80 Practical Neurology

REVIEW

Pract Neurol 2009; 9: 8084

Not all morning headaches are due to brain tumours

A J Larner
Headaches causing early morning waking, or headaches which are more prominent on waking, always raise the suspicion of raised intracranial pressure, and hence the need for prompt evaluation to exclude the diagnosis of a brain tumour (particularly if they are associated with vomiting and papilloedema). However, there are many other much more common causes of morning headache, both primary and secondary. As ever, history taking is key to the diagnosis. Attention to the possibility of analgesic medication overuse is particularly pertinent, but other treatable conditions such as depression and epilepsy must not be overlooked.
lassical clinical teaching, familiar to practically all doctors and drummed into all medical students, is that one of the features of raised intracranial pressure (ICP) is headache which causes nocturnal or early morning waking, and/or is worse on waking, then declining in severity after getting up. This nocturnal or early morning headache is thought to reflect exacerbation of raised ICP through recumbency, nocturnal hypoventilation with a rise

A J Larner
Consultant Neurologist, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool L9 7LJ, UK; a.larner@thewaltoncentre.nhs.uk 10.1136/jnnp.2008.171140

in PaCO2 and cerebral vasodilatation,1 and possibly increased brain metabolism during REM (rapid eye movement) sleep.2 Such headaches are almost invariably associated with papilloedema, and sometimes with vomiting which may lead to hyperventilation and reduction of ICP. In the UK, headache with vomiting and papilloedema is enshrined in Department of Health guidelines for urgent evaluation (the two-week rule), although in practice very few patients

Larner 81 referred under these guidelines have such features, or indeed cerebral tumours.3 In fact, any patient with all three features should be seen immediately, certainly not wait for even two weeks, because they may very well have raised ICP. So, are all morning headaches due to brain tumours with raised ICP? Clearly not, but neurologists are often referred patients with a history of nocturnal and/or awakening headachesquery raised ICP, in the apparent absence of other neurological symptoms and signs. The differential diagnosis is in fact quite broad (see box), encompassing not only intracranial hypertension but also a number of primary and secondary headache disorders, as well as general neurological, medical and psychiatric conditions.

PRIMARY HEADACHE DISORDERS Migraine

There is a circadian variation in migraine onset, with preferential (but not exclusive) onset in the night or early morning, between 04:00 h and 09:00 h.4 There is an older literature devoted to nocturnal migraine and early morning migraine, although there is no reason to believe that these forms differ from migraine at any other time of day.

and tearing (SUNCT).7 In both these conditions, attacks may occur throughout the 24-hour period.

Hemicrania continua
The precise nosological position of hemicrania continua is still debated. Although not

Differential diagnosis of nocturnal and/or awakening headaches

Raised intracranial pressure l Neoplasm l Intracranial hypertension secondary to hydrocephalus Primary headache disorders l Migraine l Trigeminal autonomic cephalalgias Cluster headache Paroxysmal hemicrania Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) l Hemicrania continua l Hypnic headache l Primary headache associated with sexual activity Secondary headache disorders l Medication-overuse headache l Hangover headache l Giant cell (temporal) arteritis l Sphenoid sinusitis l Carbon monoxide-induced headache l Subarachnoid haemorrhage Other disorders l Headache attributed to epileptic seizure l Sleep apnoea hypopnoea headache l Depression l Exploding head syndrome
www.practical-neurology.com

Trigeminal autonomic cephalalgias

Cluster headache, the most common of the trigeminal autonomic cephalalgias, is characterised not only by its unilaterality and associated autonomic symptoms and signs but also by its periodicity, the attacks often recurring at the same time of the day or night, with perhaps 50% of patients reporting attack onset during the night. For this reason, it is sometimes known as alarm clock headache (compare with hypnic headache below). Nocturnal cluster headache attack onset is said to be more predictable than daytime attack onset.5 Other disorders falling within the trigeminal autonomic cephalalgia category may also present with nocturnal attacks, but preponderance of nocturnal rather than daytime attacks is rare in both paroxysmal hemicrania6 and short-lasting unilateral neuralgiform headache attacks with conjunctival injection

