Hemicrania Continua: An Update
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315976
Source of Support: None, Conflict of Interest: None
Keywords: Hemicrania continua, indomethacin, trigeminal autonomic cephalalgias
Hemicrania continua (HC) is a primary headache disorder, which is classified by the International Classification of Headache Disorder, third edition (ICHD-3), under the heading of trigeminal autonomic cephalalgias (TACs), along with cluster headache (CH), paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA).,
The earliest published account of HC is attributed to a 1981 case series by Medina and Diamond. They described them under the heading of “cluster headache variant.” Sjaastad and Spierings coined the word “hemicrania continua” in 1984.
The incidence and prevalence of HC are not known. It was considered to be a very rare syndrome till Peres et al. reported a case series of 34 patients in 2001. Peres and colleagues titled the article “Hemicrania continua is not that rare.” There is just one study describing the prevalence of HC in the general population. The Vågå study noted 18 patients (1%) with clinical features resembling HC among 1,838 parishioners in the age group of 18–65 years. Indomethacin was not given to these patients, and the diagnosis remains in “the probable HC” category. HC was a relatively new headache when the Vågå study was conducted in 1995, and several aspects of HC were not well described in the literature. Therefore, the Vågå study may not reflect the true prevalence of HC.
Most of the data on HC have been derived from clinic-based studies. The prevalence of HC varies between 1.3 to 2.3% (mean = 1.7%) of total patients with headache attending neurology or headache clinics. HC was the third most common cause in a series of 307 patients with side-locked headaches. Wei and colleagues assessed the primary headache disorders in a multidisciplinary orofacial pain clinic. HC was the second most common primary headache disorder. Thus, HC is not an uncommon headache disorder seen in headache clinics.
HC is probably the most misdiagnosed primary headache. Patients reported by Rossi et al. (25 patients), Prakash et al. (31), Cortijo et al. (22), and de Moura et al. (10) did not get the correct diagnosis before visiting their respective headache clinics.,,, About 80% of patients in Rossi et al.'s study and 60% of patients in Prakash et al. series had already visited the neurologists without getting a correct diagnosis., Approximately 28% of patients in Rossi et al. study had already visited headache experts. In a pooled analysis, the mean delay of diagnosis for HC was 8 ± 7.2 years.
HC typically begins in the fourth or fifth decade of life. The mean age of onset varied between 28–53 years in different studies (pooled mean age = 40.2 years). However, no age is immune and it can begin at any age. HC have been reported in the literature for several childhood-onset cases (in patients as young as 5 years) and in the seventh and eighth decades of life.
Similar to migraine and tension-type headache, HC is more common in women. In an earlier review, the male-to-female ratio was 1:5. However, the female preponderance has reduced over the years, and the male: female ratio was 1:1.8 in a recent review of the literature.
Family history and genetic predisposition
Pareja and colleagues reported a 31-year-old man with episodic HC whose sister had a history of HC. Weatherall and Bahra reported a mother and daughter having HC at the same time. Both responded to indomethacin.
HC is characterized by a strictly unilateral, mild-to-moderate continuous headache with superimposed exacerbations of severe intensity in the trigeminal distribution. The exacerbation is associated with ipsilateral cranial autonomic symptoms (CAS), agitation or restlessness, and migrainous features. By definition, a case of HC should show complete response to indomethacin.
Laterality of pain
Patients with HC have a strictly unilateral headache, with a slight preponderance for the right side (53%). About 2% of patients with HC may have side-shifting pain. A few cases of bilateral HC have also been reported in the literature.
Site of pain
The headaches in TACs classically present in the ophthalmic division of the trigeminal nerve and the ICHD-3 acknowledges the presence of unilateral headache in the orbital, supraorbital, and/or temporal areas in all TACs except HC. ICHD-3 does not describe the sites of pain in HC and simply mentions “unilateral headache.” However, several large case series suggest that the pain in HC is predominantly in the orbital, supraorbital, and/or temporal area., Similarly, like other TACs, the pain in HC may spread to involve other divisions of the trigeminal nerve, and may be noted in the occiput, neck, shoulder, upper limb, maxilla, mandible, periauricular area, and oral cavity (including teeth and throat).,,, A substantial number of patients may have predominant or isolated symptoms in an atypical location, and it may create diagnostic confusion. In one study, estimating the prevalence of facial pain in different primary headaches, about 21% of patients with HC had facial pain. Hryvenko et al. noted six patients with HC in a tertiary orofacial pain clinic. Four out of six patients had facial pain. One patient had a toothache and another had jaw pain. The identification of such atypical patients is very important as they respond dramatically to indomethacin, and patients can be saved from various erroneous treatments, including invasive surgeries.
