Sage Journals: Discover world-class research

Abstract

The main known function of the pineal gland in humans is the production of melatonin. Benign cysts of the gland have been related to headache, although the mechanism of production of this assumed clinical manifestation has not been clearly determined, due to the lack of large prospective studies. The question is complicated by the fact that pineal cysts are frequently found on brain magnetic resonance imaging. Much has been published about the possible role of benign pineal cysts in the pathophisiology of headaches and the potential of melatonin in headache therapy, as well as in other disorders. The aim of this article is to review the current state of the suject. We have tried to place accurately the relation between headache and pineal cysts based on the available evidence, as well as the actual role of melatonin in physiology and pharmacology, more specifically in headache therapy. We include a clinical case to illustrate the subject.

Keywords

Pineal gland melatonin pineal cysts headache

Introduction

Benign pineal cysts are a frequent incidental finding in neuroimaging studies. They have been associated with headache as a clinical manifestation, sometimes strictly unilateral, with varied features including those of migraine and hemicrania continua, among others. Nevertheless, the physiopathology of those headaches, or even a true relation with the cysts, has not been clearly determined. The case of a female patient who suffered from a chronic headache with mixed migraine and cluster headache features, unresponsive to every pharmacological therapy including melatonin, has been selected as an example of association between headache and pineal cyst that provoked some disputed questions.

Clinical case

A 46-year-old woman presented at the clinic with a temporo-orbital headache from which she had been suffering, affecting both sides alternatively, since the age of 18 years. Both of her parents and one sister suffered from migraine without aura. Initially her pain would appear about 1 day per week. Later it increased gradually in frequency until it was present in bouts of two to three consecutive days per week, with a tendency to last longer during menstruation, since the age of 36 years. She had just been pain free during her only pregnancy in 1987; interestingly, the pain reappeared on the same day that she had gone into labour.

The pain always initiated in the temporal area, around the ear, then irradiated to the mandible, later to the lateral part of the nose and finally to the orbit, where it reached its maximum intensity. During the symptomatic bouts the headache was persistently unilateral, moderate in intensity, had a pressing and throbbing quality and was accompanied by photophobia, phonophobia, nausea and, ocasionally, vomiting and diarrhoea. Several times per day there were exacerbations superimposed on this pain, consisting of an orbital or periorbital severe stabbing pain on the same side associated with ipsilateral conjunctival injection, lacrimation, nasal congestion and rhinorrhoea, without restlessness. One of these episodes was observed at the clinic. The patient had eyelid ptosis and myosis, with no other findings—the clinical examination was normal while the patient was asymptomatic. The exacerbations were variable in frequency from one to three per day, each lasting for about 1 h, and may have appeared during the day or night, in the last case awaking the patient. From one bout to another the pain and associated symptoms might change in location, being more frequent on the right side; they never presented on both sides simultaneously. The patient usually had hyperphagia 1 or 2 days before the bouts.

During the time of illness several neuroimaging studies were performed, cranial magnetic resonance imaging (MRI) persistently showing, in all sequences, a cystic mass of 15 mm in sagital diameter and 9 mm in vertical diameter, with well-defined margins and homogeneous content, in the region of the pineal gland (Figure 1a,b). This mass was compatible with a benign pineal cyst. Magnetic resonance angiographies were also normal. Magnetic resonance cerebrospinal fluid (CSF) flow examination in 2006 demonstrated no blockage in CSF circulation. A lumbar puncture showed a clear CSF with 180 mmH₂O pressure; cytochemical, microbiological, inmunological and cytological analyses revealed no abnormality.

Figure 1.

T2-axial (a) and T1-sagittal (b) cranial MRI showing the image of a pineal cyst (arrow on the left). A mild flattening of the superior colliculi can be seen. There is no evidence of aqueductal stenosis or hydrocephalus.

During the course of disease the patient had received a series of symptomatic and prophylactic therapies. Among the first were oxygen inhalation, simple analgesics (paracetamol, metamizol), indomethacin and other non-steroidal anti-inflamatory drugs (salicilates, naproxene, ibuprofen, piroxicam, diclofenac, dexketoprofen, ketorolac, celecoxib), ergotaminics (ergotamine tartrate, dihydroergotamine), triptans (oral, intranasal and subcutaneous sumatriptan, rizatriptan, oral and intranasal zolmitriptan, eletriptan), intravenous lidocaine and opioids (codeine, tramadol, meperidine), as well as metoclopramide. The patient experienced just minor, temporal and inconstant relief with rectal ergotamine tartrate, oral tramadol, subcutaneous meperidine, intranasal zolmitriptan and subcutaneous sumatriptan.

As prophylactic treatment the patient had received, alone or in various combinations, calcium channel blockers (flunarizine, nimodipine, verapamil), β-blockers (propranolol), tryciclic antidepressants (amytriptiline), intravenous and oral steroids (methyl-prednisolone, prednisone), antiserotoninergic medications (pizotifen, methysergide), ergotaminics (oral and rectal ergotamine and dihydroergotamine), antiepileptic drugs (valproic acid, topiramate, carbamazepine, oxcarbazepine, gabapentin, lamotrigine), benzodiazepines (diazepam, clonazepam, lorazepam, clorazepate, alprazolam), selective serotonin reuptake inhibitors (fluoxetine, paroxetine), lythium carbonate, prolonged half-life triptans (naratriptan, frovatriptan), bilateral occipital nerve blocks and alternative therapies such as osteopathy and acupuncture. Given the absence of pain during pregnancy, hormonal therapy had also been tried. None of these preventive therapies produced a change in frequency or duration of the symptomatic periods.