82 Practical Neurology currently classified with the trigeminal autonomic cephalalgias in the International Headache Society schema (ICHD2),8 it has certain features in common with them, including autonomic manifestations and indomethacin responsiveness as seen in paroxysmal hemicrania. Pain is, by definition, daily and continuous, but exacerbations may occur and these frequently awaken the patient from sleep. domestic and occupational reasons, be restricted to certain times of the day, or more precisely, night.

SECONDARY HEADACHE DISORDERS Medication-overuse headache

The scenario of recurrent generalised headaches associated with escalating analgesic use, is perhaps one of the most familiar in the neurology clinic. Not infrequently there is a clear history of headache waking the patient during the night, often with the desire to consume further analgesics. My experience suggests that this is the most common cause of nocturnal headache seen in general neurology outpatient clinic practice, far exceeding either raised intracranial pressure or cluster headache, and on occasion being referred under the twoweek rule CNS/brain tumour guidelines.3

Hypnic headache
A defining characteristic of this rare primary headache disorder is onset during sleep, usually at a consistent time each night, between 01:00 h and 03:00 h, hence it too has sometimes been known as alarm clock headache (cluster headache is another alarm clock headache, see above). Recurrent attacks of headache occur, often in the middle or later stages of sleep, possibly emerging during REM sleep.9 The pathogenesis remains unknown but may be related to impaired inactivation of anti-nociceptive brain structures, such as the locus coeruleus which is normally inactivated during REM sleep. Differentiating factors from cluster headache include frequently bilateral headache, the absence of autonomic features, onset in later life, and female preponderance.10

Hangover headache
Diagnosis of hangover headache (delayed alcohol-induced headache is the preferred ICHD2 terminology8) should be obvious from the history.

Giant cell (temporal) arteritis

The headache associated with giant cell arteritis is acknowledged to be highly variable, but when present it is often persistent and worse at night,13 perhaps because of contact between the pillow and tender, inflamed scalp arteries.

Primary headache associated with sexual activity

The primary headache disorder associated with sexual activity, previously known as coital or orgasmic cephalalgia, may resemble subarachnoid haemorrhage at onset, although vomiting and loss of consciousness are very unusual. The patients are typically males. There are no specific data, but it would seem likely that most episodes occur during the evening or night hours (although the patients are clearly not asleep). The mean age of onset was 39 years in a series of patients attending a dedicated headache clinic,11 and the age range in a series presenting to general neurology clinics was 1956 years (mean 42 years).12 These data, admittedly from biased samples, suggest that it is generally not individuals in the first flush of sexual vigour but those of a certain maturity who are most likely to be both affected and to consult; a group whose sexual activities may, for various
10.1136/jnnp.2008.171140

Sphenoid sinusitis
Headache is the most common symptom of acute sphenoid sinusitis (or rhinosinusitis, as in the ICHD2 classification,8 as sinusitis in the absence of rhinitis is uncommon) often interfering with sleep. It is rare, particularly in isolation, and misdiagnosis common. The pain is severe, intractable, not specifically localised, sometimes aggravated by bending or coughing, not relieved by simple analgesics, and may be associated with facial pain. Diagnosis may be difficult because not all patients have pyrexia or purulent nasal discharge.14 As the condition has potential morbidity and mortality, it is very important not to miss it. Diagnostic investigations include CT, MRI and fibreoptic nasal endoscopy.

Larner 83

Carbon monoxide-induced headache

Classically carbon monoxide-induced headache has been described as a throbbing diffuse headache, but systematic studies have found this to be rare. In fact, the associated headache is very variable in nature, with no particular features allowing diagnosis or exclusion.15 Carbon monoxide-induced headache is seasonal, being more common in the winter months when (faulty) gas heating systems are in use, and cohabitants may also have headache. People in small enclosed spaces such as caravans and boats are particularly likely to be affected.

