Presentation and course
Trigeminal autonomic cephalalgia
Paroxysmal hemicrania. Paroxysmal hemicrania is a rare syndrome characterized by repeated attacks of strictly unilateral headaches: moderate to severe, short-lasting pain occurring with cranial autonomic features. In the ICHD-3 beta version, paroxysmal hemicrania is defined by at least 20 attacks of severe unilateral, orbital, supraorbital, and/or temporal pain, lasting 2 to 30 minutes and accompanied by at least 1 of the following symptoms or signs, ipsilateral to the pain: (A) conjunctival injection and/or lacrimation, (B) nasal congestion and/or rhinorrhea, (C) eyelid edema, (D) forehead and facial sweating, (E) conjunctival injection, (F) lacrimation, (G) nasal blockage, or (H) rhinorrhea. Such autonomic symptoms are more prominent than in hemicrania continua.
Because of the rarity of paroxysmal hemicrania, most clinical characteristics are still uncertain. A female predominance was reported previously (female:male = 2.36:1) (05), but no difference in gender was noted in prospective studies (24; 99). Attacks may begin at any age, including childhood, but they most frequently begin in the late third decade (24; 99) Maggioni reported a patient with migraine without aura who had paroxysmal hemicrania during her menstrual period (70). The patient underwent hysterectomy and bilateral ovariectomy for myomatosis and ovarian cysts, and her paroxysmal hemicrania ceased immediately after surgery. The author suspected a relationship between hormonal levels and paroxysmal hemicrania attacks. In children, paroxysmal hemicrania was estimated to account for 1.3% of all pediatric chronic headache referred to pediatric pain clinics in a clinic-based study, and the clinical characteristics and response to indomethacin were similar to that in adults (09). Piroxicam was reported to be a possible alternative treatment (08).
In a large prospective study, the distribution of pain was most commonly at orbital and temporal locations (77%), followed by retro-orbital (61%), frontal (55%), and occipital (42%), but other locations were also noted (24). Of the cohort, cranial autonomic features included lacrimation (87%), conjunctival injection (68%), rhinorrhea (58%), nasal congestion (54%), ptosis, and facial flushing. Eighty percent of the patients were agitated, restless, or both with pain, and 26% were aggressive. All patients were responsive to indomethacin treatment. Common triggers included stress or relaxation after stress (26%), exercise (23%), alcohol and neck movement (19%), a warm environment (16%), cold weather (16%), a strong smell (16%), bending down (16%), coughing (16%), sneezing (13%), tiredness (10%), and straining (10%). Unlike the pain in patients with hemicrania continua, which is continuous and moderately severe, pain in patients with paroxysmal hemicrania is severe to very severe (88% to 93%) (99). Interparoxsymal pain is reported in 47% of patients (99). The range of the attacks was between 10 seconds and 4 hours. The mean length of the attacks was 17 minutes and the median, 19 minutes. The number of attacks per day ranged from 2 to 50. The mean was 11 attacks in 24 hours, and the median was 9.
Attacks may diminish in severity or remit during pregnancy (122; 122). Secondary causes of chronic paroxysmal hemicrania include cavernous sinus lesions, pituitary adenomas, aneurysms, and phosphodiesterase inhibitors administration (144; 50; 131; 141). Chronic paroxysmal hemicrania can coexist with cough headache (71). Siow described a patient with episodic paroxysmal hemicrania with seasonal variation (121). Bilateral paroxysmal hemicrania or bilateral paroxysmal cephalalgia was also reported (73; 27).
Hemicrania continua. Hemicrania continua is characterized by a continuous, moderate to severe, unilateral headache that varies in intensity, waxing and waning without disappearing completely (96). Continuous baseline headache is the most consistent feature of hemicrania continua; it is the central feature of hemicrania continua (103). Exacerbations of pain are associated with autonomic disturbances and/or a sense of restlessness or agitation, or aggravation of the pain by movement. The autonomic symptoms are usually milder than paroxysmal hemicrania, but the pain intensity was higher than those with paroxysmal hemicrania. In the ICHD-3 beta version, the autonomic symptoms were expanded, including (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, and (G) miosis and/or ptosis (102). However, the autonomic symptoms in hemicrania continua are less prominent than seen in paroxysmal hemicranias. Lacrimation is the most common autonomic symptom (53% to 80%). Patients with side-shifting or bilateral pain have been reported (132), suggesting the condition is not side-locked. The cranial autonomic features do not always occur with exacerbation of the pain; during a detailed interview, a wider range or bilateral of cranial autonomic features can be detected (23; 132). Hemicrania continua patients were noted not only with headache but also with the symptoms of hemifacial or jaw pain in the initial presentation (55).
