Hemicrania continua

Hemicrania continua is an indomethacin-responsive primary headache disorder which is characterized by a continuous and strictly unilateral headache, with cranial autonomic symptoms and agitation during the episodes of pain exacerbation ¹. Hemicrania continua is currently classified under the heading of trigeminal autonomic cephalalgias, along with cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms ¹.

Hemicrania continua is a highly misdiagnosed and underreported primary headache ². The pooled mean delay of diagnosis of hemicrania continua is 8.0 ± 7.2 years. It is not rare with more than 1000 cases reported in the literature ². Hemicrania continua represents 1.7% of total headache patients attending headache or neurology clinic. Just like other trigeminal autonomic cephalalgias, it is characterized by strictly unilateral pain in the trigeminal distribution, cranial autonomic features in the same area and agitation during exacerbations/attacks. Hemicrania continua is different from other trigeminal autonomic cephalalgias in one aspect. While all other trigeminal autonomic cephalalgias are episodic, hemicrania continua patients have continuous headaches with superimposed severe exacerbations. The central feature of hemicrania continua is continuous background headache. However, the patients may be worried only for superimposed exacerbations. Focusing only on exacerbations and ignoring continuous background headache are the most important factors for the misdiagnosis of hemicrania continua. A large number of patients may have migrainous features during exacerbation phase. Up to 70% patients may fulfill the diagnostic criteria for migraine during exacerbations. Besides migraine, its exacerbations can mimic a large number of other primary and secondary headaches. The other specific feature of hemicrania continua is a remarkable response to indomethacin. However, a large number of patients develop side effects because of the long-term use of indomethacin ². A few other medications may also be effective in a subset of patients with hemicrania continua. Various surgical interventions have been suggested for patients who are intolerant to indomethacin.

Controversial issues

The nosological status of hemicrania continua is still debatable. Currently, it has been put into Group-3 under trigeminal autonomic cephalalgias. However, a few authors believe that it should not be the part of trigeminal autonomic cephalalgias ².

The diagnostic criteria for hemicrania continua have been revised several times over two decades. However, no large case study has been reported following present International Classification of Headache Disorder (ICHD-3 β, 2013) criteria ³. The most debatable part in the criteria is about “complete response to indomethacin.” ICHD-3 β exclude the existence of indomethacin resistant hemicrania continua. However, there are several large case series of typical hemicrania continua-phenotype headache, but without showing any response to indomethacin ⁴. The literature is silent on how to classify/diagnose patients with hemicrania continua-phenotype who do not show response to indomethacin. The literature acknowledges that several drugs (other than indomethacin) may produce complete response in a subset of patients with hemicrania continua ⁵. However, such patients may not receive the correct diagnosis of hemicrania continua in the event that a response of other medication occurs before a trial of indomethacin.

The presence of cranial autonomic symptoms was a must before the current ICHD-3 β criteria ⁶. Now, it is not a must if exacerbations are associated with agitation. Prakash and Adroja ⁷ believe that some option/alternative should also be given for the indomethacin response to hemicrania continua in the criteria. There is a need of more accommodating type alternative criteria in the appendix section of ICHD-3 β, as clinical features, therapeutic measures, and many other aspects are still to be determined in hemicrania continua ².

Hemicrania continua causes

As there are considerable overlaps among the trigeminal autonomic cephalalgias, it has been hypothesized that all trigeminal autonomic cephalalgias have a common pathophysiology ⁸. However, the pathophysiological studies on hemicrania continua are relatively sparse. A PET study in hemicrania continua patients has demonstrated the activation of the contralateral posterior hypothalamus, ipsilateral dorsal rostral pons, ipsilateral ventrolateral midbrain, and bilateral pontomedullary junction ⁹.

A number of hypothalamic connections have been suggested for the clinical features of trigeminal autonomic cephalalgias, including hemicrania continua. The orexinergic system is probably the main circuit to influence the hypothalamus in patients with hemicrania continua and other trigeminal autonomic cephalalgias ¹⁰. Somatostatinergic, serotoninergic, and opioidergic circuits may also modulate hypothalamus.