Finally, melatonin was prescribed at a dose of 3.0 mg, progressively increased to a maximun of 12 mg/day in a single nightly dose. Previously, basal serum melatonin level was determined (at 08.00 h), being <10 pg/ml. Despite maintaining this therapy for >1 year, the patient has not experienced any reduction in the frequency or intensity of pain. Currently, she has rejected bilateral occipital nerve stimulation while expecting her menopause, with the hope the symptoms will subside.

Discussion

What is the pineal gland?

The pineal gland or epiphysis is a small gland, about 9 mm of length in humans, located in the diencephalon as a midline structure of the epithalamus, rostro-dorsal to the superior colliculus in the groove between the two thalamic bodies. It is joined to the posterior roof of the third ventricle by a short ependymal recess, the pineal stalk. It is larger in children and shrinks at puberty. In adults it shows acummulation of calcareous deposits, so it may be seen as a hyperdense nodule in nearly half of skull X-ray films and in a higher proportion of brain computed tomography (CT) scans. Microscopically it is divided into two hemispheres and is composed by a cellular parenchyma, formed by pinealocytes (90%) and astroglial cells (10%), surrounded by meninges. It contains a rich capillary net, coming from the superior cerebellar artery, to receive the products released by the gland, and is innervated by both the sympathetic and parasympathetic divisions of the autonomic nervous system, from the superior cervical and the sphenopalatine ganglia, respectively. It also receives central innervation through the pineal stalk (1).

Pinealocytes, anatomically similar to retinal cones, are neurosecretory cells derived from the embryonal neuroepithelium. In lower vertebrates they evolve from neural photoreceptors, so they transduce light directly into neural impulses (2). In humans, these cells do not have this ability but retain an input from photic stimuli. It is thought that light acts on a group of specific photosensitive ganglion cells of the retina containing melanopsin, a pigment that mediates the sensitivity of these cells to light (3). When activated, these specialized cells discharge nerve impulses to the suprachiasmatic and then the paraventricular nuclei in the hypothalamus, from where the impulses project to the intermediolateral cell columns of the spinal cord, the superior cervical ganglia via the sympathetic system and finally to the pineal gland (4).

The pineal gland was long considered a rudimentary organ until the detection of melatonin as a product of pineal secretion in the late 1950s, together with the finding that this secretion was related with the circadian cycle (5, 6).

What is melatonin?

The main function of pinealocytes is to produce most of the melatonin of the body, as well as some peptides (7). Only small quantities of melatonin are synthesized in retina, intestine and other tissues. Melatonin (5-methoxy-N-acetyltryptamine) is an indolamine derived from tryptophan via intermediate synthesis of serotonin. Its chemical structure is similar to that of indomethacin. Its production is stimulated by darkness and inhibited by light, at levels that in ordinary circumstances (people who sleep at night) correlate with the day–night cycle, so the secretion of melatonin peaks in the middle (between 02.00 and 04.00 h) and then falls away during the second half of the night (8).

Since it is released into the blood, melatonin is considered a hormone. As it is also present in foods, mainly vegetables and fruits, it can also be regarded as a vitamin (9).

The production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus of the hypothalamus, which receives information from the retina about the daily pattern of light and darkness. The cyclic secretion of this hormone, which reflects hypothalamic action, appears to be its most important feature. This secretion is a consequence of the circadian rhythm and not its mechanism of production. Blood concentrations of melatonin can be measured, as well as those of its metabolite 6-sulphatoxymelatonin in urine, with a good correlation. Sequential analysis of biological samples during different moments of the day and night is useful to appreciate the circadian rhythm of secretion and its disruptions (10).

What is the function of melatonin in human beings?

Melatonin is believed to act as an internal signal to the brain (and through it to the rest of the organism) that it is time to sleep, a restorative function indispensable for survival. Thus, melatonin would be a sleep inductor, with a function mediated by specific hypothalamic receptors causing inhibition of the signal for wakefulness arising from the suprachiasmatic nuclei, translated on a rapid and reversible activation of the GABAergic system (11). So the pineal gland is an organ that converts the lack of external luminous stimuli into the secretion of a hormone responsible for the synchronization between internal homeostasis and environment.

Has melatonin any other known functions or biological properties in humans?

There is evidence that melatonin affects reproductive performance in a variety of species, particularly in seasonal-breeding ones. In human beings melatonin levels are higher in children than in adults. Its production is reduced when puberty arrives; seemingly, it may play a role in inhibition of sexual development during childhood. Some pineal tumours such as germinomas have been linked with precocious puberty (12).

As inhibition of melatonin synthesis by gonadal steroids has been observed in the laboratory (13), diurnal and nocturnal plasma concentrations have been found to be increased in Kallman's syndrome and other forms of primary hypogonadism in male subjects. Nevertheless, in spite of all these data, the role of melatonin in sexual development has not been clarified (14–16).

