oculomotor paresis: A possible cause of ophthalmoplegicmigraine. Neuropediatrics. 2000;31:145-147.

6. Doran M, Larner AJ. MRI findings in ophthalmoplegicmigraine: Nosological implications. J Neurol. 2004;251:100-101.

7. Lance JW, Zagami AS. Ophthalmoplegic migraine: Arecurrent demyelinating neuropathy? Cephalalgia.2001;21:84-89.

8. Van der Dussen DH, Bloem BR, Liauw L, Ferrari MD.Ophthalmoplegic migraine: Migrainous or inflammatory?Cephalalgia. 2004;24:312-315.

9. Bharucha DX, Campbell TB, Valencia I, Hardison HH,Kothare SV. MRI findings in pediatric ophthalmoplegic

migraine: A case report and literature review. PediatrNeurol. 2007;37:59-63.

10. Headache Classification Subcommittee. InternationalHeadache Society. The International Classification ofHeadache Disorders, 2nd edn. Cephalalgia. 2004;24(Suppl.1):1-151.

11. Carlow TJ. Oculomotor ophthalmoplegic migraine: Is itreally migraine? J Neuroophthalmology. 2002;22:215-221.

12. Satoh T, Omi M, Ohsako C, et al. Differential diagnosis ofthe infundibular dilation and aneurysm of internal carotidartery: Assessment with fusion imaging of 3D MRcisternography/angiography. AJNR Am J Neuroradiol.2006;27:306-312.

Hemicrania Continua Evolving From Cluster HeadacheResponsive to Valproic Acid

Giorgio Lambru, MD; Paola Castellini, MD; Annamaria Bini, MD; Andrea Evangelista, MD;

Gian Camillo Manzoni, MD; Paola Torelli, MD

Hemicrania continua (HC) is a rare type of primary headache characterized by a prompt and enduring response toindomethacin. We describe a patient who suffered from cluster headache evolving into ipsilateral HC, who does not tolerate along-term indomethacin therapy. The case was complex in terms of diagnosis, associated comorbidity, and choice of treatment;after several trials with different therapeutic regimens, we started the patient on a therapy with valproic acid and obtained animprovement of her HC.

Key words: hemicrania continua, cluster headache, valproic acid, indomethacin

INTRODUCTIONHemicrania continua (HC) is a rare type of primary

headache characterized by a complete response to thera-peutic doses of indomethacin. It was first described in 1984by Sjaastad and Spiering.1 Clinically, it is characterized bymoderate pain, continuous and unilateral without side-shift,but with severe exacerbations accompanied by ipsilateralautonomic phenomena, such as miosis, ptosis, lacrimation,and nasal congestion.2

Pathogenetically, an overlapping of the circuitsinvolved in HC and cluster headache (CH) could behypothesized. Using positron emission tomography,

Matharu et al3 demonstrated that there was a significantactivation of the posterior hypothalamus contralaterally topain, an activation of the rostral dorsal pons ipsilaterally, aswell as an activation of some subcortical formations. Cen-tonze et al4 describe a case of CH evolving into HC, inwhich the pain side remained unchanged.

We report here what, to our knowledge, is the first caseever observed of CH evolving into HC responsive to valp-roic acid (VPA).

CASE REPORTIn December 2005, a 51-year-old woman, without pre-

vious history of headache, sought treatment at the ParmaHeadache Centre for a headache that had begun in June2005.The headache was characterized by unbearable, excru-ciating pain in the right temporal-orbital region radiatingipsilaterally into the nasal wing, ramus of the mandible, and

From the Headache Centre, Department of Neurology, Univer-sity of Parma, Parma, Italy.

Address all correspondence to G. Lambru, Headache Centre,Department of Neurology, University of Parma, c/o OspedaleMaggiore, via Gramsci 14, 43100 Parma, Italy.

Accepted for publication July 19, 2008. Conflict of Interest: None

1374 October 2008

mastoid region. The pain was associated with ipsilateralptosis of the lid, photophobia, nausea, and psychomotoragitation. The attacks lasted from 30 to 50 minutes. Theyoccurred 2-3 times a day. She was a heavy smoker andweighed 45 kg and was 162 cm tall (BMI = 17).

During the first visit, the neurological examinationrevealed mild right pyramidal hemisyndrome; blood pres-sure was 100/60; the examination of the ocular fundus wasnormal. As we suspected a form of secondary headache, weperformed: blood tests, instrumental tests for vascularscreening, magnetic resonance imaging (MRI) of the braintogether with angio-MRI of the intracranial arteries. Whilethe angio-MRI scan did not show any alterations, the brainMRI scan revealed the presence of small areas of alteredsignals a few millimeters in diameter at the level of thesubcortical white matter in the right and left superior andinferior frontal gyri, probably a consequence of an impair-ment of cerebral microcirculation. A lumbar puncture wasalso performed, but fluid pressure and cytochemistry werenormal, with no evidence of oligoclonal bands. We made adiagnosis of CH according to ICHD-II2 (code 3.1). Atherapy with oxygen and verapamil (only 80 mg t.i.d., causearterial hypotension) proved ineffective.