Hemicrania continua is not triggered by neck movements, but tender spots in the neck may be present. Migrainous features including photophobia, phonophobia, and nausea can occur. Hemicrania continua can also be accompanied by a family history of hemiplegic spells (33) and associated with aura (97). Medication overuse can be present. The clinical characteristics cannot predict the response to indomethacin. In another study, the most common diagnoses for patients who did not respond to indomethacin included chronic migraine with and without medication overuse, new daily-persistent headache (NDPH), nummular headache, or cervicogenic headache. Topiramate add-on with low-dose indomethacin, acemethacin, melatonin, and occipital nerve stimulation were reported to be possible alternative treatments with less adverse events of the gastrointestinal tract (83; 54; 77; 104).
Because of the rarity of hemicrania continua, the incidence and prevalence are still unknown. The range of onset was between 10 and 67 years old in the largest clinic-based study (23). A preponderance of women reported earlier decreased gradually from 5:1 to 1.6 to 1.8:1 (10; 82; 23).
Hemicrania continua can be divided into 3 distinct temporal patterns: (1) continuous from onset, (2) continuous transformed from remitting, and (3) episodic and remitting.
Hemicrania continua is rarely related to an underlying cause. Secondary cases of hemicrania continua have been reported, including mesenchymal tumor, HIV, carotid artery dissection, nasopharyngeal carcinoma, and lung cancer (12; 151).
Other primary headaches
Primary cough headache. Primary cough headache represents headache provoked by cough without any intracranial disorder. The diagnostic criteria of the ICHD-3, beta version for primary cough headache require that (1) sudden onset of headache is brought on by and occurs only in association with coughing, straining, or Valsalva maneuver, and (2) it lasts from 1 second to 2 hours. Primary cough headache is moderate to severe in intensity, with mostly explosive or dull pain at onset, but it can be pulsatile, stabbing, or sharp sometimes. The duration of headache is usually short; however, contrary to the ICHD-2 criteria, 10.8% of primary cough headache patients had headache durations of greater than 30 minutes (18). Most patients suffered headache bilaterally, usually located in the occipital, but also in the frontal, temporal, or vertex, areas. Notably, the associated features such as nausea, vomiting, photophobia, and phonophobia were uncommon. Many patients had other headache triggers in addition to coughing. The triggers included straining at stool, bending down, heavy lifting, Valsalva maneuver, laughing, sneezing, crying, exertion, and sexual activity (92; 91). Of note, exertion and heavy lifting were less common in primary cough headache patients than in those with a secondary etiology (18).
There are about 40% of cough headache patients with secondary causes. The neuroimaging study to exclude the possible intracranial lesions is important for these patients. The most common secondary cause is Arnold-Chiari malformation type I, and other causes included CSF hypotension, carotid or vertebrobasilar diseases, middle cranial fossa or posterior fossa tumors, midbrain cyst, basilar impression, platybasia, subdural hematoma, cerebral aneurysms, bilateral internal jugular vein valve incompetence, and reversible cerebral vasoconstriction syndrome (32; 18; 85; 36; 68). The response to indomethacin could not be used to differentiate primary or secondary cough headache.
Primary exercise headache. Primary exercise headache was previously called primary exertional headache or benign exertional headache and has been recognized for decades, but the definition of exertion has been historically imprecise (142; 112; 92). Some used the term exertional headache to describe headaches precipitated mainly by Valsalva-like maneuvers, which had a prompt mode of onset and lasted for seconds to minutes (112); others specifically referred to headaches that occurred during or after sustained physical exercise, which tended to be less abrupt at onset and lasted longer (92; 124; 20). In the ICHD-3, it is renamed as primary exercise headache. Primary exercise headache is commonly bilateral, pulsating, and short-lasting; however, these characteristics are not invariable.