In experimental settings melatonin has shown some interesting properties, such as antioxidant and anti-inflammatory effects: it forms several stable end-products after reacting with free radicals (17) and inhibits prostaglandin synthesis (18). By contrast, it stimulates cytokine production and enhances interleukin-2 expression, suggesting it may be involved in the clonal expansion of antigen-stimulated T lymphocytes (19). It also inhibits nitric oxide synthase (NOS) activity and dopamine release, potentiates opioid analgesia, depresses calcium uptake and promotes membrane stabilization (20).

Has melatonin any application as a pharmacological agent?

In the USA melatonin is classified as a dietary supplement and has been made freely accessible. In Spain and some other European countries it is not available for medical use. As a matter of fact, there have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on observations or small, incomplete, clinical trials. Some of the reasons for the limited efficacy of exogenous melatonin as a drug are related to its extreme short half-life in the circulation, and to the fact that sleep maintenance is also regulated by mechanisms other than melatonergic actions. Other melatonin receptor agonists, such as ramelteon and agomelatine, have a longer half-life and could be more suitable as therapeutic agents. Both are currently considered experimental (21).

Nevertheless, bearing in mind its function and its biological properties in some experimental work, melatonin has been proposed as a therapeutic agent in a number of disorders.

Hypnotic agent

The most constant effect after the administration of exogenous melatonin is sedation. With doses as low as 0.1 mg it induces sleep, reduces anxiety and provides a sensation of well-being, with slight analgesia (22). As a consequence, it has been proposed as a hypnotic drug or to assist in restoring a normal sleep pattern. This ability has been demonstrated in circadian rhythm sleep disorders, such as jet lag syndrome in adult travellers flying across five or more time zones, particularly in an easterly direction, especially if experienced on previous journeys (with equally effective doses from 0.5 to 5 mg in data from a Cochrane systematic review) (23). It has also shown effectiveness in delayed sleep phase syndrome, shift-work sleep disorders and the non-24-h sleep–wake syndrome in unsighted persons.

In an open study by Boeve et al. melatonin significantly improved rapid eye movement sleep behaviour disorder in 10 out of 14 patients with different central nervous system (CNS) disorders, unresponsive to clonazepam because of tolerance, disturbing side-effects or development or aggravation of a sleep apnoea syndrome (24). According to this and other studies, melatonin may be of value in these subjects (25–27). These uses apart, recent meta-analyses have revealed that melatonin is not effective in treating most primary sleep disorders (28, 29).

Melatonin and depression

Although there are some reports of decreased serum melatonin concentration in patients with depression (30) and a few authors have found it might ameliorate certain depressive syndromes such as seasonal affective disorder (SAD) (31), more recent work supports that melatonin has a negative effect on mood (32, 33). SAD is characterized by depressive annual episodes, usually between December and February (the months with the shortest days in the northern hemisphere), with a tendency to hypersomnia and hyperphagia (with a selective predilection for carbohydrates), whose specific cause remains unknown. It has been theorized that SAD may be due to an increase in the production of melatonin during the longer nights of winter. Some patients respond to phototherapy (34).

Melatonin could ameliorate sleep disturbances associated with depression, a symptom that most current treatments fail to address and may even aggravate. Some melatonin analogues, such as agomelatine, could solve this problem because of its affinity for melatonin receptors and, unlike melatonin, its antagonism of the serotonin 5-HT_2C receptor subtype (which would explain an antidepressive action) (35).

Analgesia

It has been found that melatonin has moderate antinociceptive effects, mainly attributed to an increase of pain thresholds. This would be mainly explained by its sedative and anxiolytic properties, like those of midazolam and other anaesthetic premedications. GABA-A receptor function has been recognized as an important pathway underlying the depressant effects of many of these agents and it has been demonstrated that melatonin increases GABA concentrations in the CNS. So these central anaesthetic effects of melatonin would be mediated, at least in part, by this GABAergic system activation (36, 37).

Melatonin has been shown to enhance antinociceptive effects of opioids and promote the release of β-endorphin in mice (38, 39). The scope of these findings has not been established in human beings. Therefore, except for a possible application as a pre-anaesthetic medication (40, 41), melatonin utility as an analgesic agent has not been established.

Taking into account its properties in the laboratory, melatonin has been proposed by some authors for treating sexual dysfunction, immune and infectious disorders or even cancer (42). Such potential clinical indications of melatonin have not been proved. Again, sleep and its known effect as an inmune system modulator might explain some of these presumed melatonin actions (43).

Does melatonin cause adverse effects?

In short-term treatment, melatonin exhibits almost no side-effects, as demonstrated in a systematic review in >600 patients with sleep disorders related to jet lag, shift work and other diagnoses. Doses up to 6 mg were not accompanied by important adverse effects, although headache, nausea, drowsiness, irritability, vivid dreams or nightmares were seen, as well as worsening of orthostatic hypotension (44). No studies have been conducted to determine long-term security and tolerability, and the actual risk of protracted consumption remains unknown. Nevertheless, there are case reports of patients who have taken melatonin for years that have not revealed any serious side-effect. The current synthetic form does not carry the risk of infective transmission.

Has melatonin any application in neurological disorders?

