Abstract
We report a patient with headaches meeting the criteria of chronic paroxysmal hemicrania, as defined by the International Headache Society classification. Headaches were fully responsive to indomethacin during the first 3 months of treatment but recurred when daily doses were lowered. Investigations revealed a macroprolactinoma. Headaches stopped after cabergoline treatment. This report further suggests that patients with paroxysmal hemicrania should be investigated for pituitary abnormalities.
Keywords
Introduction
Paroxysmal hemicrania (PH) is a rare trigeminal autonomic cephalalgia (TAC) characterized by recurrent short-lasting unilateral attacks of severe orbital, supra-orbital or temporal pain accompanied by local signs and symptoms of autonomic dysfunction including conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, eyelid oedema, forehead and facial sweating, ptosis or myosis (1). Several features help to distinguish PH from cluster headache. First, PH attacks are shorter-lasting (2–30 min). Second, PH attacks are more frequent, above five per day for more than half of the time according to the second version of the International Classification of Headache Disorders (ICHD-II) and ranging from one to 40 per day according to published case reports (2). Third, in contrast to cluster headache, PH has no male predominance. Finally, PH is absolutely responsive to indomethacin. Efficient doses may vary from 50 to more than 200 mg per day.
According to the ICHD-II, episodic PH is characterized by attacks periods lasting 7–365 days with pain-free remission periods of ≥1 month, while in chronic PH attacks occur for more than 1 year without remission or with remissions lasting less than 1 month. The pathophysiological mechanisms of PH remain largely unknown. Most cases of PH described in the literature are primary but several patients have been reported to have secondary PH (3). We report a new case of chronic PH associated with a macroprolactinoma.
Case report
A 27-year-old woman, without past history of headache, experienced for 13 months short attacks of unilateral facial pain. The attacks consisted of severe burning pain in the right orbital and supraorbital area, lasting 2–3 min. This was accompanied by ipsilateral ptosis, lacrimation and eyelid oedema. Initially, these attacks occurred three to four times per day and could be triggered by physical exercise. Over time, the frequency of attacks gradually increased to 15 attacks per day without a period of remission. Aspirin, ibuprofen and zolmitriptan were tried without effect. Her neurological and general examinations were normal. Indomethacin was started at an initial dose of 200 mg/day and attacks completely stopped. Subsequently, indomethacin was slowly tapered down and the patient remained pain free during 3 months with 75 mg/day. After the 3 months, the attacks recurred. Neurological and general examinations were still normal. A computed tomographic scan followed by a magnetic resonance imaging (MRI) revealed a pituitary macroadenoma, with a suprasellar extension compressing the chiasmatic cistern and a slight right lateral extension not invading the right cavernous sinus (Fig. 1). Formal visual field testing was normal. Serum prolactin was 920 ng/ml (normal range 9–20 ng/ml). Serum levels of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), basal cortisol, adrenocorticotropic hormone (ACTH), oestrogen and growth hormone (GH) were all in the normal range. When interviewed to elicit clinical features of pituitary dysfunction, the patient reported a short episode of galactorrhoea before the onset of her headaches, that stopped after changing her oral contraceptives. Cabergoline was started and headaches began to improve a few days later. The frequency and severity of attacks gradually decreased over 3 months and finally stopped altogether. Prolactine levels normalized within 3 months. During a follow-up of 9 months, the patient remained headache free.
Magnetic resonance imaging (T1 weighted image with gadolinium injection) shows a pituitary tumour. The pituitary tumour has both solid and cystic components and is compressing the optic chiasm.
Discussion
This patient had symptomatic chronic PH secondary to a macroprolactinoma. During more than 1 year she experienced unilateral headache attacks that fulfilled the IHCD-II criteria for PH. Response to indomethacin was absolute during the first 3 months of treatment. Her neurological examination was normal. When PH attacks started again while she was treated with indomethacin, brain imaging permitted the diagnosis. Retrospectively, she admitted to symptoms of galactorrhoea and the serum prolactin was found to be elevated. The causal relationship between the macroprolactinoma and the headaches is supported by two main arguments: first, the adenoma growth preceded the onset of PH as demonstrated by the occurrence of a transient galactorrhoea before the headache started; and second, the PH attacks subsided after aetiological treatment by dopaminergic agonists and total remission was achieved when prolactin returned to a normal level. Finally, there was no recurrence of PH during the 9 months of follow-up.
