as prophy- previously treated with lamotrigine met criteria for mi- laxis of aura/migraine with patent aura.
graine with typical aura, while only patients with dis- REFERENCES
turbing, atypical migraine aura were included in thisstudy, which makes it easier to test a specific benefit 1. Headache Classification Subcommittee of the Inter- national Headache Society. The International Classi- Migraine is an unpredictable disease with a re- fication of Headache Disorders, 2nd edition. Cepha- markable placebo effect. The fact that this is an open trial and partly retrospective obliges us to interpret the 2. Bates D, Ashford E, Dawson R, et al. Subcutaneous results with great caution. Nevertheless, the careful se- sumatriptan during the migraine aura. Sumatriptan lection of patients with only severe auras, the fact that Aura Study Group. Neurology. 1994;44:1587-1592.
half of our responders had not shown any benefit with 3. Silberstein SD, McCrory DC. Ergotamine and dihy- other preventatives and the prompt reappearance of droergotamine: history, pharmacology and efficacy.
Headache. 2002;43:144-146.
the auras in most patients who stopped this treatment 4. Yu W, Horowitz SH. Familial hemiplegic migraine further support lamotrigine as a useful drug in this indi- and its abortive therapy with intravenous verapamil.
cation. These results do not agree with those reported Neurology. 2001;57:1732-1733.
in a double-blind, placebo-controlled, parallel study 5. Yu W, Horowitz SH. Treatment of sporadic hemi- on the efficacy of lamotrigine in 53 migraine with and plegic migraine with calcium-channel blocker vera- without aura patients.14 In this trial there was no signif- pamil. Neurology. 2003;60:120-121.
icant difference between active and placebo; however, 6. Rozen TD. Treatment of a prolonged migrain- the results for the 14 migraine with aura patients were ous aura with intravenous furosemide. Neurology.
7. Kaube H, Herzog J, Kaufer T, Dichgans M, Diener 18. Lauritzen M. Pathophysiology of the migraine aura.
HC. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neu- 19. Castillo J, Mart´ınez F, Leira R, Prieto JM, Lema M, Noya M. Changes in neuroexcitatory amino acids 8. Prendes JL. Considerations on the use of propranolol during and between migraine attacks. Neurolog´ıa.
in complicated migraine. Headache. 1980;20:93-95.
9. Gilbert GJ. An occurrence of complicated migraine 20. Mart´ınez F, Castillo J, Rodr´ıguez JR, Leira R, Noya during propranolol therapy. Headache. 1982;22:81- M. Neuroexcitatory amino acid levels in plasma and cerebrospinal fluid during migraine attacks. Cepha- 10. Bardwell A, Trott JA. Stroke in migraine as a conse- quence of propranolol. Headache. 1987;27:381-383.
21. Cananzi AR, D’Andrea G, Perini F, Zamberlan F, 11. Mendizabal JE, Greiner F, Hamilton WJ, Rothrock Welch KMA. Platelet and plasma levels of glutamate JF. Migrainous stroke causing thalamic infarction and glutamine in migraine with and without aura.
and amnesia during treatment with propranolol.
Cephalalgia. 1995;15:132-135.
22. Welch KMA, D’Andrea G, Tepley N, Barkley G, 12. Rothrock JF. Successful treatment of persistent mi- Ramadan NM. The concept of migraine as a state graine aura with divalproex sodium. Neurology.
of central neuronal hyperexcitability. Neurol Clin.
13. Lampl C, Bonelli S, Ransmayr G. Efficacy of topi- 23. Lang DG, Wang CM, Cooper BR. Lamotrigine, ramate in migraine aura prophylaxis: preliminary re- phenytoin and carbamazepine interactions on the sults of 12 patients. Headache. 2004;44:174-176.
sodium current present in N4TG1 mouse neurob- 14. Steiner TJ, Findley LJ, Yuen AWC. Lamotrigine ver- lastoma cells. J Pharmacol Exp Ther. 1993;266:829- sus placebo in the prophylaxis of migraine with and without aura. Cephalalgia. 1997;17:109-112.
24. Leach MJ, Lees G, Riddal DR. Lamotrigine. Mecha- 15. Chen WT, Fuh JL, Lu SR, Wang SJ. Persistent mi- nisms of action. In: Levy RH, Mattson RH, Meldrum grainous visual phenomena might be responsive to BS, eds. Antiepileptic Drugs, 4th edition. New York: lamotrigine. Headache. 2001;41:823-825.
16. D’Andrea G, Granella F, Cadaldicini N, Manzoni 25. Stefani A, Spadoni F, Siniscalchi A, Bernardi G.
GC. Effectiveness of lamotrigine in the prophylaxis Lamotrigine inhibits Ca2+ currents in cortical neu- of migraine with aura: an open study. Cephalalgia.
rons: functional implications. Eur J Pharmacol.
17. Lampl C, Buzath A, Klinger D, Neuman K. Lamo- 26. Wang SJ, Tsai JJ, Gean PW. Lamotrigine inhibits trigine in the prophylactic treatment of migraine depolarization-evoked Ca influx in dissociated amyg- aura—a pilot study. Cephalalgia. 1999;19:58-63.
dale neurons. Synapse. 1998;29:355-362.

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