Pineal gland and its function are not among the subjects causing more interest in clinical neurology. This is partly explained by the usually rare occurrence of gland removal and consequent reduction of melatonin levels. So far, its use in neurological disorders is limited to the treatment of sundowning in some Alzheimer's patients, usually combined with exposure to light, with just moderate success (45). Furthermore, melatonin has undergone a few trials as a preventative medication for certain headache types (see below) (46).

What are pineal cysts?

Cysts in the pineal gland may be found in 25% of autopsies (47). Most are small, measuring < 5 mm, whereas it is thought that presumed symptomatic cysts are usually larger, generally > 10 mm. Histologically, the cyst wall is composed of an inner layer of gliosis surrounded by another layer of attenuated pineal parenchyma and an outer one of leptomeningeal fibrous tissue (48).

As a result of the generalized use of CT and MRI, benign pineal cysts are detected with increasing frequency also in neuroradiological studies, with MRI being more sensitive (they are often confused with the quadrigeminal cistern on CT scans). They are said to appear in 1–3% of all brain MRI examinations in different series (either retrospective or prospective), with a slightly higher frequency in women in the third and fourth decades (49–51). In one prospective study with specific imaging of the pineal region, the incidence reported was higher (4.3%; 29 of 678 MRIs) (52).

On T1-weighted images benign pineal cysts appear as ovoid or round lesions with margins slightly less intense than the surrounding tissue, and a content that is isointense or moderately hyperintense compared with CSF. On T2-weighted images they are homogeneous and brighter than CSF. Enhancement of the cyst wall, often incomplete, and uniform enhancement mimicking a solid mass have been found in some cases (53). Unlike benign cysts, cystic teratomas usually have signal characteristics similar to fat, whereas primary pineal tumours commonly show a T1 signal similar to that of grey matter.

However, distinction between pineal cysts and pineal neoplasms, either pilocytic astrocytomas or pineal parenchymal tumours, may be difficult by only radiological criteria in an initial stage (54). Pineal tumours account for 1% of all intracranial tumours, 10 times more frequent in children. In > 90% of cases clinical presentation is that of intracranial hypertension, often caused by hydrocephalus (55, 56). Only a small percentage present as sexual precociousness, which may be due to gonadal stimulation by ectopic beta-human chorionic gonadotropin produced by germinomas or to hypothalamic affection (57, 58). Rare initial symptoms are sleep alterations or behavioural problems (59).

Is there a true relation between pineal cysts and headache?

For some authors benign pineal cysts in headache patients may not be incidental. Whereas large benign cysts can, in rare instances, produce a hydrocephalus resulting in headache (60), a number of case series have described headache to be a more usual than expected symptom in patients with cysts not associated with hydrocephalus. Some possible mechanisms for headache have even been suggested (61). For example, in a small series of seven patients with large cysts on MRI (from 15 to 20 mm in diameter), four of them showed no mass effect or hydrocephalus (62). One of these presented with a history of positional headaches. Although the authors suggest that the cyst in this case could have compressed the vein of Galen and/or the aqueduct of Sylvius in particular positions of the head, the truth is that many patients with compression of the quadrigeminal lamina by pineal cysts on MRI are completely asymptomatic.

When considering pineal cysts of at least 5 mm of maximum diameter, we have observed two tendencies in the studies analysed. On one hand, benign cysts appear to be less common in patients without CNS manifestations in the largest series of radiological studies. On the other hand, headache is the most frequent complaint in those with any neurological signs or symptoms (apparently not due to an unmistakeable cause) (63).

For example, in a retrospective study of all CTs and MRIs made in a neurology department for 8 years (1999–2006), pineal cysts were identified in 51 patients (41 female, 10 male, average age 38 years), of which 26 (51%; 24 female, two male) had headache, none of them with hydrocephalus. In the age- and sex-matched control group, only 13 (25%) suffered from headache. This particular study suggests a relationship between pineal cysts and headache, more specifically with migraine-like headache, with no difference in mean cyst diameter between the two groups (around 11 mm). The authors suggest a causal relationship in some cases between pineal cysts and headache not related to intracranial hypertension, but their findings do not support the hypothesis of a link between the presence of headache and the cyst size, as has often been proposed (64).

When taking into account asymptomatic patients, pineal cysts were detected in only two out of 1000 adult volunteers (0.2%) in the largest retrospective analysis conducted to establish their incidence in people of all ages without any neurological symptoms or signs (65). A small prospective study conducted among healthy volunteers aged between 22 and 40 years (13 men and 14 women) reported the prevalence of benign pineal cysts to be as high as 7.4% (66). Finally, in another more recent study of high-resolution (1.9-T) MRI images from 100 healthy subjects, extracted retrospectively from a database of reference neuroradiological examinations, prevalence was 23%, similar to that on autopsies; however, in this study all cystic changes of at least 2 mm diameter were considered as pineal cysts and the mean of the largest diameter of the cysts was as low as 4.3 mm (67).

The mechanisms of headache in these patients remain obscure. Prospective trials must confirm the association of headache and pineal cysts, clarify its pathophysiological mechanism and elucidate the relevance of the cyst size. Perhaps functional neuroimaging showing specific activation areas would be of help for this purpose.

Which would be the pathophysiology of headache in these patients?

There are some reports in which levels of melatonin are lower in patients with benign cysts; at the same time, unilateral headaches have been reported in pinealectomized subjects (68). Although abnormal melatonin secretion has been suggested as the origin of headache, its true role has to be determined. A possible explanation is that headache could depend on the lack of melatonin as a natural sleep inductor.

