Hemicrania continua

INTRODUCTION — Hemicrania continua (HC) is a unilateral headache that is continuous in nature. HC belongs to the trigeminal autonomic cephalalgias (TACs), a group of idiopathic headache disorders characterized by unilateral headaches accompanied by ipsilateral cranial autonomic symptoms. Other TACs include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks.

Other types of chronic daily headache include chronic migraine, chronic tension-type headache, medication overuse headache, and new daily persistent headache and are reviewed separately. (See "Chronic daily headache: Associated syndromes, evaluation, and management".)

Other TACs are discussed elsewhere.

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

●(See "Paroxysmal hemicrania: Clinical features and diagnosis" and "Paroxysmal hemicrania: Treatment and prognosis".)

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

PATHOPHYSIOLOGY — The posterior hypothalamus, dorsal rostral pons, and trigeminal nociceptive pathways in the caudal brainstem play a role in the physiology of HC. A controlled positron emission tomography (PET) study of seven patients with HC showed significant activation of the contralateral posterior hypothalamus and ipsilateral rostral pons during baseline pain [1]. This activation was blocked by administration of intramuscular indomethacin.

It is hypothesized that the presence of cranial autonomic nervous system symptoms in HC is due, at least in part, to hypothalamic activation with secondary disinhibition of the trigeminal-autonomic reflex [2]. A similar mechanism may be implicated in cluster headache and the short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) headache syndromes. The exact role of the dorsal rostral pons in HC is unclear, but this region is also activated in migraine and may play a role in the inhibition of nociceptive traffic along the trigeminovascular system.

EPIDEMIOLOGY — The term "hemicrania continua" was coined in 1984 when the first cases were described [3]. The true frequency of HC in the general population is unknown as only about 1000 cases have been published in the literature [4]. However, HC accounts for up to 2 percent of patients with headache presenting to headache specialty or neurology clinics, suggesting the disorder may be more prevalent than previously considered [4,5].

HC tends to have onset in the fourth to sixth decades of life but with a range from the first to eighth decades [6]. The estimated female to male ratio is 2:1 [7].

CLINICAL FEATURES — As the name implies, HC is a unilateral headache that is continuous in nature, at least for the unremitting form. Additional common features of HC include cranial autonomic symptoms, a sense of restlessness or agitation during exacerbations, and responsiveness to indomethacin [5].

Most patients with HC have unremitting pain, but up to 20 percent have pain-free periods that can last for one day to several months [8]. Pain is most commonly located anteriorly in the orbit, frontal regions, and temporal regions, but pain in the occiput is not rare [9]. Involvement of other regions of the head and neck has also been described. Although pain is continuous, it fluctuates in severity with superimposed attacks of more severe pain. Pain exacerbations last from minutes to several days [10]. Pain intensity ranges from mild to severe, but the pain of HC is not as excruciatingly severe as the pain of cluster headache.

During episodes of superimposed severe pain, there is usually evidence of cranial autonomic activation, although some patients with HC do not report cranial autonomic symptoms [8,11]. The most common cranial autonomic features, in approximate order of frequency, are the following [8]:

●Lacrimation

●Nasal congestion

●Conjunctival injection

●Ptosis

●Forehead/facial flushing

●Rhinorrhea

●Forehead/facial sweating

●Eyelid edema

●Aural fullness

●Aural swelling

●Miosis

●Mydriasis

●Facial edema

●Dripping sensation at the back of the throat

Eye itching or a sense of ocular discomfort, as if there is something in the eye (termed the false foreign body sensation), is often reported by patients with HC [8,9,12]. The autonomic features of HC are generally less prominent than those seen with the other trigeminal autonomic cephalalgias (eg, cluster headache and paroxysmal hemicrania). (See "Cluster headache: Epidemiology, clinical features, and diagnosis" and "Paroxysmal hemicrania: Clinical features and diagnosis".)

