Paroxysmal hemicrania: Clinical features and diagnosis

INTRODUCTION — The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with ipsilateral cranial autonomic features [1,2]. The TACs include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua [3].

This topic will review the epidemiology, clinical features, and diagnosis of paroxysmal hemicrania. Management and prognosis are reviewed separately. (See "Paroxysmal hemicrania: Treatment and prognosis".)

Other trigeminal autonomic cephalalgias are discussed elsewhere.

●(See "Cluster headache: Epidemiology, clinical features, and diagnosis" and "Cluster headache: Treatment and prognosis".)

●(See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis" and "Short-lasting unilateral neuralgiform headache attacks: Treatment and prognosis".)

●(See "Hemicrania continua".)

HISTORICAL ASPECTS — Paroxysmal hemicrania was first described in 1974 [4]. The initial cases were characterized by daily headaches for years without remission, and the condition was termed "chronic paroxysmal hemicrania" [5]. Subsequently, it became apparent that not all patients experienced a chronic, unremitting course; in some patients, discrete headache bouts were separated by prolonged pain-free remissions [1,6-11]. This remitting pattern was named episodic paroxysmal hemicrania.

EPIDEMIOLOGY — Paroxysmal hemicrania is a rare condition. The exact incidence and prevalence of paroxysmal hemicrania are not known, but it has been reported in various parts of the world [12-14] and affects different races [15,16].

By one estimate, the prevalence of paroxysmal hemicrania is 1 to 3 percent of the prevalence of cluster headache [17]. Given that the prevalence of cluster headache is approximately 1 per 500 [18], the prevalence of paroxysmal hemicrania would be approximately 1 per 25,000. However, epidemiologic data are scarce and many cases of paroxysmal hemicrania are probably still overlooked.

In a headache epidemiology study of 1838 adults from Norway, no definite cases of paroxysmal hemicrania were confirmed, although a possible variant of chronic paroxysmal hemicrania was identified in one individual (0.05 percent) [19]. In contrast, cluster headache was identified in seven (0.4 percent) [20].

Sex distribution — Retrospective surveys suggested a female predominance in paroxysmal hemicrania [17,21,22], but a later prospective study found that the female-to-male ratio is approximately 1 to 1 [23].

Age of onset — Paroxysmal hemicrania may begin at any age, although onset usually occurs during adulthood. The mean age of onset ranges from 34 to 41 years [17,22,23]. The youngest age at onset was one year and the oldest was 81 years [17,24]. In one case series, episodic paroxysmal hemicrania began earlier (mean 27 years) than chronic paroxysmal hemicrania (mean 37 years) [17].

CLINICAL FEATURES — The clinical phenotype of paroxysmal hemicrania is highly characteristic [17,21,22,25,26]. Patients typically have unilateral, brief, severe attacks of pain associated with cranial autonomic features that recur several times per day.

Character and location of pain — The pain of paroxysmal hemicrania is typically excruciating in severity and most often described with the terms sharp, stabbing, throbbing, shooting, burning, or boring [23].

The headache is strictly unilateral. It occurs without side shift in >95 percent of patients [23].The pain is most often in the ophthalmic trigeminal distribution (V1), but it can be extratrigeminal. The maximum pain is usually centered on the orbital, retroorbital, temporal, and frontal regions. Less often, the pain involves the occipital region, maxillary region, neck, ear, and teeth [23]. The pain may occasionally radiate into the ipsilateral shoulder and arm [17].

Associated symptoms — Attacks of paroxysmal hemicrania typically occur in association with ipsilateral cranial autonomic features.

●Lacrimation, conjunctival injection, rhinorrhea, nasal congestion, ptosis, or facial flushing frequently accompany the headache [23].

●Eyelid edema, forehead or facial sweating, aural fullness, aural swelling, miosis, or mydriasis are less frequently reported [23].