The hypothalamus is considered not only the circadian pace-maker but also the ‘departure station’ of the autonomic, sleep and endogenous analgesic systems, this last one connected with the trigeminal spinal nucleus, to which it could modulate. The hypothalamus might be the headache trigger in patients with pineal cysts, as in cluster headache, in which it is believed that a dysfunction in the suprachiasmatic nucleus cyclically turns on a disnociceptive mechanism leading to headache by activation of the trigeminal nerve (69, 70). Whether this is due to changes in the normal interaction between the hypothalamus and the pineal gland, not necessarily mediated by melatonin (at least solely), is open to conjecture.

Is melatonin effective in the treatment of any type of headache?

Considering that melatonin inhibits the activity of NOS and posesses anti-inflamatory effects, some clinical studies have been carried out to consider it as a preventative therapy of some forms of headache. Possitive effects have been reported in migraine and cluster headache, but only with low levels of evidence in cluster patients.

Migraine

There have been many attempts to relate melatonin to migraine, with several studies reporting an association with low melatonin levels at baseline, during attacks or with sleep comorbidity (71–74). Nevertheless, controlled trials of melatonin in migraine do not exist (75).

In a meta-analysis of ‘natural’ therapies in the treatment of headache, there was at best grade B evidence (limited evidence from a single randomized trial, non-randomized trials or multiple trials with inconsistent results) for all the agents discussed except for melatonin. The other agents considered were petasites, magnesium, feverfew, riboflavin and coenzyme Q10 (76).

Melatonin could be more important in migraine comorbidity through an improvement of sleep. Jet lag and delayed sleep phase syndromes in migraneurs can provoke worsening of their headaches, sometimes with a good response to melatonin (77). Thus, insomnia would be the most likely associated condition in migraine amenable to improvement. In summary, the most consistent implication of melatonin in migraine seems to be a relationship to sleep disorders or to seasonal circ-annual effects.

Cluster headache

Several authors have shown a reduction of serum melatonin and its rythm of secretion in cluster headache patients, particularly during bouts (78). Although treatment of cluster headache is mainly empirical, melatonin has been tried as a prophylactic medication, owing to the classical circadian pattern of this headache and the presumed involvement of the hypothalamus in its pathophysiology.

In this respect, melatonin (10 mg orally for 2 weeks) was effective in a single double-blind, placebo-controlled study in 20 patients (18 episodic, two chronic), with five patients pain-free after 5 days. No patient in the placebo group responded, nor the two patients with chronic forms (79). Melatonin has also been found effective in a number of clinical observations, alone or as an add-on therapy, including a few patients with chronic cluster headache (80). However, in cases refractory to other medication, melatonin used open-label did not produce any additional efficacy (81). According to the Official Guidelines of the European Federation of Neurological Societies, melatonin is considered to be of possible use (level C recommendation) (82).

Melatonin and other headaches

Hypnic headache also has a circadian pattern of presentation. There are some descriptions of a few patients effectively treated with melatonin at bedtime (83, 84). Its pathophysiology is unclear, although it has been speculated to be an impairment of suprachiasmatic nucleus function in elder persons (85).

Other headaches sporadically reported to be responsive to melatonin have been hemicrania continua and stabbing primary headache (86–89).

Could melatonin be effective in the treatment of headache in patients with pineal cysts?

Any answer to this question would be merely speculative. Our experience with this patient has been negative. A significant number of clinical observations would be necessary before any conclusions could be drawn.

Conclusions

Benign pineal cysts are a frequent finding in neuroimaging studies. In most cases they are purely incidental, without any clinical expression, and an unchanging condition. From a literature review, it appears that cases of symptomatic pineal cysts have been overemphasized, appart from the rare cases of large cysts with manifestations of an expansive lesion in the midline. In those patients with headache, the lack of clinical details or specificity does not establish a clear relation between headache and the cysts; nor has physiopathology of those headaches been clearly determined. Currently, there is no clear evidence that benign pineal cysts may produce headache. As a matter of fact, it is not considered a specific entity in the International Classification of Headache Disorders, although we believe it might be included in the codified as 7.9 subtype (Headache attributed to other non-vascular intracranial disorder).

However, several well-designed epidemiological studies have associated benign pineal cysts to headache as a manifestation (unilateral, bilateral or alternating), giving cause for considering a relationship in particular cases. It would be of interest to establish if headache is more frequent in the case of patients with some type of biological predisposition, such as that for migraine. There is a need for prospective trials to confirm a true association of benign pyneal cysts and headache and clarify the pathophysiological mechanisms involved. Functional neuroimaging could be of help for this purpose.

As for melatonin, its utility as an analgesic agent has not been established, except for a possible application as an anaesthetic premedication. Nevertheless, it has undergone a few trials as a preventative therapy for certain headache types. Positive effects have been reported in migraine and cluster headache, but only with a low level of evidence in cluster patients (level C of recommendation). This use of melatonin is based on the classical circadian pattern of cluster headache and the presumed involvement of the hypothalamus, a structure with a close interaction with the pineal gland, in its pathophysiology. As for the reduction in melatonin secretion described in some migraneurs, it may simply be a marker of hypothalamic dysfunction. In migraine, melatonin could play a more important role in certain comorbid disorders, particularly in some types of insomnia, in which it could achieve an improvement in sleep.