Although mild migrainous features are occasionally present with the baseline continuous headache of HC, they are most often absent [13]. However, migrainous features, such as photophobia and phonophobia, are commonly present during the headache exacerbations of HC [6]. Less common clinical features that have been attributed to HC include a preceding aura, transition from episodic headaches (hemicrania episodica) to HC, side-alternating attacks, bilateral pain, and evolution from cluster headache [7,14,15]. Whether these are truly features of HC as opposed to similar headache disorders is uncertain.

Superimposed jabs and jolts (stabbing headache) occur frequently in patients with HC [6]. Thus, some patients with HC also have primary stabbing headache and would be diagnosed with both headache types.

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. (See "Primary stabbing headache".)

Absolute response to indomethacin therapy is required for the diagnosis of HC. This is discussed in greater detail below.

DIAGNOSIS — The diagnosis of HC is dependent upon the clinical features of the headache and the response to indomethacin. Diagnostic criteria (table 1), according to the International Classification of Headache Disorders, 3^rd edition (ICHD-3) are as follows [16]:

●(A) Unilateral headache

●(B) Present for more than three months, with exacerbations of moderate or greater intensity

●(C) 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 or aggravation of the pain by movement

●(D) Responds absolutely to therapeutic doses of indomethacin

●(E) Not better accounted for by another ICHD-3 diagnosis

The ICHD-3 classification includes two subtypes of HC, a remitting form and an unremitting form [16]. The remitting subtype of HC is characterized by pain that is not continuous but is interrupted by remission periods of at least 24 hours without treatment. The unremitting subtype of HC is characterized by continuous pain for at least one year without remission periods of at least 24 hours.

Despite the definition of HC, some patients with the clinical phenotype of HC do not respond to indomethacin [11,17]. A retrospective report from a tertiary headache center identified 165 patients seen from 1998 to 2007 with a putative diagnosis of HC who then had an adequate trial of indomethacin [17]. An absolute response to indomethacin was observed in only 43 patients (26 percent). Furthermore, no predictors for indomethacin response were identified. This included the presence of autonomic symptoms, which were present in 57 percent of indomethacin-responsive and 61 percent of indomethacin-nonresponsive patients.

The lack of predictors for indomethacin response led the investigators to suggest that all patients with continuous side-locked primary headaches receive an indomethacin trial (in the absence of contraindications to indomethacin) [17]. However, the strength of this finding and recommendation is limited by the retrospective study design and sample size.

Diagnostic indomethacin trial — As currently defined, the diagnosis of HC requires complete responsiveness to indomethacin [16]. Either oral or parenteral indomethacin (where available) can be used to confirm the diagnosis of HC.

●An oral indomethacin test can be used for the diagnosis of HC. Although there are variations in recommended titration schedules and doses, we start at 25 mg three times daily for three days, followed by 50 mg three times daily for three days, then 75 mg three times daily for three days as needed for headache resolution. Patients continue at the lowest effective dose. Completion of the test without headache resolution is considered a failed trial.

●Parenteral indomethacin given intramuscularly (the "indotest") has been used in clinical research as a standardized diagnostic test of HC [18]. The indotest can also be applied in clinical practice for patient diagnosis. However, parenteral indomethacin for this purpose is not available in the United States. The test involves administration of intramuscular (IM) indomethacin (50 to 200 mg) to a patient who otherwise meets the clinical criteria for HC; the high end of this dose range comes from the ICHD-3 [16]. In an open-label study of the indotest that included 12 patients with HC, administration of indomethacin 50 mg IM resulted in pain resolution after a mean interval from injection of 73 minutes [18]. This beneficial effect endured for a mean of 13 hours [18]. In four patients treated with indomethacin 100 mg IM, resolution of pain was noted after a mean of 61 minutes and the benefit endured for a mean of 13 hours. The indotest is also used for the diagnosis of paroxysmal hemicrania, another indomethacin-responsive primary headache disorder. (See "Paroxysmal hemicrania: Clinical features and diagnosis".)