Photophobia and nausea may accompany some attacks, though vomiting and phonophobia are rare [17]. In a retrospective study of patients with chronic paroxysmal hemicrania, at least one migrainous feature of photophobia, nausea, or vomiting during an attack was present in 27 of 31 patients (87 percent) [22]. In a prospective study, photophobia accompanying chronic paroxysmal hemicrania was unilateral and on the same side as the pain in four of six patients [27]. Similarly, photophobia was unilateral in approximately one-half of patients with other trigeminal autonomic cephalalgias. In contrast, photophobia associated with migraine was unilateral in less than 10 percent of cases.

Agitation and pacing are often present during attacks of paroxysmal hemicrania. A prospective study of 31 patients found that agitation or restlessness was present in 25 patients (80 percent) during episodes of pain, while eight subjects (25 percent) were aggressive, more often verbally than physically [23]. In an earlier retrospective study, approximately one-half of patients with paroxysmal hemicrania attacks assumed the pacing activity usually seen with cluster headaches, while the other half preferred to sit or lie still [17].

Temporal features — Paroxysmal hemicrania attacks are typically brief, lasting several minutes, but may recur several times each day.

●Duration of the individual attacks — The headache usually lasts 2 to 30 minutes but may go on for up to two hours.

•In a prospective study of 105 attacks, the mean duration was 13 minutes, with a range of 3 to 46 minutes [25,28].

•Another prospective study of 31 patients reported a mean duration of 17 minutes, with a range of 10 seconds to 4 hours [23].

•Two retrospective studies, consisting of 84 and 74 patients, reported mean attack durations of 21 minutes (range 2 to 120 minutes) and 26 minutes, respectively [17,22].

The headache has an abrupt onset and cessation. Interictal discomfort or pain is present in up to one-third of patients [17].

●Frequency and periodicity of attacks — In paroxysmal hemicrania, the attacks tend to occur at a high frequency, with a range from 1 to 40 daily.

•In a prospective study of 31 patients, the mean attack frequency was 11 (range 2 to 50) in 24 hours [29]. An earlier prospective study of 105 paroxysmal hemicrania attacks in five patients reported a mean attack frequency of 14 (range 4 to 38) [28].

•In two retrospective studies consisting of 84 and 74 patients, the mean attack frequency was 11 (range 2 to 40) and 6 daily, respectively [17,22].

The attacks occur regularly throughout the 24-hour period without a preponderance of nocturnal attacks as is seen in cluster headache. However, nocturnal attacks associated with the rapid eye movement (REM) phase of sleep have been described [30].

Attacks frequently recur continuously or with brief remissions, but some patients may have episodic bouts with remissions lasting for months or years. (See 'Chronic and episodic forms' below.)

Triggers — Most attacks of paroxysmal hemicrania are spontaneous. However, a number of attack triggers have been reported. In a prospective report of 31 patients, the most common triggers of paroxysmal hemicrania attacks were stress or relaxation after stress in eight patients (26 percent), exercise in seven (23 percent), alcohol in six (19 percent), and neck movement in six (19 percent) [23]. Cutaneous triggering, such as touching the skin, chewing, or talking, is uncommon with paroxysmal hemicrania [23].

The relationship between menstruation and paroxysmal hemicrania attacks, if any, is undetermined. Oral contraceptive medications do not seem to influence the attack frequency. In some case series, paroxysmal hemicrania attacks improved or disappeared during pregnancy but reappeared after delivery [31,32]. There is no reported effect of menopause.

Atypical features — There are case reports documenting unusual clinical features of paroxysmal hemicrania, including the following:

●Side-alternating attacks [33-36].

●Bilateral, short-lasting, frequent, indomethacin-responsive headaches without cranial autonomic features [37-39]. While these cases were reported as bilateral paroxysmal hemicrania, they may instead represent bilateral paroxysmal cephalalgia, a novel indomethacin-responsive primary headache syndrome [40].

●Unilateral paroxysmal hemicrania with no autonomic features [33,34,41] and other cases of paroxysmal hemicrania with dissociation between pain and autonomic features [36,42]. Alternatively, it is possible that current criteria do not recognize the breadth of cranial autonomic features that may be associated with paroxysmal hemicrania. As an example, the sense of aural fullness reported by two patients [41] may be part of the spectrum of symptoms associated with cranial parasympathetic autonomic activation [23].