The ICHD-3 beta version proposes the headache is brought on by and occurs only during or after strenuous physical exercise and lasts less than 48 hours. The pulsating headache listed in the ICHD-1 and ICHD-2 is not required in the new criteria because only 59% of adolescent patients (20) and 87% of exercise headache sufferers in the Vaga study (125) had pulsating headache characteristics. In addition, the duration of exercise headache was less than 5 minutes in 46% of adolescent sufferers. The Vaga study found that 46% of patients had both exercise headache and migraine (124); the Taiwanese adolescent headache study also found that 48% of migraineurs had exercise headache (20). Subjects with comorbid migraine may have exercise headache bearing more migrainous features (20).
Primary headache associated with sexual activity. Primary headache associated with sexual activity was previously called benign orgasmic cephalgia, benign coital headache, or benign sexual headache (94; 64; 86; 87). The ICHD-2 uses the term primary headache associated with sexual activity because these headaches are not only precipitated during sexual intercourse or orgasm. Even though a secondary cause is less common (7% to 11%), it is mandatory to exclude the secondary etiologies, including subarachnoid hemorrhage, arterial dissection, and reversible cerebral vasoconstriction syndrome (RCVS) prior to treating these patients by indomethacin (92; 91; 150). Pain is typically bilateral and occipital, usually lasting from 10 minutes to 6 hours (38; 150). These headaches are occasionally associated with nausea, vomiting, and mood disturbance (38). Comorbidity with other primary headaches such as migraine, benign exercise headache, and tension-type headache is common (38; 150).
The ICHD-1 and ICHD-2 proposed diagnostic criteria for 2 subtypes of primary headache associated with sexual activity: preorgasmic headache and orgasmic headache. However, the only comparative study between the 2 subtypes found no significant differences in demographics, clinical features, comorbidities, and prognosis, except for the mode of headache onset (38; 39; 150). It is believed that they are different manifestations of the same disorder (38).
In the ICHD-3 (beta version), headache associated with sexual activity is now regarded as a single entity with variable presentation. The headache could be a dull ache in the occipital head and neck associated with awareness of neck and/or jaw muscle contraction. The headache usually occurs during sexual activity and increases with sexual excitement. At orgasm, a sudden, severe "explosive" headache develops. Primary headache associated with sexual activity is also commonly associated with migraine. The frequencies vary from 19% to 47% (86; 87; 38).
Primary stabbing headache. Primary stabbing headache is characterized by transient, sharp jabbing pains that occur within a small, localized area of the scalp. Many terms have been used in the literature to describe the symptoms of stabbing headache, including "ice pick-like pains" (110), "sharp short-lived head pains" (117), "needle-in-the-eye syndrome," and "jabs and jolts syndrome" (90).
The ICHD-3 (beta version) has proposed diagnostic criteria for primary stabbing headache, which requires that (1) each stab lasts for up to a few seconds, (2) stabs recur with irregular frequency, from 1 to many per day, and (3) no cranial autonomic symptoms. The exclusive distribution of first division of trigeminal nerve was not necessary in the ICHD-3 criteria. Nevertheless, a study field-tested the criteria and found that 70% of the patients could not fulfill the criterion that head pain occur exclusively or predominantly in the distribution of the first division of the trigeminal nerve, and 15% could not fulfill the criterion of no accompanying symptoms (40). Most primary stabbing headache patients have very brief attacks (less than 3 seconds); nevertheless, long-lasting cephalic jabs have been reported (128). Clinic-based studies showed that primary stabbing headache occurred more often in migraineurs (110; 90; 40). In 1 small sample clinical-based study, primary stabbing headache was not usually the main cause of referral to a headache clinic (48). Unlike paroxysmal hemicrania and hemicrania continua, response to indomethacin is not listed under the diagnostic criteria of primary stabbing headache, likely because response to this treatment can be variable. Pareja and colleagues prescribed a trial of indomethacin 75 mg daily for 15 days and found complete improvement in 6 of 17 participants (35%), partial improvement in 5 (30%), and no response in 6 (35%) (90; 22). In 1 clinical based study including 65 patients, primary stabbing headache presented with either an acute or chronic course. The characteristics of patients with acute/subacute primary stabbing headache included more localized locations, greater intensity, more stabs per day, daily occurrence, and more previous primary stabbing headache history. Chronic daily primary stabbing headache was reported associated with female predominance, frequent allodynia, longer lasting stabs, and multiple or migrating locations on bilateral or alternating sides. The characteristics of intermittent primary stabbing headache included female predominance and sporadic stabs with less intensity (60).