In January 2006, the headache began to exhibit differ-ent features than those at onset 7 months before. Pain wascontinuous, mild to moderate, strictly unilateral, and local-ized in the right orbital, supraorbital and temporal regions.The patient had about 8 exacerbations a day lasting 30minutes. During these exacerbations, she would usually liedown, because the pain was very severe, sometimes throb-bing, and associated with pallor, asthenia, nausea, and ipsi-lateral nasal congestion. Oddly, just around this time thepatient reduced her cigarette smoking from 30 to 10 ciga-rettes a day. We performed a second brain MRI scan, whichwas comparable to the previous one.Verapamil was discon-tinued and replaced by indomethacin 25 mg t.i.d. The com-plete remission of headache within 48 hours led to adiagnosis of HC according to ICHD-II2 (code 4.7). InAugust 2006, after 6 months of complete headache remis-sion, the patient developed a severe dyspepsia and gastritisin spite of the administration of gastroprotective medica-tion; indomethacin was discontinued and the headachereappeared soon after.A therapy with melatonin 12 mg/dayhad no benefits.

When a month later, in October 2006, the patientdeveloped panic attacks and mood depression, she initiateda combination drug therapy with 20 mg/day of citalopramalongside cognitive-behavioral therapy with benefits onpatient’s psychopathological condition. In November 2007,due to the persistence of headache and taking into account

the associated comorbid disorders, we decided to initiate atherapy with VPA at a dose of 750 mg/day. At 7-monthfollow-up in May 2008, the patient reported a markedimprovement of her headache, which no longer had apattern of daily recurrences, but was now characterized byshorter-lived exacerbations with entire symptom-free days.

DISCUSSIONTo our knowledge, this is the second case ever reported

of CH evolving into HC.Our case was different from Centonze et al’s in some

respects. First, our patient had CH for a shorter period (7months) with no remission intervals. Second, in our patientthere was no time separation between one form of head-ache and the other, but CH evolved directly into HC.

As regards possible drug treatments for HC patientswho cannot tolerate long-term indomethacin therapy, theliterature reports isolated cases of either a complete or apartial response to several drugs.5-8 Considering the pos-sible side effects in our patient, we did not deem it advisableto use any of these drugs as an alternative to indomethacin.Taking into account that in our patient HC was associatedwith an anxiety-depression syndrome, we chose a therapywith VPA, even though no data on the use of VPA in HChave ever been reported in the literature. We do know,however, that VPA has beneficial therapeutic effects at thepsychic level, as it helps stabilize mood; moreover, amongits possible side effects there is weight gain, which wouldalso have been beneficial to our patient.

Valproic acid (2-propylpentanoic acid) is a simplebranched-chain fatty acid, effectively used in the prophylac-tic treatment of migraine without aura, of chronic dailyheadache, and of CH,9 as well as in the treatment ofmedication-overuse headache.10

Valproic acid’s major mechanism of action is toenhance GABA-ergic neurotransmission. Its mechanism ofaction is complex and also entails a reduction of aspartateconcentrations in the brain, increased serotonin anddopamine concentrations in animal models. VPA inhibitsvoltage-dependent sodium channels in the neuronal mem-branes and increases potassium conductance, thus leadingto higher intracellular potassium concentrations and to aconsequent hyperpolarization of membranes at rest.11

Recently, Goadsby12 suggested that in the pathogenesisof CH – and of trigeminal autonomic cephalalgias (TACs),too – the hypothalamus might play a central role. The exist-ence of trigeminohypothalamic connections could lead tothe disinhibition of the trigeminal-autonomic reflex.13

In CH, VPA might help resynchronize circadian rhythmsby inhibiting neuronal activity inside the hypothalamic

Headache 1375

“generator” or by interacting with the second messengersinvolved in circadian rhythm modulation.14

Clinically, and perhaps also pathogenetically, HCshares features with TACs. Based also on recent neuroradi-ological data for HC,3 we could assume that in our caseVPA suppressed or reduced pain in HC by its direct actionon the hypothalamic generator, thus leading to the inhibi-tion of the trigeminal-autonomic reflex.

CONCLUSIONIn conclusion, VPA might represent an interesting

therapeutic option in HC patients who cannot toleratelong-term indomethacin therapy and also in HC patientswith certain psychiatric comorbid conditions, such asanxiety and depression.

If we consider the natural history of HC,15 however, wecannot exclude the possibility that the clinical improvementobserved in our patient may be the consequence of a spon-taneous remission of headache, independently of any VPAaction.

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