●Paroxysmal hemicrania manifested by ear pain and a sensation of external acoustic meatus obstruction and paroxysmal hemicrania associated with red ear syndrome [41]. The red ear syndrome is a rare condition characterized by otalgia and associated autonomic phenomena, including cutaneous erythema of the ear ipsilateral to the pain [43,44].

●Primarily extratrigeminal pain with paroxysmal hemicrania [45,46].

●Typical migrainous aura occurring in association with paroxysmal hemicrania attacks [42].

Comorbidity — Paroxysmal hemicrania has been observed in association with other headache disorders, including the following:

●Trigeminal neuralgia [47-52] (see "Trigeminal neuralgia")

●Cluster headache [13,53-55] (see "Cluster headache: Epidemiology, clinical features, and diagnosis")

●Migraine [22,56,57] (see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults")

●Tension-type headache [22] (see "Tension-type headache in adults: Etiology, clinical features, and diagnosis")

●Primary stabbing headache [58] (see "Primary stabbing headache")

●Primary cough headache [59] (see "Primary cough headache")

●Hemicrania continua [60] (see 'Hemicrania continua' below)

Typically, each type of headache must be treated for the patient to be headache free. Exceptions are primary stabbing headache and primary cough headache, which are also responsive to indomethacin.

DIAGNOSIS AND EVALUATION — The diagnosis of paroxysmal hemicrania is based upon a compatible clinical history in the setting of a normal neurologic examination. The diagnosis is confirmed by an optimum response to a therapeutic trial of indomethacin. (See 'Indomethacin trial' below.)

In addition, we suggest performing a magnetic resonance imaging (MRI) of the brain with gadolinium contrast in all patients with paroxysmal hemicrania to exclude a structural brain lesion [61]. (See 'Neuroimaging' below.)

Diagnostic criteria — For the diagnosis of paroxysmal hemicrania, the International Classification of Headache Disorders, 3^rd edition (ICHD-3) requires fulfilling all of the following criteria (table 1) [3]:

●At least 20 attacks

●Severe unilateral orbital, supra-orbital, and/or temporal pain lasting 2 to 30 minutes

●Either or both of the following:

(1) At least one of the following symptoms or signs, ipsilateral to the headache:

-Conjunctival injection and/or lacrimation

-Nasal congestion and/or rhinorrhea

-Eyelid edema

-Forehead and facial sweating

-Miosis and/or ptosis

(2) A sense of restlessness or agitation

●Attacks have a frequency >5 per day for more than half of the active time course

●Prevented absolutely by therapeutic doses of indomethacin

●Not better accounted for by another ICHD-3 disorder

Chronic and episodic forms — Paroxysmal hemicrania is further classified depending on the presence of a remission period [3]:

●Chronic paroxysmal hemicrania (CPH) – Persistent symptoms with no remission within one year or brief remissions that last less than three months. CPH represents approximately 80 percent of patients with paroxysmal hemicrania.

●Episodic paroxysmal hemicrania (EPH) – Characterized by recurrent bouts, each with a duration of seven days to one year (when untreated), separated by pain-free remissions lasting three months or longer. EPH occurs in 20 percent of patients with paroxysmal hemicrania.

In EPH, the typical duration of the headache bout ranges from two weeks to four and a half months; remission periods range from 1 to 36 months [21]. EPH has been reported to stay episodic for up to 35 years [17]. EPH can evolve into typical CPH and vice versa. Notably in paroxysmal hemicrania, the chronic form dominates the clinical presentation. Approximately one-quarter of the CPH cases evolve from EPH, while the remaining three-quarters are chronic from onset [17].

Indomethacin trial — We recommend a therapeutic trial of oral indomethacin for patients with active paroxysmal hemicrania who do not have a contraindication. In patients who do not respond to an optimum trial of indomethacin, the diagnosis of paroxysmal hemicrania should be reconsidered. Paroxysmal hemicrania responds in a dramatic and absolute fashion to indomethacin, thereby underlining the importance of distinguishing it from cluster headache and the syndrome of short-lasting unilateral neuralgiform headache attacks, both of which are not responsive to indomethacin [62,63]. (See "Short-lasting unilateral neuralgiform headache attacks: Treatment and prognosis".)