Hypnic headache. Hypnic headache is a rare, primary headache disorder of the elderly, initially described by Raskin in 1988. Based on a series of reports over the past 16 years, the disorder was included in the ICHD-2 (34; 57). In the ICHD-3 (beta version), the criteria for hypnic headache require headaches of short duration that occur exclusively during sleep without autonomic accompaniments (52). The duration of hypnic headache is 15 minutes to 4 hours, and the frequency should be equal to or more than 10 days per month for more than 3 months. The pain is generally dull in nature and regularly awakens sufferers during sleep. Though the overwhelming majority of cases occur in the elderly, young adult and even pediatric patients have been reported (47). There is some evidence that hypnic headache is related to REM sleep. Hypnic headache most probably is an entity among the idiopathic headache disorders unassociated with structural lesions and does not belong to the trigeminal-autonomic cephalalgias. Indomethacin has been described as a possible treatment for hypnic headaches and showed distinct efficacy in patients with unilateral hypnic headache, especially if there were subtle trigeminal autonomic symptoms (nasal stuffiness, lacrimation, etc.) (46; 98; 67). Other options available are lithium, flunarizine, amitriptyline, topiramate, melatonin, and caffeine (53).
Prognosis and complications
Espada and colleagues reported 5 men and 4 women who had hemicrania continua: 8 continuous and 1 remitting, with a mean age of onset of 53.3 years (range 29 to 69 years of age). All 9 patients had initial relief with indomethacin. Follow-up was possible in 8 patients. Indomethacin could be discontinued after 3 months, 7 months, and 15 months respectively, and patients remained pain-free. Three patients discontinued treatment because of side effects and had headache recurrence; 2 had relief with aspirin. Two other patients continue to take indomethacin with partial relief.
The rarity of chronic paroxysmal hemicrania makes statements about its prognosis uncertain. The disorder does have an episodic form, which is even rarer than the chronic form and is characterized by remissions and relapses (62). It appears that the episodic form may evolve into a chronic form, and there occasionally may be long-lasting remissions (122). In some cases, therapy with indomethacin may need to be life-long.
The course of primary cough headache is generally self-limited, with 50% to 90% of patients in remission within 2 years (140; 18), whether responsive to indomethacin or not. Patients with a poor response to indomethacin treatment predict a poor outcome at follow-up. Those cases of cough headache that are secondary to a structural cause, such as a Chiari malformation, carry the prognosis of the underlying cause.
The prognosis of primary stabbing headache and primary exercise headache is highly variable, but patients generally improve over time and respond to therapy and symptomatic measures.
The complications of headaches that are exclusively or preferentially responsive to indomethacin relate primarily to treatment with the drug itself. A significant percentage of patients have trouble tolerating the drug, with side effects primarily affecting the gastrointestinal tract. Bleeding, perforation, anorexia, nausea, and vomiting may all occur, as may diarrhea. For patients chronically using indomethacin, gradual dose escalation and gastrointestinal protective measures, such as histamine 2-blockers and misoprostol, may help. Periodic eye examinations have also been advocated (108).
Clinical vignette
A 65-year-old woman had been suffering from frequent headaches for 6 months. The headaches were only provoked when she coughed or bended. The attacks were severe and explosive, essentially from onset. The headaches were localized on the occipital region and lasted only 2 to 3 minutes. During the attacks, there were no associated symptoms like nausea, vomiting, photophobia, or phonophobia. Her general and neurologic examinations were normal. MRI of the brain was normal. She had failed trials of acetaminophen and naproxen treatment, but 25 mg of indomethacin orally, 3 times a day terminated the attacks. The indomethacin was discontinued 8 weeks later, and the attacks did not recur. This was a typical case of primary cough headache.