Some of the reasons for the limited efficacy of exogenous melatonin as a drug appear to be related to its pharmacokinetic properties, among which its extreme short half-life in the circulation seems to be of the utmost importance.

References

Erlich

Apuzzo

. The pineal gland: anatomy, physiology, and clinical significance. J Neurosurg 1985; 63: 321–341.

Klein

. The 2004 Aschoff/Pittendrigh lecture: theory of the origin of the pineal gland—a tale of conflict and resolution. J Biol Rhythms 2004; 19: 264–279.

Kawasaki

Kardon

. Intrinsically photosensitive retinal ganglion cells. J Neuroophthalmol 2007; 27: 195–204.

Erlich

Apuzzo

. The pineal gland: anatomy, physiology, and clinical significance. J Neurosurg 1985; 63: 321–341.

Lerner

Case

Takayashi

. Isolation of melatonin and 5-methoxyindole-3- acetic acid from bovine pineal glands. J Biol Chem 1960; 235: 1992–1997.

Wurtman

Axelrod

Phillips

. Melatonin synthesis in the pineal gland: control by light. Science 1963; 142: 1071–1073.

Motilva

Cabeza

Alarcón de la Lastra

. New issues about melatonin and its effects on the digestive system. Curr Pharm Des 2001; 7: 909–931.

Reiter

Calvo

Karbownik

Tan

. Melatonin and its relation to the immune system and inflammation. Ann NY Acad Sci 2000; 917: 376–386.

Tan

Manchester

Hardeland

Lopez-Burillo

Mayo

Sainz

Reiter

. Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res 2003; 34: 75–78.

10.

Markey

Higa

Shih

Danforth

Tamarkin

. The correlation between human plasma melatonin levels and urinary 6-hydroxymelatonin excretion. Clin Chim Acta 1985; 150: 221–225.

11.

Cajochen

Kräuchi

Wirz-Justice

. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol 2003; 15: 432–437.

12.

Rivarola

Belgorosky

Mendilaharzu

Vidal

. Precocious puberty in children with tumours of the suprasellar and pineal areas: organic central precocious puberty. Acta Paediatr 2001; 90: 751–756.

13.

Okatani

Hayashi

Watanabe

Morioka

Sagara

. Estrogen modulates the nocturnal synthesis of melatonin in peripubertal female rats. J Pineal Res 1998; 24: 224–229.

14.

Kadva

Djahanbakhch

Monson

Silman

. Elevated nocturnal melatonin is a consequence of gonadotropin-releasing hormone deficiency in women with hypothalamic amenorrhea. J Clin Endocrinol Metab 1998; 83: 3653–3662.

15.

Luboshitzky

Lavie

. Melatonin and sex hormone interrelationships—a review. J Pediatr Endocrinol Metab 1999; 12: 355–362.

16.

Brzezinski

. Melatonin in humans. N Engl J Med 1997; 336: 186–195.

17.

Tan

Manchester

Terron

Flores

Reiter

. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007; 42: 28–42.

18.

De la Rocha

Rotelli

Aguilar

Pelzer

. Structural basis of the anti-inflammatory activity of melatonin. Arzneimittelforschung 2007; 57: 782–786.

19.

Carrillo-Vico

Lardone

Fernández-Santos

Martín-Lacave

Calvo

Karasek

Guerrero

. Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system. J Clin Endocrinol Metab 2005; 90: 992–1000.

20.

Peres

. Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia 2005; 25: 403–411.

21.

Hardeland

Poeggeler

Srinivasan

Trakht

Pandi-Perumal

Cardinali

. Melatonergic drugs in clinical practice. Arzneimittelforschung 2008; 58: 1–10.

22.

Acil

Basgul

Celiker

Karagöz

Demir

Aypar

. Perioperative effects of melatonin and midazolam premedication on sedation, orientation, anxiety scores and psychomotor performance. Eur J Anaesthesiol 2004; 21: 553–557.

23.

Herxheimer

Petrie

. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev 2002; 2, CD001520.

24.

Boeve

Silber

. Melatonin for treatment of REM sleep behaviour disorder in neurologic disorders: results in 14 patients. Sleep Med 2003; 4: 281–284.

25.

Billiard

. Sleep disorders. In: Candelise

Hughes

Liberati

Uitdehaag

BMJ

Warlow

(eds) Evidence-based neurology. Oxford: Blackwell Publishing, 2000, 70–78.

26.

Gagnon

Postuma

Montplaisir

. Update on the pharmacology of REM sleep behavior disorder. Neurology 2006; 67: 742–747.

27.

Gugger

Wagner

. Rapid eye movement sleep behavior disorder. Ann Pharmacother 2007; 41: 1833–1841.

28.

Morgenthaler

Lee-Chiong

Alessi

Friedman

Aurora

Boehlecke

. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American academy of sleep medicine report. Sleep 2007; 30: 1445–1459.

29.

Morin

Jarvis

Lynch

. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy 2007; 27: 89–110.

30.

Srinivasan

Smits

Spence

Lowe

Kayumov

Pandi-Perumal

. Melatonin in mood disorders. World J Biol Psychiatry 2006; 7: 138–151.