Pain characteristics and pattern
The headache in HC has two components: 1) continuous background pain and 2) superimposed severe exacerbations [Figure 1]a. Continuous background headache is the most consistent and central feature of HC. Missing the history of background pain is probably the most common reason for a delayed or wrong diagnosis. The background pain is perceived as dull and pressure like a tension-type headache. It is typically mild to moderate in severity, 3.3 to 5.2 on the visual analog scale (VAS), and does not hamper any routine activities. In Peres et al.'s study on 34 patients, 82% of patients had no or very mild physical disability due to background pain. Patients considered this background headache as “normal” and they may not volunteer about the background pain.
The exacerbations are highly variable in terms of intensity, character, duration, and frequency. The character of exacerbation is typically throbbing or stabbing (jabs and jolts) or a combination of both. The VAS for severe exacerbations ranges from 5 to 10 (mean pooled VAS score = 9). Approximately 40% of patients graded the superimposed pain at 10 of VAS. In Cittadini and Goadsby's observations, about 50% of patients felt that their pains were the most painful conditions they had ever experienced, compared with labor pain, a broken bone, toothache, and burned hands. In this regard, the pain of exacerbations matches the pain of CH and PH. Like CH and PH, the patients with HC may have suicidal ideation during exacerbations.
ICHD-3 is silent regarding the frequency and duration of superimposed attacks. The literature review suggests a variable duration of exacerbations, which can vary from a few seconds to a few weeks. Similarly, the frequency of superimposed attacks is also highly variable and varies from >20 attacks/day to one attack in 4-month duration.
None of the studies showed any circadian periodicity. Exacerbations can occur at any time, including at night. About 53% of patients in Cittadini and Goadsby's series had exacerbations during the night time. Unlike CH, only a few case reports of HC have mentioned the worsening of headache attacks (or relapses in remitting subtypes) during particular seasons. Remitting HC with seasonal predilection can be misdiagnosed as CH. The continuous background pain is the clinical clue in such patients, and a dramatic response to indomethacin clinch the diagnosis of HC.
The prevalence of at least one migrainous symptom (nausea, vomiting, photophobia, and phonophobia) varies from 17% to 90% (with mean pooled prevalence = 60%). About 56% of patients met the criteria for migraine during the exacerbations. A few patients may have an aura during exacerbations. Visual auras are the most common aura in patients with HC. Other reported auras in HC were sensory and olfactory auras.,
Cranial autonomic symptoms (CAS)
Ipsilateral CAS in the trigeminal distribution is a very important accompanying feature of TACs, including HC. However, its position in ICHD criteria has changed over the years. In ICHD-2 criteria, there were six CAS for HC (although there had been 8 CAS for CH and PH; eyelid edema, and forehead and facial sweating were not included for HC). A diagnosis of HC could not be made in the absence of CAS according to ICHD-2. A significant change was made in the ICHD-3β criteria and they recognized 10 different types of CAS: (i) conjunctival injection, (ii) lacrimation, (iii) nasal congestion, (iv) rhinorrhea, (v) ptosis, (vi) miosis, (vii) eyelid edema, (viii) forehead and facial sweating, (ix) forehead and facial flushing, and (x) sensation of fullness in the ear. Moreover, the presence of CAS was not an essential feature as agitation was included as an alternative to CAS in the diagnostic criteria. In the third edition (ICHD-3), two CAS were again removed from the list (forehead and facial flushing and sensation of fullness in the ear).
The mean prevalence of at least one CAS in HC varies between 57%–100% in different studies. Lacrimation is the most common CAS (33%–77%) in most of the case series. Conjunctival injection, nasal congestion, and rhinorrhea are other common CAS. Sand in eye sensation or itching eye was common in a few studies (up to 35%). Although not included in the criteria, it is considered as a type of CAS.