It has been suggested that dysfunction in the hypothalamus may result in destabilization of various inputs on the trigeminovascular system, leading to various clinical features of hemicrania continua and other trigeminal autonomic cephalalgias. The cranial autonomic features of trigeminal autonomic cephalalgias are probably because of the central disinhibition of the trigeminal autonomic reflex by the hypothalamus, possibly through direct hypothalamic-trigeminal connections ¹¹.

Hemicrania continua symptoms

Hemicrania continua is a subtype of trigeminal autonomic cephalalgias ⁷. Therefore, its clinical features overlap with other trigeminal autonomic cephalalgias. Ttrigeminal autonomic cephalalgias are classically characterized by strictly unilateral pain in the trigeminal distribution and cranial autonomic symptoms in the same areas.

Side and sites of pain

Hemicrania continua is characterized by a strictly unilateral, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity. The exacerbations are associated with cranial autonomic features, restlessness and migrainous features. By definition, there should be a complete response to indomethacin. Most of the patients have side-locked headache. However, a few patients may have side-alternating attacks. There are a total nine cases of side-shifting hemicrania continua in the literature ¹². A few cases of bilateral hemicrania continua have also been reported in the literature ¹³. However, as side-shifting hemicrania continua or bilateral hemicrania continua is very rare, a diagnosis of hemicrania continua should be considered only with strictly unilateral headache. Review of the literature suggested a slight preponderance for the right side involvement ¹⁴.

Just like other trigeminal autonomic cephalalgias, the pain in hemicrania continua is predominantly located in the first division of the trigeminal nerve (orbital, supraorbital, or temporal) ¹. However, a substantial number of patients may have pain in the other areas, including extratrigeminal areas. Pain may spread to involve other division of trigeminal nerves and rarely to extra trigeminal nerves. It may radiate to involve cheek, jaw, ear, nose, periauricular region, neck, occiput, shoulder, arm, and oral cavity (including teeth and throat) ¹⁵. In a few patients, the pain may be predominantly located in V2/V3 distribution of the trigeminal nerve (teeth, oral cavity, jaw, ear, temporomandibular joint [TMJ], and ear) ¹⁶.

Pain characteristics and pattern

There are two components of hemicrania continua: (1) continuous background unilateral headache and (2) superimposed severe exacerbations (see Figure 1). Continuous background headache is the central feature of hemicrania continua. The background pain is typically dull and mild-to-moderate in intensity. The intensity of background pain varies from 3.3 to 5.2 in visual analog scale (VAS) (range 0–10) ¹⁷. The background pain does not hamper physical activity ¹⁸.

Figure 1. Hemicrania continua headache pain characteristics and pattern

[Source ² ]

Majority of the patients report superimposed exacerbations over the background pain. The superimposed exacerbations are extremely variables in the terms of character, intensity, duration, and frequency. The character of pain during exacerbation is typically throbbing or stabbing (jabs and jolts). The intensity of exacerbations is usually severe to very severe. The pooled mean VAS (visual analog scale) of exacerbations pain was 9.0 in Prakash and Patel analyses ². Almost all patients have some form of physical disability with the exacerbation ¹⁹. Just like cluster headache and paroxysmal hemicranias, about 50% patients in Cittadini series ²⁰ reported that their pain was the most painful condition they had ever experienced, comparing it to labor pain, a broken bone, toothache, and burned hands. Patients with hemicrania continua may have suicidal thoughts during severe exacerbations ²¹.

Cluster headache is widely recognized as a most painful condition. However, clinical characteristics of hemicrania continua during exacerbations suggest that it may be as severe as of cluster headache attacks in a subset of hemicrania continua patients.

The frequency and duration are well defined in the diagnostic criteria of cluster headache, paroxysmal hemicranias, and short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) ³. However, the pattern of exacerbations of hemicrania continua is highly variable in the terms of frequency and duration. The duration of exacerbations may vary from a few seconds to 2 weeks ². Whereas the mean length of exacerbations was 32 minutes in Cortijo et al. ²² observations, it was 31 hours in Benítez-Rivero et al. study ²³. The duration of exacerbations may vary from attack per attack in the same patient. The frequency of the exacerbations is also highly variable. It may vary from >20 attacks in a day to one attack in 4 months duration ². About 49%–60% patients report at least one attack daily ⁴. About 17% patients had >5 attacks in a day in Prakash and Golwala observations ⁴.