The existence of indomethacin-insensitive paroxysmal hemicrania is controversial, but some patients who have clinical symptoms consistent with paroxysmal hemicrania do not respond to indomethacin [22,64].

Regimen

●Typical dosing – The starting dose of indomethacin is 75 mg daily in three divided doses (ie, 25 mg three times a day). The indomethacin dose should be increased to 150 mg daily in three divided doses for 3 to 10 days if there is no response or a partial response to the starting dose after three days. The dose should be further increased to 225 mg daily in three divided doses for 10 days for partial responders if the index of suspicion is high.

Complete resolution of the headache is usually prompt, occurring within one to two days of initiating the effective dose, though we have a patient who required 10 days to respond completely to indomethacin (unpublished observation). It is therefore worth considering prolonging the administration of the maximum indomethacin dose to 10 days.

●Parenteral dosing option – Where available, parenteral indomethacin given intramuscularly has been proposed as a diagnostic test (the "indotest") for paroxysmal hemicrania. Two open-label studies of intramuscular indomethacin (100 mg) in six and seven patients reported complete pain relief for a mean of 11.1±3.5 and 13.4±7.7 hours, respectively [65,66].

The indotest has the advantage that the diagnosis can be rapidly established, although it needs further validation at this stage with placebo-controlled trials. Intramuscular indomethacin is not available in some countries, including the United States.

Utility of trial for other trigeminal autonomic cephalalgias — It could be advocated that all patients diagnosed with trigeminal autonomic cephalalgias (table 2) who do not have a contraindication to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) should have a trial of indomethacin at the start of treatment to detect the indomethacin-sensitive group, at least until a reliable biologic marker becomes available. However, the diagnostic yield will be low, since paroxysmal hemicrania is rare. In addition, this approach will delay appropriate treatment by one to two weeks in patients with cluster headache, unless there is access to the indotest. (See 'Indomethacin trial' above.)

The alternative approach is to consider an indomethacin trial only in patients with a high likelihood of having paroxysmal hemicrania. We routinely perform a trial of indomethacin in patients with trigeminal autonomic cephalalgias having more than five attacks daily or attacks lasting less than 30 minutes or both. In addition, we consider such a trial in patients with chronic trigeminal autonomic cephalalgias (before committing them to potentially multiple trials of treatment if paroxysmal hemicrania is missed) and patients with cluster headache who are refractory to usual cluster headache treatments.

Pathophysiologic rationale — What is the basis of the robust effect of indomethacin in paroxysmal hemicrania? Though various hypotheses have been proposed to account for the efficacy of indomethacin in certain primary headache syndromes, its mechanism and site of action remain unclear.

This engenders the question as to whether paroxysmal hemicrania (and hemicrania continua) always demonstrate a robust response to indomethacin and, therefore, can be classified on the basis of this specific treatment response. Though the current classification criteria require an absolute response to indomethacin for diagnosis [3], this is problematic for several reasons [63,67]:

●The therapeutic response in patients with paroxysmal hemicrania or hemicrania continua is not exclusive to indomethacin; a variety of other medications have been reported to be effective.

●A response to indomethacin is not specific to paroxysmal hemicrania or hemicrania continua; other primary headache syndromes also demonstrate a robust, albeit less consistent, response to indomethacin.

●Patients have been described who had the clinical phenotype of paroxysmal hemicrania or hemicrania continua but did not respond to indomethacin. This raises the possibility that there is a subset of patients with the underlying biology and clinical phenotype of these syndromes who do not respond to indomethacin. Alternatively, the indomethacin-resistant cases do not represent true paroxysmal hemicrania or hemicrania continua if the mode of action of indomethacin involves interrupting the central pathogenetic mechanism of these syndromes.

These considerations highlight the importance of understanding the mechanism of action of indomethacin and the pathophysiologic basis of these disorders.