31.

Lewy

Bauer

Cutler

Sack

. Melatonin treatment of winter depression: a pilot study. Psychiatry Res 1998; 77: 57–61.

32.

Carvalho

Gorenstein

Moreno

Markus

. Melatonin levels in drug-free patients with major depression from the southern hemisphere. Psychoneuroendocrinology 2006; 31: 761–768.

33.

Riemersma-van der Lek

Swaab

Twisk

Hol

Hoogendijk

Van Someren

. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 2008; 299: 2642–2655.

34.

Westrin

Lam

. Seasonal affective disorder: a clinical update. Ann Clin Psychiatry 2007; 19: 239–246.

35.

Zupancic

Guilleminault

. Agomelatine: a preliminary review of a new antidepressant. CNS Drugs 2006; 20: 981–992.

36.

Golombek

Pévet

Cardinali

. Melatonin effects on behavior: possible mediation by the central GABAergic system. Neurosci Biobehav Rev 1996; 20: 403–412.

37.

Naguib

Gottumukkala

Goldstein

. Melatonin and anesthesia: a clinical perspective. J Pineal Res 2007; 42: 12–21.

38.

Wang

Dai

Chen

. Melatonin enhances antinociceptive effects of delta-, but not mu-opioid agonist in mice. Brain Res 2005; 1043: 132–138.

39.

Shavali

Govitrapong

Sawlom

Ajjimaporn

Klongpanichapak

Ebadi

. Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin, an endogenous opioid. Brain Res Bull 2005; 64: 471–479.

40.

Naguib

Samarkandi

. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. Br J Anaesth 1999; 82: 875–880.

41.

Samarkandi

Naguib

Riad

Thalaj

Alotibi

Aldammas

Albassam

. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. Eur J Anaesthesiol 2005; 22: 189–196.

42.

Szczepanik

. Melatonin and its influence on immune system. J Physiol Pharmacol 2007; 58(Suppl. 6): 115–124.

43.

Palma

Tiba

Machado

Tufik

Suchecki

. Immune outcomes of sleep disorders: the hypothalamic–pituitary–adrenal axis as a modulatory factor. Rev Bras Psiquiatr 2007; 29(Suppl. 1): 33–38.

44.

Buscemi

Vandermeer

Hooton

Pandya

Tjosvold

Hartling

. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006; 332: 385–393.

45.

Klaffke

Staedt

. Sundowning and circadian rhythm disorders in dementia. Acta Neurol Belg 2006; 106: 168–175.

46.

Dodick

Capobianco

. Treatment and management of cluster headache. Curr Pain Headache Rep 2001; 5: 83–91.

47.

Hasegawa

Ohtsubo

Mori

. Pineal gland in old age; quantitative and qualitative morphological study of 168 human autopsy cases. Brain Res 1987; 409: 343–349.

48.

Lantos

Vandenberg

Kleihues

. Tumours of the nervous system. In: Graham

Lantos

(eds) Greenfield's neuropathology. Vol. 2 6th ed. London: Arnold, 1997, 583–789.

49.

Mamourian

Yarnell

. Enhancement of pineal cysts on MR images. AJNR Am J Neuroradiol 1991; 12: 773–774.

50.

Wöber-Bingöl

Wöber

Prayer

Wagner-Ennsgraber

Karwautz

Vesely

. Magnetic resonance imaging for recurrent headache in childhood and adolescence. Headache 1996; 36: 83–90.

51.

Di Costanzo

Tedeschi

Di Salle

Golia

Morrone

Bonavita

. Pineal cysts: an incidental MRI finding? J Neurol Neurosurg Psychiatry 1993; 56: 207–208.

52.

Sawamura

Ikeda

Ozawa

Minoshima

Saito

Abe

. Magnetic resonance images reveal a high incidence of asymptomatic pineal cysts in young women. Neurosurgery 1995; 37: 11–15.

53.

Mamourian

Towfighi

. Pineal cysts: MR imaging. AMJR 1986; 7: 1081–1086.

54.

Kaztman

Dagher

Patronas

. Incidental findings on brain magnetic resonance imaging from 1000 asymptomatic volunteers. JAMA 1999; 282: 36–39.

55.

Bodensteiner

Schaefer

Keller

McConnell

. Incidental pineal cysts in a prospectively ascertained normal cohort. Clin Pediatr (Phila) 1996; 35: 277–279.

56.

Mahankali

Hou

Lancaster

Gao

. High prevalence of pineal cysts in healthy adults demonstrated by high-resolution, noncontrast brain MR imaging. AJNR Am J Neuroradiol 2007; 28: 1706–1709.

57.

Korogi

Takahashi

Ushio

. MRI of pineal region tumors. J Neurooncol 2001; 54: 251–261.

58.

Hoffman

Yoshida

Becker

Hendrick

Humphreys

. Pineal region tumors in childhood. Pediatr Neurosurg 1994; 21: 91–104.

59.

Cho

Wang

Nam

Kim

Jung

Kim

. Pineal tumors: experience with 48 cases over 10 years. Childs Nerv Syst 1998; 14: 53–58.

60.

Fetell

Stein

. Neuroendocrine aspects of pineal tumors. Neurol Clin 1986; 4: 877–905.

61.