More than 50% may have nocturnal exacerbations ²⁰. Two patients in Cittadini et al. ²⁰ series have fixed timing for the exacerbations. Otherwise, a circadian periodicity for exacerbations (like cluster headache) is largely unknown. There are a few cases in the literature in which worsening of exacerbations was noted in particular months (a circannual periodicity) ²⁰.

Cranial autonomic symptoms

Ipsilateral cranial autonomic features are one of the cardinal features of all five trigeminal autonomic cephalalgias. International Classification of Headache Disorder (ICHD-3 β, 2013) ³ describes 10 different types of cranial autonomic features in relation to trigeminal autonomic cephalalgias. These cranial autonomic symptoms are related to eye/eye lid (conjunctival injection, lacrimation, ptosis, meiosis, and eyelid edema), nose (nasal congestion and rhinorrhea), ear (sensation of fullness in the ear), and face/forehead (sweating and flushing) ³.

The mean prevalence of cranial autonomic symptoms during exacerbations is about 74% ². This prevalence is slightly lower than the prevalence of cranial autonomic symptoms observed in cluster headache and paroxysmal hemicranias patients. Tearing and conjunctival injection are two most common cranial autonomic feature ⁴. Less frequent autonomic features such as ptosis, miosis, eyelid edema, and facial sweating may also occur with exacerbations. A sense of aural fullness has been recently incorporated as one of the autonomic features in International Classification of Headache Disorder (ICHD-3 β, 2013) ³ criteria. It was reported in 19% cases in Cittadini et al. case series ²⁰.

A feeling of foreign body sensation in the eye (or sand in eye sensation or itching eye) is a peculiar feature during exacerbation of hemicrania continua. It may be noted in more than one-third patients with hemicrania continua ⁴. It is considered as a part of cranial autonomic symptoms. It is not reported in other trigeminal autonomic cephalalgias or any other primary headache disorder.

Intensity and components of cranial autonomic symptoms are usually meager in hemicrania continua as compared to other trigeminal autonomic cephalalgias ⁴. The patients may not be aware of its presence. Therefore, an objective assessment of the patients for the presence cranial autonomic symptoms during exacerbations should be done in doubtful cases of hemicrania continua ⁴.

Restlessness or agitation

Just like cluster headache and other trigeminal autonomic cephalalgias, hemicrania continua patients may have restlessness during exacerbations. It is noted in about 50% of hemicrania continua patients ⁴. They may show pacing or jogging like activity. The patients may rock from side to side, hit their heads, or even hit the head against the wall. They may press on the eye or temples with the hand or a cloth or with an ice pack. Patients find difficulty in sitting or lying down comfortably during exacerbations.

Restlessness or agitation has recently been included in hemicrania continua criteria ³. It provides an alternative to cranial autonomic features in the diagnostic criteria.

Migrainous features

Migrainous features (nausea, vomiting, photophobia, and phonophobia) are quite common in patients with hemicrania continua during exacerbations. The mean prevalence of at least one migrainous feature was 60% in Prakash and Patel observation ². About 56% fulfilled the migraine criteria during exacerbation phase ². However, auras are not that common. There are just a few case reports of visual auras in hemicrania continua ²⁴. One case with olfactory aura has also been reported in the literature ²⁵.

Hemicrania continua diagnosis

The diagnosis of hemicrania continua is made according to International Classification of Headache Disorder (ICHD-3 β, 2013) criteria for hemicrania continua and exclusion of a secondary cause ³.