(and possibly right) temporal region. Before her follow-up appointment was due, the patient was found dead in bed one morning, perhaps as the consequence of a seizure. Other clues to the diagnosis of nocturnal seizures are waking up on the floor, and dishevelled bedclothes.

Obstructive sleep apnoea hypopnoea syndrome

Early morning headache has been cited as a feature of the obstructive sleep apnoea hypopnoea syndrome, presumably due to nocturnal hypercapnia secondary to alveolar hypoventilation with resultant intracranial vasodilatation. Although encountered on occasion in the neurology clinic,17 some authorities with extensive experience of this syndrome say early morning headache is in fact rare.18 Moreover, the situation may be confounded, because sleep disturbance is a migraine trigger and, possibly, by sleep apnoea per se being a risk factor for cluster headache.19

Subarachnoid haemorrhage
Onset of subarachnoid haemorrhage during sleep is extremely rare, if it occurs at all. The history here is critical, particularly whether the patient was actually asleep, because headache secondary to sexual activity enters the differential. Stroke apparent on awakening is more likely to be ischaemic than haemorrhagic.16

Depression
Early morning waking is one of the classic vegetative symptoms of depression, often in association with depressive thinking. Although headache is not a feature of depressive disorders as enshrined in the Diagnostic and Statistical Manual (DSM-IV) criteria, it should not be forgotten that this symptom is not uncommon in clinical practice. Moreover, mood disorders can complicate migraine and possibly chronic tension type headache, and hence need to be identified and treated in their own right.

OTHER DISORDERS Epilepsy

Nocturnal seizures may present with morning headache. Although the history should clearly indicate this diagnosis, absence of a bed partner may mean that the diagnosis is delayed, as exemplified by the case of a 65year-old single lady referred to my clinic with a diagnosis of migraine, who gave a five-year history of occasional (approximately monthly) headaches present only on waking and which gradually cleared over the course of the morning. She also mentioned that on occasion she had noticed blood on her pillow on headache mornings because she had bitten her tongue, and on two occasions she had wet the bed as well. The headache was an oppressive, dopey sensation precluding attendance at work, and sometimes associated with the need for daytime sleep. A provisional diagnosis of nocturnal (secondary generalised) seizures was made, but the patient declined antiepileptic drug treatment pending further investigation. The EEG was abnormal with predominantly left-sided slow wave activity, and occasional sharp wave discharges over both temporal regions, suggesting a potential epileptogenic focus in the left

PRACTICE POINTS
l

Patients with headaches which wake them during the night or are present on waking and improve after getting up, and who have associated papilloedema and vomiting, require immediate assessment because they may have raised intracranial pressure. Many other and more common conditions may also be associated with nocturnal or early morning headaches. The chronobiology of many primary headache disorders has a circadian pattern with preferential headache timing during the night or early morning, including migraine, cluster headache and hypnic headache. Medication overuse headache is a common cause of nocturnal headache, with the patient waking to consume more analgesia. Non-headache disorders such as depression and nocturnal epileptic seizures also enter the differential diagnosis.
www.practical-neurology.com