Perilongo

Rigon

Murgia

. Oncologic causes of precocious puberty. Pediatr Hematol Oncol 1989; 6: 331–340.

62.

Echevarría

Fangusaro

Goldman

. Pediatric central nervous system germ cell tumors: a review. Oncologist 2008; 13: 690–699.

63.

Metellus

Fuentes

Levrier

Adetchessi

Dufour

Donnet

Grisoli

. Endoscopic treatment of a voluminous benign symptomatic cyst of the pineal region responsible for an obstructive hydrocephalus. Neurochirurgie 2005; 51: 173–178.

64.

Peres

Zuckerman

Porto

Brandt

. Headaches and pineal cyst: a (more than) coincidental relationship? Headache 2004; 44: 929–930.

65.

Pérez López-Fraile

Bestué-Cardiel

Usón

Barrena

. Pineal gland cysts: clinical and radiological course. Neurologia 1997; 12: 232–237.

66.

Seifert

Woeller

Valet

Zimmer

Berthele

Tölle

Sprenger

. Headaches and pineal cyst: a case–control study. Headache 2008; 48: 448–452.

67.

Klein

Rubinstein

. Benign symptomatic glial cysts of the pineal gland: a report of seven cases and review of the literature. J Neurol Neurosurg Psychiatry 1989; 52: 991–995.

68.

Mandera

Marcol

Bierzyńska-Macyszyn

Kluczewska

. Pineal cysts in childhood. Childs Nerv Syst 2003; 19: 750–755.

69.

May

. Cluster headache: pathogenesis, diagnosis, and management. Lancet 2005; 366: 843–855.

70.

Cortelli

Pierangeli

. Hypothalamus and headaches. Neurol Sci 2007; 28(Suppl. 2): 198–202.

71.

Gagnier

. The therapeutic potential of melatonin in migraines and other headache types. Altern Med Rev 2001; 6: 383–389.

72.

Peres

Masruha

Zukerman

Moreira-Filho

Cavalheiro

. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs 2006; 15: 367–375.

73.

Masruha

de Souza Vieira

Minett

Cipolla-Neto

Zukerman

Vilanova

Peres

. Low urinary 6-sulphatoxymelatonin concentrations in acute migraine. J Headache Pain 2008; 9: 221–224.

74.

Claustrat

Brun

Geoffriau

Zaidan

Mallo

Chazot

. Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus. Cephalalgia 1997; 17: 511–517.

75.

Vogler

Rapoport

Tepper

Sheftell

Bigal

. Role of melatonin in the pathophysiology of migraine: implications for treatment. CNS Drugs 2006; 20: 343–350.

76.

Evans

Taylor

. ‘Natural’ or alternative medications for migraine prevention. Headache 2006; 46: 1012–1018.

77.

Rains

Poceta

. Headache and sleep disorders: review and clinical implications for headache management. Headache 2006; 46: 1344–1363.

78.

Leone

Lucini

D'Amico

Grazzi

Moschiano

Fraschini

Bussone

. Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache. Cephalalgia 1998; 18: 664–667.

79.

Leone

D'Amico

Moschiano

Fraschini

Bussone

. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996; 16: 494–496.

80.

Peres

Rozen

. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia 2001; 21: 993–995.

81.

Pringsheim

Magnoux

Dobson

Hamel

Aubé

. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache 2002; 42: 787–792.

82.

May

Leone

Afra

Linde

Sándor

Evers

Goadsby

. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol 2006; 13: 1066–1077.

83.

Capo

Esposito

. Hypnic headache: a new Italian case with a good response to pizotifen and melatonin. Cephalalgia 2001; 21: 505–506.

84.

Martins

Gouveia

. Hypnic headache and travel across time zones: a case report. Cephalalgia 2001; 21: 928–931.

85.

De Simone

Marano

Ranieri

Bonavita

. Hypnic headache: an update. Neurol Sci 2006; 27(Suppl. 2): 144–148.

86.

Peres

Stiles

Oshinsky

Rozen

. Remitting form of hemicrania continua with seasonal pattern. Headache 2001; 41: 592–594.

87.

Spears

. Hemicrania continua: a case in which a patient experienced complete relief on melatonin. Headache 2006; 46: 524–527.

88.

Rozen

. Melatonin responsive hemicrania continua. Headache 2006; 46: 1203–1204.

89.

Rozen

. Melatonin as treatment for idiopathic stabbing headache. Neurology 2003; 61: 865–866.

Some questions provoked by a chronic headache (with mixed migraine and cluster headache features) in a woman with a pineal cyst. Answers from a literature review

Abstract

Keywords

Introduction

Clinical case

Discussion

What is the pineal gland?

What is melatonin?

What is the function of melatonin in human beings?

Has melatonin any other known functions or biological properties in humans?

Has melatonin any application as a pharmacological agent?

Hypnotic agent

Melatonin and depression

Analgesia

Does melatonin cause adverse effects?

Has melatonin any application in neurological disorders?

What are pineal cysts?

Is there a true relation between pineal cysts and headache?

Which would be the pathophysiology of headache in these patients?

Is melatonin effective in the treatment of any type of headache?

Migraine

Cluster headache

Melatonin and other headaches

Could melatonin be effective in the treatment of headache in patients with pineal cysts?

Conclusions

References