Neuroimaging — We suggest performing a brain magnetic resonance imaging scan with contrast for all patients with suspected HC to exclude a structural brain lesion, particularly one involving the pituitary fossa. Even cases fitting all criteria for HC, including a complete response to indomethacin, can have a secondary etiology. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of primary HC (a strictly unilateral, continuous headache with superimposed exacerbations accompanied by autonomic features and migrainous symptoms) includes the following:

●Secondary hemicrania continua

●Chronic migraine

●Other trigeminal autonomic cephalalgias (TACs):

•Cluster headache

•The syndromes of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA)

•Paroxysmal hemicrania

Secondary hemicrania continua — There are case reports of headaches mimicking primary HC (including response to indomethacin) that are found to be secondary in nature [19-24]. Associated etiologies have included internal carotid or vertebral artery dissection [25,26], carotid cavernous fistula [27], pineal cyst [23], pituitary tumor [28], ipsilateral mesenchymal tumor of the sphenoidal bone involving the clinoid process at the base of the skull [20], lung adenocarcinoma [29], pontine stroke [21], nasopharyngeal carcinoma [30], and inflammatory orbital pseudotumor [31].

Secondary HC should always be considered since secondary HC can be clinically indistinguishable from primary HC. However, secondary HC is more likely when any of the following conditions are present:

●The clinical picture is atypical.

●There are associated neurologic signs.

●The treatment response is poor.

Chronic migraine — Chronic migraine, when strictly unilateral and side-locked, can be confused with HC. Autonomic features (eg, nasal congestion, rhinorrhea, lacrimation) can be associated with migraine headache, although they are typically less prominent than those seen with HC or other trigeminal autonomic cephalalgias. (See "Chronic migraine" and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

Other trigeminal autonomic cephalalgias — The TACs are a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with ipsilateral cranial autonomic features (eg, ptosis, miosis, lacrimation, conjunctival injection, rhinorrhea, and nasal congestion). Cluster headache, SUNCT and SUNA headache syndromes, and paroxysmal hemicrania are types of trigeminal autonomic cephalalgias that may occasionally be confused with HC (table 2).

●Cluster headache is characterized by attacks of severe unilateral orbital, supraorbital, or temporal pain accompanied by ipsilateral autonomic phenomena. Attacks usually last 15 to 180 minutes. In the episodic form, attacks occur daily, usually for weeks, followed by a period of remission. The chronic form of cluster headache lacks sustained remissions. (See "Cluster headache: Epidemiology, clinical features, and diagnosis".)

●SUNCT and SUNA are characterized by sudden brief attacks of severe unilateral head pain in orbital, periorbital, or temporal regions accompanied by ipsilateral cranial autonomic symptoms. The attack duration is 1 to 600 seconds, with at least 20 attacks per day. (See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis".)

●Paroxysmal hemicrania is characterized by unilateral, brief, and severe attacks of pain associated with ipsilateral cranial autonomic features that recur several times per day. The headache is most often in the ophthalmic trigeminal distribution and lasts 2 to 30 minutes. The mean attack frequency is 11 to 14 daily. The syndrome is exquisitely responsive to indomethacin. (See "Paroxysmal hemicrania: Clinical features and diagnosis".)

Features that help to distinguish HC from the other TACs include the following:

●By definition, headache attacks are short lasting with SUNCT and SUNA (≤10 minutes) and paroxysmal hemicrania (≤30 minutes), and even cluster attacks are usually relatively short lived (≤180 minutes). In contrast, the pain in HC is continuous.

●In general, the pain of HC is not as excruciatingly severe as the pain of other TACs.

TREATMENT — Indomethacin is the treatment of choice for HC. Because the diagnosis of HC requires complete responsiveness to indomethacin, patients with HC typically continue taking the medication after their diagnostic trial. (See 'Diagnosis' above.)

Indomethacin regimen — Among patients with HC, the response to indomethacin is generally quite fast once reaching the appropriate dose, although the appropriate dose varies.

Maintenance dosing — The initial therapeutic dose is that which results in resolution of headache during the diagnostic indomethacin trial. (See 'Diagnostic indomethacin trial' above.)

Sustained relief, which may be achieved at a lower maintenance dose, may help to minimize potential adverse effects [16]. In a retrospective study, 16 adults with HC were started on indomethacin (25 mg every eight hours), and the dose was adjusted up or down as needed after two weeks [32]. Complete symptomatic relief was achieved with a mean indomethacin dose of 78 mg (± 22 mg) daily. Seven patients were able to reduce the dose by a significant 56 percent, eight did not have any significant dose change, and one required a dose increase from 75 to 100 mg daily.