International Classification of Headache Disorder (ICHD-3 β, 2013) identifies two forms of hemicrania continua (1) hemicrania continua, unremitting subtype and (2) hemicrania continua, remitting subtype. In remitting hemicrania continua, the pain is not continuous but is interrupted by remission periods of at least 1 day. Remitting form hemicrania continua constitutes 15% of total hemicrania continua ³. Unremitting hemicrania continua is characterized by the continuous pain for at least 1 year, without any symptom-free period. Unremitting hemicrania continua can arise de novo (i.e., chronic from the onset) may or evolve from hemicrania continua, remitting subtype. About 50%–60% hemicrania continua have the unremitting subtype from onset. Other 25%–35% hemicrania continua evolved into unremitting subtype from the remitting form ².

Diagnostic criteria of different subtypes of hemicrania continua (ICHD-3 β criteria)

3.4 Hemicrania continua

• A Unilateral headache fulfilling criteria B–D
• B Present for >3 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:
    • a) Conjunctival injection and/or lacrimation
    • b) Nasal congestion and/or rhinorrhea
    • c) Eyelid edema
    • d) Forehead and facial sweating
    • e) Forehead and facial flushing
    • f) Sensation of fullness in the ear
    • g) 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 Icluster headacheD-3β diagnosis

3.4.1 Hemicrania continua, remitting subtype

• A Headache fulfilling criteria for 3.4 hemicrania continua and criterion B below
• B Headache is not daily or continuous, but interrupted by remission periods of ≥1 day without treatment

3.4.2 Hemicrania continua, unremitting subtype

• A Headache fulfilling criteria for 3.4 hemicrania continua and criterion B below
• B Headache is daily and continuous, for at least 1 year without remission periods of ≥1 day

Exclusion of secondary hemicrania continua (by clinical features and investigations)

Prakash and Patel noted 66 cases of secondary hemicrania continua in a recent review ². There are a total 25 different pathologies related to secondary hemicrania continua in the literature ². A few secondary hemicrania continua may be temporally related to certain events (head injury, intracranial surgeries, other surgeries, and postpartum state) ²⁶. A large number of secondary hemicrania continua (up to 55%) are related to such events ². Posttraumatic headache is the most common secondary hemicrania continua ². It constitutes 39% of total cases of secondary hemicrania continua. Postcraniotomy hemicrania continua is the second most common secondary hemicrania continua ². Event-related secondary hemicrania continua is mostly benign ²⁶. Therefore, a history inquiring about such events preceding the onset of hemicrania continua is very important.

Intracranial space occupying lesion, head and neck vessel pathology, and pathologies related to extracranial surrounding tissues (sinus, nose, eye, neck, oral cavity, etc.) may mimic hemicrania continua ²⁶. Prolactinoma is the most common intracranial structural pathology associated with hemicrania continua ². Internal carotid artery (ICA) dissection is the most common vascular pathology ². Extracranial pathologies such as sinus pathologies, dental lesions, TMJ pathologies, neck pathologies, and eye lesions may cause continuous pain in the trigeminal or surrounding distribution ². A pathology in the thorax may cause referred pain in head and face and may mimic hemicrania continua. There are several cases of facial pain because of carcinoma lung. A few of them mimic hemicrania continua ²⁷.

Hence, a large number of intracranial and extracranial pathologies may simulate hemicrania continua. Therefore, thorough physical and neurological examinations are essential in each patient with a putative diagnosis of hemicrania continua. However, several secondary hemicrania continua mimic primary hemicrania continua, and there may be normal physical or neurological examinations. Therefore, MRI study has been recommended in all the patients presenting as hemicrania continua-like headaches ²⁶. MRI study should include the screening of pituitary, orbit, and trigeminal pathway. Headache and neck vessel pathologies (especially ICA dissection and aneurysm) require urgent therapies. Features suggesting vessels pathology include a short duration of illness, frequent and short-lived exacerbations, recent neck or head trauma, neck tenderness, and the presence of miosis. Magnetic resonance angiogram or digital subtraction angiography should be recommended for such patients. Carcinoma lung is the most dangerous condition associated with hemicrania continua-like headaches. The red flag for carcinoma lung includes older age, smoking habit, short duration of complaint, constitutional and respiratory symptoms and signs, and raised erythrocyte sedimentation rate ²⁶. Such patients should be subjected for computed tomography thorax, as carcinoma lung may be missed with routine chest X-ray ²⁶.