So what special feature of the pharmacology of indomethacin accounts for its specific effect in these headache syndromes? Similar to other NSAIDs, indomethacin is a potent reversible inhibitor of prostaglandin-forming cyclooxygenase (COX). However, the mechanism of action of indomethacin in paroxysmal hemicrania and hemicrania continua seems to be independent of an effect on prostaglandin synthesis, since other NSAIDs or COX-2 inhibitors appear to have a poor, partial, or inconsistent effect in these disorders. Although indomethacin shows selectivity for COX-1 over COX-2 inhibition, aspirin and piroxicam are equally potent COX-1 inhibitors and yet do not have as robust a treatment effect on these disorders [68].

The description of plasma protein extravasation into the dura mater of the rat after stimulation of the trigeminal ganglion led to the suggestion that this form of neurogenic inflammation may be partly responsible for the maintenance of head pain in primary neurovascular syndromes [69]. Plasma protein extravasation can be blocked by indomethacin but also by aspirin, triptans, ergots, gamma-aminobutyric acid agonists, glucocorticoids, and substance P antagonists, thereby making it unlikely to be the mechanism of action of indomethacin in the indomethacin-responsive headache syndromes [70-72]. Moreover, the potent inhibition of plasma protein extravasation by triptans [73] contrasts with its rather indifferent effect in paroxysmal hemicrania and hemicrania continua.

The neuropeptide calcitonin gene-related peptide (CGRP) is expressed in the trigeminovascular system and is a marker of trigeminal nociception. It is released in primary headache syndromes such as migraine, cluster headache, and PH, and levels normalized following successful treatment with indomethacin [74].

Indomethacin has also been shown to inhibit the production of nitric oxide [75]. Nitric oxide plays a critical role in the neurogenic control of the cerebral circulation and has been implicated in the pathogenesis of primary neurovascular headaches, including the trigeminal autonomic cephalalgias [76]. While other NSAIDS inhibit neurogenic induced vasodilation, an in vivo study in mice found that only indomethacin was able to inhibit nitric oxide-induced vasodilation, thus distinguishing it from naproxen and ibuprofen [77]. As discussed separately, the pathophysiology of the trigeminal autonomic cephalalgias revolves around the trigeminal-autonomic reflex. (See "Pathophysiology of the trigeminal autonomic cephalalgias".)

The facial (cranial nerve VII) cranial parasympathetic outflow ganglia, sphenopalatine, and otic ganglia contain nitric oxide synthase, and nitric oxide generation is involved in the vasodilator responses of this system [78]. Nitric oxide is colocalized with vasoactive intestinal peptide [78,79], a neuropeptide that is markedly increased during an attack of paroxysmal hemicrania and normalized after treatment with indomethacin [74]. Thus, indomethacin may antagonize one or more steps in the nitric oxide pathway and, in this way, exert its effect on disorders characterized by activation of the cranial parasympathetic system. However, if this is the mechanism and site of action of indomethacin, then it remains unclear why it is ineffective for cluster headache and for the syndrome of short-lasting unilateral neuralgiform headache attacks. Another possibility that demands further study is that indomethacin may also act by inhibiting central nitrergic mechanisms.

Several studies in animals, normal volunteers, and patients with traumatic brain edema have demonstrated that indomethacin lowers intracranial pressure, improves cerebral perfusion pressure, and causes a substantial dose-related reduction of the cerebral blood flow [80-83]. However, this mechanism of action of indomethacin is unlikely to be the mode of action in paroxysmal hemicrania and hemicrania continua; there is no pathophysiologic evidence that these headaches are caused by disordered intracranial pressure.

Neuroimaging — Since a relatively high number of secondary cases of paroxysmal hemicrania have been reported, we suggest a brain MRI with gadolinium for all patients with paroxysmal hemicrania to exclude a structural brain lesion, particularly one involving the pituitary fossa [61]. Even cases fitting all criteria for paroxysmal hemicrania, including a complete response to indomethacin, can have a potential secondary etiology.

Additional testing for patients with atypical features — Further investigations are required when features are atypical to evaluate for secondary paroxysmal hemicrania. These features include:

●Atypical character or pain or temporal features.

●Abnormal neurologic signs on examination.

●Response to indomethacin is poor, or dose is escalating for symptom management.