The number and severity of CAS are related to the intensity of the pain. Severe headache attacks may have a higher number of CAS with higher severity. However, the intensity of CAS in HC is relatively less than those during the attacks of CH and PH. CAS may be mild or barely perceptible in HC, a prospective observation during headache attacks is important before labeling it as “absent.”,
Agitation in hemicrania continua
Patients with HC can show restlessness or agitation. Patients find difficulty in staying still during attacks or exacerbations, and rarely lie down comfortably. Rubbing or pressing or holding the aching part (65%) is the most common behavioral abnormality. Other common behavioral abnormalities are rolling on bed/ground (45%), walking back and forth (39%), pacing/rocking (32%), and putting something on the aching part (26%). Suicidal ideation was felt in 10% of patients during exacerbations. The prevalence of restlessness in HC varied from 10%–69% in different studies and it is less than that of PH and CH.,,
Both peripheral and central pathophysiological mechanisms are suggested in HC. A positron emission tomography (PET) study has demonstrated the activation of the contralateral posterior hypothalamus, ipsilateral ventrolateral midbrain, ipsilateral dorsal rostral pons, and bilateral pontomedullary junction. The hypothalamic orexinergic system is the main circuit to regulate the hypothalamus. Somatostatinergic, opioidergic, and serotoninergic circuits also influence the hypothalamus. The hypothalamus controls the trigeminal autonomic reflex (TAR), and the disinhibition of TAR by the hypothalamus leads to various cranial autonomic symptoms.,
Diagnosis of hemicrania continua
A suspicion for HC should arise in all cases of side-locked headaches. The diagnosis of HC is made according to the criteria proposed by ICHD-3. However, a diagnosis of primary HC is made once you rule out secondary pathologies.
There have been about 75 cases of secondary HC in the literature, and it includes more than 25 different pathologies [Table 1]. HC-like headaches may arise from both intracranial and extracranial structures such as the cranium, neck, eyes, nose, sinuses, ears, teeth, mouth, and the other facial or cervical structures, including vessels. [Table 1] shows the common secondary HC (at least 2 cases with each). Posttraumatic headache is the most common cause of secondary HC, followed by postsurgery, dissection, prolactinoma, carcinoma lung, and nasopharyngeal carcinoma.,,,,,,,,,,,,,,,,,, There is one case each with pituitary infarct, internal carotid artery (ICA) aneurysm, venous malformation, vertebral artery dissection, carotid-cavernous fistula, cerebral venous thrombosis, angiolipoma in the temporal region, poststroke, cerebellopontine (CP) angle epidermoid, pineal cyst, idiopathic hypertrophic pachymeningitis, transdermal nitroglycerine, analgesic rebound, HIV, sphenoidal tumor, sphenoid sinusitis, orbital tumor/pseudotumor, exfoliation glaucoma, disc herniation, and vitreous hemorrhage.,,,,,
Carcinoma lung and nasopharyngeal carcinoma may have HC-like pain. An elderly patient with a smoking habit, short duration of illness, constitutional and respiratory symptoms, and raised erythrocyte sedimentation rate (ESR) should be screened for carcinoma lung.,,,
The diagnosis of HC is easy when you recognize both components of HC: (i) continuous background headache and (ii) superimposed severe exacerbations [Figure 1]a. Patients with mild background pain and severe exacerbations may not volunteer about the background pain, and the diagnosis depends on the exacerbations phase [Figure 1]b. As most of the primary headaches have well-defined duration and frequency of attacks, the patient may get a wrong diagnosis if only the duration of exacerbations is taken into account. For example, if the duration is short, the misdiagnosis of PH or CH may be made whereas long-duration exacerbations mimic migraine.
Some patients may have more severe background pain (>7 in VAS), and there may not be many fluctuations. In Cittadini and Goadsby's series, two patients had continuous pain with a severity score of 10. Moreover, patients may have infrequent exacerbations, for example, one attack in a 1–4 month interval. In such cases, physicians and patients may not focus on the exacerbations, and diagnosis will be dependent on the characteristics of background pain and may suggest secondary headaches, atypical facial pain, or new persistent daily headache (NDPH) [Figure 1]c.
Commonly HC is misdiagnosed as migraine (52% by Rossi et al. and 71% by Prakash et al.)., [Table 2] highlights the differentiating features between side-locked migraine and HC.
A suspicion for HC (or any TACs) should arise in all cases of side-locked headaches. All TACs share a few unique clinical symptoms, which can be easily remembered by a mnemonic '3A of TACs,, which include: (i) “anteriorly located unilateral pain” (orbital, frontal and temporal) pain, (ii) “autonomic symptoms” in the same areas, and (iii) “agitation” during attacks. If all components of 3A are present, the case is most likely one of the types of TACs (after excluding secondary causes). All TACs have short-duration headache episodes, except HC in which the pain is continuous. Therefore, getting a history of continuous background pain is the most important clinical clue for HC. Such a patient needs a trial of indomethacin, and a positive response confirms the diagnosis of HC. Injectable indomethacin (INDOTEST) can also provide a dramatic and immediate response.