Diagnosis of primary hemicrania continua

Once you rule out secondary hemicrania continua, a diagnosis of primary hemicrania continua can be made according to ICHD-3 β criteria for hemicrania continua [see diagnostic criteria above]. The criteria seem to be easy. However, a misdiagnosis is very common for hemicrania continua. A misdiagnosis of hemicrania continua is perhaps maximum among all primary headache disorders. The pooled mean delay of diagnosis for hemicrania continua is 8 ± 7.2 years ². A case of hemicrania continua is missed by even neurologists and headache experts. None of the neurologists and headache experts made the correct diagnosis of hemicrania continua in Rossi et al. series of 25 patients ²⁸. 20 neurologists, and seven headache experts had seen these case before.

There are classically three features in the diagnostic criteria (1) strictly unilateral continuous pain for 3 months, (2) presence of either ipsilateral cranial autonomic or agitation during exacerbations, (3) a complete response to indomethacin. A “complete” response to indomethacin is as “sine qua non” for hemicrania continua. Typically, oral indomethacin is given to find out the response. However, injectable indomethacin 50–100 mg IM (“INDOTEST”) has also been advocated as a diagnostic test for hemicrania continua ²⁹. A complete response is usually noted within 2 h of injection. A few authors suggested a trial of indomethacin in all patients with chronic unilateral headache to find out the cases of hemicrania continua ²⁸.

Another important feature of hemicrania continua is “immediate reappearance of headache (within 6–24 hours) on skipping indomethacin” ⁴. Antonaci and Sjaastad ³⁰ and a few other authors ³¹ advocated that its diagnostic value (i.e., reappearance of headache after skipping of indomethacin) is stronger than INDOTEST itself. A subset of hemicrania continua patients may show a complete or excellent response to drugs other than indomethacin. A few patients may receive such effective drugs even without getting a correct diagnosis of hemicrania continua ³¹. The skipping or withdrawal of even such drugs may lead to immediate reappearance of headaches ⁴. Therefore, if patients with side-locked headaches had a history of complete or excellent response to some drugs as long as they had continued those drugs, a possibility of hemicrania continua exists, as no other headache reappears so fast on withdrawal of the effective drugs.

Hemicrania continua treatment

Indomethacin

Indomethacin is usually started at the dose of 25 mg three times a day. However, only 10%–18% patients showed complete response on this dose (≤75 mg) ⁴. Therefore, the drug is slowly titrated (25 mg tid every 3–5 days) up to 100 mg tid or until the patient gets complete relief ⁴. About 40%–50% hemicrania continua patients show complete response at or below to 150 mg/day. >40% patients may require ≥225 mg indomethacin per day ⁴.

A response to indomethacin usually starts immediately. However, the patients may take time to show a complete response (depending on the duration of titration of effective doses). Patients with longer duration may have delayed response ³². In Prakash and Golwala observation, 20% patients took >4 weeks to show complete response to indomethacin ⁴.

A gradual reduction of the dose is recommended every 3–6 months to find out the lowest effective dose in particular patients, as about 60% hemicrania continua patients may need a lower dose with the passage of time ³³. In this way, we can also find out the remitting form of hemicrania continua. Dose reduction is usually done by 25 mg every 3 days, until either the pain resurfaces or the patient gets completely off indomethacin.

Other medications for hemicrania continua

About 20%–75% may develop indomethacin-related side effects and may require alternative drugs ⁵. Various drugs have been found effective in case reports and open-label studies. It includes COX-2 inhibitors (celecoxib and rofecoxib,), topiramate, melatonin, gabapentin, ibuprofen, piroxicam, naproxen, aspirin, acemethacin verapamil, and steroids ⁵. However, the response of these all drugs are not predictable and may not show any response in a particular patient. You can find the best effective drug only by trial and error method.

Surgical interventions for hemicrania continua

Surgical interventions can be tried in patients who are intolerant to indomethacin.