Weaning — Because sustained resolution during treatment may represent remission, patients should consider a trial of discontinuation of therapy [33]. Trial of weaning after a six-month interval is reasonable [32]. However, long-term treatment with indomethacin is often required due to recurrence of HC symptoms when doses of indomethacin are reduced.

Relapse of symptoms may occur in some within days to weeks [34]; patients may be able to resume prior effective maintenance dose. In a prospective study, 12 patients with HC discontinued indomethacin until headache recurred [35]. Oral indomethacin was then restarted, based upon prior dose, at either 25 or 50 mg every eight hours until complete resolution of pain. The cumulative amount of indomethacin necessary to abort pain ranged from 25 to 150 mg. Complete pain relief was obtained within 8, 24, and 48 hours in 9, 10, and 12 patients, respectively.

Side effects — Potential side effects from indomethacin include the development of peptic ulcers, bleeding from platelet inhibition, exacerbation of anemia, hepatic dysfunction, renal dysfunction, exacerbation of hypertension, exacerbation of congestive heart failure, dizziness, and others. These issues are discussed elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects".)

To minimize risk of gastrointestinal side effects, we suggest using the lowest effective maintenance dose. For patients with a history of peptic ulcer disease, we suggest using gastroprotection with proton pump inhibitors, H2-receptor antagonists, or (less often) misoprostol. Evidence to support this is discussed separately.

As an alternative, indomethacin suppositories are occasionally helpful if gastric intolerance is a major problem or when high doses, such as 300 mg daily, are required. These issues are discussed separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Alternative agents — Contraindications to treatment with indomethacin or discontinuation due to intolerance limits its usage in HC.

There are case reports of improvement with several medications including cyclooxygenase-2 inhibitors, gabapentin, melatonin, topiramate, galcanezumab, and verapamil [36-41]. A 2017 review highlighted piroxicam and celecoxib as beneficial for acute treatment and additionally included topiramate and gabapentin for maintenance treatment [42]. However, the actual benefit of each of these treatments should be considered unknown until larger studies are available.

In addition, therapeutic benefit has been reported with several locally invasive neuromodulatory procedures:

●OnabotulinumtoxinA [43,44]

●Greater occipital nerve blocks [8]

●Occipital nerve stimulation [45]

●Sphenopalatine ganglion blocks or ablation [46,47]

●Vagus nerve stimulation [7,43,48-54]

If multiple agents fail to provide substantial or sustained relief, reevaluation to consider secondary HC or another headache condition is warranted (see 'Differential diagnosis' above). Referral to a specialized center with expertise in treating these conditions, such as The American Migraine Foundation, can be considered.

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

●Clinical features – Hemicrania continua (HC) is a strictly unilateral, persistent headache with superimposed exacerbations of moderate to severe intensity that is typically associated with ipsilateral cranial autonomic symptoms, a sense of restlessness or agitation during exacerbations, and responsiveness to indomethacin. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of HC is dependent upon the clinical features of the headache and the response to indomethacin (table 1). (See 'Diagnosis' above.)

•Either oral or parenteral indomethacin (where available) can be used to confirm the diagnosis of HC. (See 'Diagnostic indomethacin trial' above.)

•For patients with suspected HC, we suggest performing a brain magnetic resonance imaging scan to exclude a structural brain lesion. (See 'Neuroimaging' above.)

●Differential diagnosis – The differential diagnosis of primary HC includes secondary HC, chronic migraine, cluster headache, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) headache syndromes, and paroxysmal hemicrania (table 2). (See 'Differential diagnosis' above.)

●Treatment – Indomethacin is the treatment of choice for HC, which is defined by its responsiveness to this drug. Gastroprotection with proton pump inhibitors reduces the risk of gastrointestinal side effects. When indomethacin treatment is not tolerated, trials of alternative agents are reasonable. (See 'Treatment' above.)