More than 20 cases of unilateral headaches considered as PH secondary to various causes have been reported in the literature (3–5). The causes have included vascular pathologies, intracranial or extracranial space-occupying lesions, general or localized inflammatory or infectious diseases, a parietal arterioveinous malformation with Chiari malformation and a head trauma. However, those cases did not always fulfil all the IHCD criteria for PH. Moreover, a well-defined post-treatment remission followed by a prolonged follow-up was reported in only a few cases. Several of those cases described patients having chronic PH associated with pituitary tumours. A patient with chronic PH responsive to indomethacin had a prolactin-secreting adenoma. The attacks stopped after surgical resection of the adenoma (4). A 41-year-old man had typical PH with complete indomethacin response for 7 years. He was found to have a pituitary macroprolactinoma. After tumour removal, he was able to stop indomethacin and had no attack during the 2.5 years of follow-up (5).
A 20-year-old man with PH for at least 1 year was found to have a microadenoma of cells producing TSH, ACTH and prolactin (6). His headache attacks fulfilled all but one of the ICHD-II criteria for chronic PH, i.e. indomethacin markedly improved the intensity and frequency of attacks without stopping them totally. However, he received only 75 mg of indomethacin per day. After surgical removing of the adenoma, attacks gradually decreased and stopped within 1 month. The following 13 months were attack free.
A 34-year-old woman with left chronic PH for 5 years was found to have a large intrasellar gangliocytoma extending into the left cavernous sinus and into the suprasellar region (7). Headache attacks fulfilled all ICHD-II criteria for PH. After shrinkage of the tumour by means of partial surgical removal, followed by radiation therapy, the attacks subsided. The duration of follow-up was not mentioned.
Pituitary adenomas have also been found in five patients with secondary short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) (8–11). One patient had a non-functioning macroadenoma and four patients had a prolactinoma (a macroprolactinoma in two patients and a microprolactinoma in two others). Primary SUNCT is a very rare trigeminal autonomic cephalalgia characterized by strictly unilateral headaches, lasting 5–240 s, associated with ipsilateral conjunctival injection and tearing (1). The frequency of attacks ranges from a few per day to several per hour (3–200 per day). Those attacks are unresponsive to indomethacin and often to all other medications.
Finally, pituitary adenomas have also been reported in at least 10 patients with cluster-like headaches (12–15). These adenomas were either microscopic or macroscopic and most of them secreted prolactin. Cluster-like headaches ceased after aetiological treatment.
Several hypothesis have been put forward to explain the association between pituitary adenomas and trigeminoautomonic cephalalgias. Those tumours may have a mechanical effect on anatomic structures leading either to PH, to SUNCT or to cluster-like attacks, depending on the patient. Relevant structures may be the sympathetic fibres around the internal carotid artery and the trigeminal branches within the cavernous sinus, as well as the hypothalamic nuclei in the floor of the third ventricle. In the macroadenomas associated with SUNCT described in the literature, the unilateral extension of the tumour was concordant with the side of pain attacks. However, in our patient the macroadenoma had no right extension into the cavernous sinus. Moreover, a case of PH and two cases of SUNCT secondary to a microadenoma have been described, demonstrating that direct compression is not the only mechanism of pituitary-associated TAC. The role of an increased intrasellar pressure has also been stressed. In a study of patients with pituitary adenomas, those complaining of headaches had an increased intrasellar pressure, which was not directly correlated with the tumour volume (16). Finally, it has been proposed that pituitary headaches were predominantly neurohumorally mediated rather than provoked by a mechanical effect related to the size of the tumour (17). The hypothalamo–pituitary dopaminergic axis may be implicated. Indeed, in four of the five published patients with SUNCT secondary to a prolactinoma, the intake of dopaminergic agonists inhibiting prolactin secretion immediately exacerbated the SUNCT attacks (8, 9, 11). Such an exacerbation was not found in our patient with PH.
This case report has important clinical implications. Patients presenting with PH, SUNCT or other trigeminal autonomic cephalalgias should be carefully interviewed for symptoms and signs of hyperprolactinaemia, including galactorrhoea, amenorrhoea and gynaecomastia. If one of these symptoms is present, an MRI is needed even in typical PH fulfilling all ICHD-II criteria. Moreover, in patients with a presumed diagnosis of PH who do not respond robustly to indomethacin, the presence of a pituitary tumour should be considered. Finally, this case raises questions concerning the need for a systematic brain and pituitary MRI together with pituitary hormonal level measurements, including at least prolactin, in all cases with PH.