84 Practical Neurology Headache patients with depression (and anxiety) have greater functional impairment than those without.20
4. 5. Fox AW, Davis RL. Migraine chronobiology. Headache 1998;38:43641. Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study with diagnostic implications. Neurology 2002;58:35461. Kayed K, Godtlibsen OB, Sjaastad O. Chronic paroxysmal hemicrania IV: REM sleep locked nocturnal attacks. Sleep 1978;1:915. Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA): a prospective clinical study of SUNCT and SUNA. Brain 2006;129:274660. International Headache Society Classification Subcommittee. The international classification of headache disorders. Second edn. Cephalalgia 2004;24(Suppl 1):1160. Dodick DW, Mosek AC, Campbell JK. The hypnic (alarm clock) headache syndrome. Cephalalgia 1998;18:1526. Evers S, Goadsby PJ. Hypnic headache. Neurology 2003;60:9059. Frese A, Eikermann A, Frese K, et al. Headache associated with sexual activity. Demography, clinical features, and comorbidity. Neurology 2003;61:796800. Larner AJ. Late presentation of primary headache associated with sexual activity: is non-invasive angiography worthwhile? J Headache Pain 2006;7:13940. British Association for the Study of Headache. Guidelines for all healthcare professionals in the diagnosis and management of migraine, tensiontype, cluster and medication-overuse headache. BASH: London, 2007:17. Lew D, Southwick FS, Montgomery WW, et al. Sphenoid sinusitis: a review of 30 cases. N Engl J Med 1983;319:114954. Hampson NB, Hampson LA. Characteristics of headache associated with acute carbon monoxide poisoning. Headache 2002;42:2203. Wroe SJ, Sandercock P, Bamford J, et al. Diurnal variation in incidence of stroke: Oxfordshire community stroke project. BMJ 1992;304:1557. Larner AJ. Obstructive sleep apnoea syndrome presenting in a neurology outpatient clinic. Int J Clin Pract 2003;57:1502. Stradling JR. Sleep apnoea syndromes. In: Brewis RAL, Corrin B, Geddes DM, Gibson GJ, eds. Respiratory medicine. Second edn. WB Saunders: London, 1995:9731005. Rains JC, Poceta JS. Sleep-related headache syndromes. Semin Neurol 2005;25:6980. Page LA, Howard LM, Husain K, et al. Psychiatric morbidity and cognitive representations of illness in chronic daily headache. J Psychosom Res 2004;57:54955. Pearce JM. Clinical features of the exploding head syndrome. J Neurol Neurosurg Psychiatry 1989;52:90710. Wall M. The headache profile of idiopathic intracranial hypertension. Cephalalgia 1990;10:3315. Davenport R. Headache. Pract Neurol 2008;8:33543.

Exploding head syndrome

The precise nosological position of this condition is uncertain. It may be regarded as a physiological phenomenon in the transition from wakefulness to sleep, akin to nocturnal myoclonus. Although said to be quite common,21 it is seldom a presenting symptom in the neurology clinic.

6.

7.

8.

CONCLUSIONS
Although raised ICP is the most alarming possible cause of nocturnal and/or awakening headaches, the sensitivity and specificity of this symptom for the diagnosis of intracranial hypertension has not, to my knowledge, been systematically evaluated. ICHD2 lists only two categories in which headache worse in the morning is included among the diagnostic criteria, namely Headache attributed directly to neoplasm and Headache attributed to intracranial hypertension secondary to hydrocephalus.8 However, morning headaches may occur with other causes of raised ICP for example, the headache of idiopathic intracranial hypertension may awaken the patient at night.22 Nocturnal and/or awakening headache is clearly not a pathognomonic symptom for raised ICP, far from it. Many other headache disorders, some very common such as migraine, as well as other neurological and medical conditions enter the differential diagnosis. History taking is key to identifying them,23 and hence determining the most appropriate pathway for investigation (if any) and management.
9.

10. 11.

12.

13.

14.

15.

16.

17.

18.

ACKNOWLEDGEMENTS
This article was reviewed by David HiltonJones, Oxford, UK.

19. 20.

REFERENCES
1. 2. North B, Reilly P. Raised intracranial pressure. A clinical guide. Oxford: Heinemann, 1990:268. Cooper R, Hulme A. Intracranial pressure and related phenomena during sleep. J Neurol Neurosurg Psychiatry 1966;29:56470. Abernethy Holland AJ, Larner AJ. Central nervous system/brain tumour 2-week referral guidelines: prospective 3-year audit. Clin Oncol 2008;20:2012. 21.

22.

3.

23.

10.1136/jnnp.2008.171140