Hemicrania continua associated with other primary headache disorders
The association of HC with other primary headaches can be classified into three groups: (i) both HC and other primary headache existing simultaneously, (ii) other primary headache evolve into HC, and (iii) HC evolving into another primary headache. The diagnosis of such an association is important, as patients may need two different types of drugs. CH is the most common headache associated with HC. Patients may need a combination of indomethacin and lithium/verapamil. HC with trigeminal neuralgia (hemicrania continua-tic syndrome) may need a combination of indomethacin and carbamazepine.
Indomethacin is the drug of choice and absolute response to indomethacin is included as one of the diagnostic criteria for HC. Treatment is usually started at a dose of 25 mg three times a day (TID), and it is titrated (25 mg TID every 3–5 days) up to 75 mg TID or until the patient gets complete relief. The mean indomethacin dose varies between 75 and 200 mg/day in various case studies. ICHD-3 recognizes the upper therapeutic dose of indomethacin as 225 mg daily. Up to 15% of patients may need a dose higher than 225 mg/day., A response to indomethacin usually starts immediately in all patients. As the mean therapeutic dose is >75 mg in most of the studies, patients show a complete response only after an escalation of the initial dose of indomethacin, and about 50%–80% of patients get a complete response within a week., Patients with a longer duration of headache (i.e. more chronic headaches) may have delayed response to indomethacin, and about 20% of patients show a complete response after 4 weeks of indomethacin administration. About 60%–77% of patients with HC need a lower dose of indomethacin over time., Moreover, about 10%–15% of patients may have a remitting type of HC. Therefore, a dose reduction is recommended in each patient after a certain interval. A gradual reduction of the dose should be done at every 3–6 months interval. Indomethacin is tapered 25 mg every 3–5 days, until either the headache reappears or the patient gets completely off indomethacin. In this way, the remission phase of the patient or the lowest possible dose for a particular patient can be discovered. HC-like headache unresponsive or partially responsive to indomethacin has been reported in the literature. However, ICHD does not recognize this entity.
About 20%–75% may develop indomethacin-related side effects and may require alternative drugs. Various drugs have been found effective in case reports and open-label studies., The effects of these drugs are not uniform and consistent in every patient. It is difficult to predict which patient will respond to which class of drugs. Topiramate is probably the best alternative to indomethacin. Cyclooxygenase-2 inhibitors (rofecoxib and celecoxib), gabapentin, and melatonin can be other alternatives.
The reappearance of pain on skipping or missing indomethacin and other effective drugs
Headache reappears within a few hours to a few days after missing the effective drugs (indomethacin or others) and a few authors consider it as a “strong testimony” for HC., It may be a clinical clue to identify HC in patients with side-locked headaches, especially in those who did not take indomethacin but there was a complete response in headaches by other drugs. Such patients claim that “response continues as long as they receive the drug.”
The modulation of structures involved in the pathogenesis of HC may help in reducing or preventing symptoms of HC. Several surgical approaches have been tried in patients with HC [Table 3].,,,,,,,,,,,,,,,, Although the effects of these surgical measures are mixed, they could be used in patients who are intolerant to indomethacin or cannot use indomethacin for the long term because of associate comorbid conditions.
The literature is relatively silent regarding long-term remission in patients with HC. In 1999, Espada et al. reported 10 patients with HC. A follow-up study was available for eight patients (mean follow-up 13 months, range 1–22 months). In three patients, indomethacin could be discontinued (after 3, 7, and 15 months). However, the authors did not report how long these patients had been followed up after discontinuation of indomethacin. Prakash et al. did a long-term prospective study in 31 patients with HC. The mean follow-up was 30 months (± 10.6). The dose reduction of indomethacin was done at every 4-6 months interval. None of the patients were completely off the drug in 2.5 years of follow-up. Indomethacin could be withdrawn in three patients for a limited period. Headaches reappeared in all three patients in 2–5 months. A few authors suggest that it may be a life-long disorder.
HC represents an intriguing primary headache disorder that is included under TACS. The patients may remain undiagnosed for several years as they may not volunteer the history of continuous background pain and associated CAS. The exacerbations are highly variable in terms of frequency, duration, intensity, and associated clinical symptoms. The exacerbation part mimics several primary headaches and neuralgias. More than 25 secondary pathologies mimic primary HC, and routine investigations may not detect those cases. Hence, neuroimaging is done in all suspected cases of HC. Cases of coexistence of HC with other primary headaches are increasing in number. Although the response to indomethacin is absolute, the immediate reappearance of pain on skipping or missing the drug is well documented.
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[Table 1], [Table 2], [Table 3]