Peripheral nerve block

In earlier observations, there was no positive influence of nerve block in hemicrania continua patients. There was only partial response to supraorbital nerve in a few patients in Antonaci et al’s ³⁴ series. Only one patient (out of seven) showed complete response in Afridi et al’s ³⁵ series. In Cittadini and Goadsby’s series ¹², nerve block was performed in greater occipital nerve in 23 patients. Approximately one-third responded to greater occipital nerve injection ¹².

Recently, Guerrero et al ³⁶ reported nine patients with hemicrania continua who received greater occipital nerve, supraorbital nerve, trochlear nerve or a combination of supraorbital nerve and greater occipital nerve blocks. Each patient had some tenderness over the represented peripheral nerves. Injections were chosen based on the tenderness. Five patients showed a complete response, while the rest had a partial response. The response started immediately after the block and persisted from 2 to 10 months. Repetition of blocks resulted in prolonged effects. The authors suggested that peripheral nerve block will be more effective if local tenderness is considered before the block.

Sphenopalatine ganglion block

Very recently, Androulakis et al ³⁷ have shown an effect of repetitive blocks of sphenopalatine ganglion block. Initially, it was performed twice per week. This was followed by maintenance treatment every 4–5 weeks. It produced significant (not complete) improvement on each occasion.

Radiofrequency ablation

Beams et al ³⁸ have demonstrated positive effects of radio-frequency ablation of the C2 ventral ramus (one case), C2 dorsal root ganglion (two cases) and sphenopalatine ganglion (one case). The response after each radiofrequency procedure was long lasting and it persisted from 1 to 2.5 years. Weyker et al ³⁹ used radiofrequency ablation of the supraorbital nerve in three patients with hemicrania continua. Radiofrequency ablation showed complete relief of headache at 7–12-month follow-up.

Occipital nerve stimulation

Occipital nerve stimulation is an effective treatment for various intractable primary headache disorders. Schwedt et al ⁴⁰ first examined the role of occipital nerve stimulation in a patient with hemicrania continua. The patient had significant improvement in pain (although not complete). However, the patient had episodes of cranial autonomic manifestation without headache. Schwedt et al ⁴¹ treated two more patients by occipital nerve stimulation. There was a marked reduction in headache frequency and pain intensity. However, both patients developed complications that include stimulator lead migration and infection.

Burns et al ⁴² treated six patients with a newer wireless stimulator device (Bion). In this crossover study design, the Bion was on for 3 months, off for the fourth month and on again during the long-term follow-up. Four patients reported substantial improvement (80%–95%) and one noted a 30% improvement. The onset of the benefit was delayed by days to weeks, and the headaches did not recur for a similar period when the device was switched off. Recently, Miller et al ⁴³ treated 16 patients by occipital nerve stimulation in an open-label prospective study. The mean monthly moderate-to-severe headache days fell by 48.9%. A favorable response (>50% reduction in monthly moderate-to-severe headache days) was observed in 50% patients.

Vagus nerve stimulation

Nesbitt et al ⁴⁴ and Eren et al ⁴⁵ assessed the effect noninvasive vagus nerve stimulation device in patients with hemicrania continua. The patients were asked to stimulate the left vagus nerve in the neck with a transcutaneous vagus nerve stimulator. There was a reduction in pain intensity immediately after the stimulation in all three patients. Some more observations are required before it could be suggested for hemicrania continua.

Botulinum toxin

There are a total of three case reports or series in the literature ⁴⁶. In the first case, the patient showed marked improvement (not complete) in headache days by trimestral injections. However, episodes of cranial autonomic occurred even in the absence of pain ⁴⁷. Khalil and Ahmed ⁴⁸ reported another patient with hemicrania continua, where the response was complete that persisted for ~10–12 weeks. Recently, Miller et al ⁴⁶ reported nine patients with hemicrania continua who were treated with multiple sessions of onabotulinumtoxin A injection. Five subjects had a response of ≥50% reduction in moderate-to-severe headache days to mild headache days or pain-free state. The median reduction in total headache days was 90% and in moderate-to-severe headache days 80%. The median duration of response of the five responders was 11 weeks. However, more studies are necessary before it could be recommended for hemicrania continua.

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