In such cases, in addition to an appropriate initial neuroimaging study that adequately evaluates the pituitary fossa, we also recommend the following investigations:

●Pituitary function tests

●Complete blood count

●Vasculitis laboratory screening (see "Overview of and approach to the vasculitides in adults")

●Lumbar puncture (including opening pressure to assess for intracranial hypertension, even in the face of response to indomethacin, particularly if the pain becomes bilateral)

●Chest radiograph (eg, to assess for a Pancoast tumor)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of strictly unilateral, brief but frequent headaches is:

●Paroxysmal hemicrania (primary and secondary forms)

●Cluster headache

●The syndrome of short-lasting unilateral neuralgiform headache attacks

●Trigeminal neuralgia

●Primary stabbing headache

One-third of patients with paroxysmal hemicrania report interictal pain. In such cases, hemicrania continua should be considered in the differential diagnosis.

Secondary paroxysmal hemicrania — Secondary (symptomatic) paroxysmal hemicrania is relatively common and can be associated with diverse pathologic processes at various sites, including the following:

●Vascular

•Following coil embolization of a supraclinoid carotid artery aneurysm [84]

•Cerebral arteriovenous malformation [85]

•Middle cerebral artery territory infarction [85]

•Occipital infarction [86]

●Tumors

•Pituitary adenoma [22,87,88]

•Frontal lobe tumor [89]

•Gangliocytoma of the sella turcica [90]

•Cavernous sinus meningioma [91]

•Petrous ridge meningioma [22]

•Intracranial parotid carcinoma metastases [92,93]

•Pancoast tumor [94]

•Tuber cinereum hamartoma [21]

●Miscellaneous

•Collagen vascular disease [89]

•Essential thrombocythemia [95]

•Intracranial hypertension [96]

•Maxillary cyst [87]

•Ophthalmic herpes zoster [97]

•Post-traumatic [42]

•Medication adverse effect (eg, phosphodiesterase inhibitors) [98]

Even cases fitting all criteria for paroxysmal hemicrania, including a complete response to indomethacin, can have a potential secondary etiology. Thus, we suggest neuroimaging for all patients with suspected paroxysmal hemicrania [61].

Cluster headache — There is a considerable overlap in the clinical phenotype of paroxysmal hemicrania and cluster headache; both are strictly unilateral and relatively brief but frequent headaches that occur in association with ipsilateral cranial autonomic features. (See "Cluster headache: Epidemiology, clinical features, and diagnosis".)

Paroxysmal hemicrania differs from cluster headache because of its female predominance, shorter duration of headaches, more frequent attacks, and the absolute response to indomethacin. The episodic form of headache attacks are more common in cluster headache. In addition, circannual periodicity does not appear to be a feature of EPH, though three cases with seasonal onset have been described [10,11,46]. However, the utility of these features to distinguish paroxysmal hemicrania from cluster headache is limited by the considerable overlap of these characteristics in the two syndromes.

Mistaking paroxysmal hemicrania for cluster headache is problematic since generally treatments for cluster headache are not effective for paroxysmal hemicrania. The possible role of an indomethacin trial in the diagnosis of trigeminal autonomic cephalalgias is discussed above. (See 'Utility of trial for other trigeminal autonomic cephalalgias' above.)

Short-lasting unilateral neuralgiform headache attacks — The syndrome of short-lasting unilateral neuralgiform headache attacks is divided into two subtypes:

●Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)

●Short-lasting unilateral neuralgiform headache attacks with cranial autonomic features (SUNA)

These headaches differ from paroxysmal hemicrania with regard to attack duration, temporal distribution of attacks, attack triggers, sex preponderance, and response to indomethacin (table 2). (See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis".)

Ophthalmic division trigeminal neuralgia — Trigeminal neuralgia attacks involving the first division (ophthalmic or V1) of the trigeminal nerve generally last less than five seconds, with durations longer than 30 seconds being very rare [99]. The attacks are accompanied by sparse or no autonomic features [29]. Ophthalmic division trigeminal neuralgia attacks are typically precipitated by stimuli within the trigeminal-innervated distribution. Some patients with paroxysmal hemicrania exhibit precipitation mechanisms acting on the nuchal and cervical areas, but no trigeminal trigger zones have been described. Trigeminal neuralgia typically responds well to carbamazepine. (See "Trigeminal neuralgia".)

Primary stabbing headache — Primary stabbing headache refers to brief, sharp, or jabbing pain in the head that occurs either as a single episode or in brief repeated volleys. The pain is usually over the ophthalmic trigeminal distribution, while the face is generally spared. The pain usually lasts a fraction of a second but can persist for up to one minute and recurs at irregular intervals (hours to days). The attacks commonly subside with the administration of indomethacin [100]. (See "Primary stabbing headache".)

These headaches are generally easily distinguishable clinically as they differ in several respects: in primary stabbing headache, the site and radiation of pain often varies between attacks, the attacks are very brief, and cranial autonomic features are absent.

Hemicrania continua — Hemicrania continua is a strictly unilateral, continuous headache of mild to moderate intensity, with superimposed exacerbations of moderate to severe intensity that are accompanied by trigeminal autonomic features and migrainous symptoms. The syndrome is exquisitely responsive to indomethacin. (See "Hemicrania continua".)

Differentiating hemicrania continua and paroxysmal hemicrania, when the latter has interictal pain, can be particularly problematic. Some clinical features can help:

●Interictal pain in paroxysmal hemicrania is usually described as mild only, whereas background pain in hemicrania continua is often moderate (although it can be mild).

●Exacerbations in paroxysmal hemicrania are short-lasting, whereas those in hemicrania continua are longer, often lasting several hours.

●The severity of pain during exacerbations is excruciating in paroxysmal hemicrania, whereas it is often moderate or severe in hemicrania continua.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Paroxysmal hemicrania is an uncommon-type trigeminal autonomic cephalalgia (table 2). Paroxysmal hemicrania may begin at any age, although onset usually occurs during adulthood. (See 'Epidemiology' above.)

●Clinical features – Patients with paroxysmal hemicrania characteristically have unilateral, brief, severe attacks of pain associated with cranial autonomic features that recur several times per day. (See 'Clinical features' above.)

•The headache is strictly unilateral, most often in the ophthalmic trigeminal distribution. The headache usually lasts 2 to 30 minutes but may persist for up to two hours. The mean attack frequency is 11 to 14 daily.

•Ipsilateral cranial autonomic features, such as lacrimation, conjunctival injection, nasal congestion, or rhinorrhea, frequently accompany the headache; eyelid edema, ptosis, miosis, and facial sweating are less frequent.

●Diagnostic evaluation – The diagnosis of paroxysmal hemicrania is based upon a compatible clinical history in the setting of a normal neurologic examination (table 1). The diagnosis is confirmed by an optimum therapeutic trial of indomethacin once structural causes have been excluded with neuroimaging. (See 'Diagnosis and evaluation' above.)

•Indomethacin trial – For patients with active paroxysmal hemicrania who do not have contraindication, we recommend a therapeutic trial of oral indomethacin. Complete resolution of the headache is usually prompt, occurring within one to two days of initiating the effective dose. (See 'Indomethacin trial' above.)

•Neuroimaging – For all patients with suspected paroxysmal hemicrania, we suggest magnetic resonance imaging of the brain with gadolinium to exclude a structural brain or pituitary lesion. (See 'Neuroimaging' above.)

•Additional testing for atypical cases – Laboratory and other diagnostic testing is generally reserved for patients with atypical symptoms, abnormal neurologic examination, or poor response to indomethacin. These include (see 'Additional testing for patients with atypical features' above):

-Pituitary function tests

-Complete blood count

-Vasculitis laboratory screen

-Lumbar puncture

-Chest radiograph

●Differential diagnosis – The differential diagnosis of strictly unilateral, brief but frequent headaches is (see 'Differential diagnosis' above):

•Primary and secondary forms of paroxysmal hemicrania

•Cluster headache

•The syndrome of short-lasting unilateral neuralgiform headache attacks

•Trigeminal neuralgia

•Primary stabbing headache