Indomethacin-Responsive TACS

Chronic paroxysmal hemicrania (CPH) and hemicrania continua (HC) are defined by their response to indomethacin. A short discussion on these two syndromes will be followed by treatment suggestions.

Chronic Paroxysmal Hemicrania

ICHD-3 diagnostic criteria:

  • • At least 20 attacks fulfilling criteria B-E
  • • Severe unilateral orbital, supraorbital, and/or temporal pain lasting 2-30 minutes
  • • Either or both of the following:

=> 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

° Sense of restlessness or agitation

  • • Occurring with a frequency of >5 per day
  • • Prevented absolutely by therapeutic doses of indomethacin

Chronic paroxysmal hemicrania is a rare syndrome marked by headaches of short duration, a high frequency of attacks, and associated autonomic symptoms. CPH pain location is normally orbital, temporal, and above or behind the ear and is one-sided. The pain is severe in intensity. Normal headache duration is between 2 and 30 minutes and frequency is greater than five attacks per day. Unlike cluster headache, there is no predilection for nocturnal attacks, although attacks can certainly awaken a patient from sleep. Associated symptoms are marked by autonomic phenomena. CPH attacks can sometimes be triggered by rotating the neck or flexing the head to the side of the headaches, or by applying external pressure to the transverse processes of C4-C5 or the C2 nerve root on the symptomatic side. This syndrome used to be termed female cluster headache but it is not cluster headache based on the frequency and duration of attacks, and a misdiagnosis can lead to continued disability as indomethacin is not suggested for CH but is for CPH.

Hemicrania Continua

ICHD-3 diagnostic criteria:

  • • Unilateral headache fulfilling criteria B-D
  • • Present for >3 months, with exacerbations of moderate or greater intensity
  • • Either or both of the following:

=> 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

=> A sense of restlessness or agitation, or aggravation of the pain by movement

• Responds absolutely to therapeutic doses of indomethacin

Initially hemicrania continua was felt to be a very rare syndrome although it is now felt to be more common and probably routinely misdiagnosed. Hemicrania continua, like CPH, has a female predominance. There are two recognized forms of HC: non-remitting (typically daily from onset), which occurs in about 85% of patients (no remission periods), and the remitting form. The nonremitting form can evolve from the remitting form. In regard to the clinical characteristics of HC there are two patterns of headache. Hemicrania continua patients will experience a continuous daily head pain which is present 24 hours per day, 7 days per week and then pain exacerbation periods which occur with varying frequency from multiple times per week to every third month or less. The daily continuous pain is usually of mild to moderate intensity. It is always present on the same side of the head. There are some reports of the pain of HC switching sides or being bilateral but that would be a rarity. The pain exacerbation periods are marked by moderate to severe pain lasting hours to days in duration with associated symptoms that are seen in migraine and cluster headache. Migrainous symptoms include nausea, vomiting, photophobia, and phonophobia. Cranial autonomic symptoms include unilateral lacrimation, ptosis, nasal congestion and rhinorrhea, and agitation. Other key symptoms that are commonly seen during a pain exacerbation period include eyelid swelling, eyelid twitching, and “stabbing” headaches. Some HC patients will also complain of a foreign body sensation in the eye on the same side as their headaches such as a feeling as if there is a piece of sand in the eye or an eyelash. HC patients can also experience auras typically occurring just prior to a pain exacerbation period.

Pathogenesis: as TAC spectrum disorders, a hypothalamic involvement is suggestive for CPH and HC as is noted for cluster headache even though the indomethacin-responsive TAC syndromes do not have the same circadian rhythmicity as CH. Functional neuroimaging for CPH notes activation of the contralateral posterior hypothalamus and contralateral ventral midbrain, while for HC there is noted contralateral posterior hypothalamus and ipsilateral dorsal rostral pons activation.7677

Indomethacin Treatment

The normal starting dosage of indomethacin for both CPH and HC is one 25 mg tablet three times a day for 3 days; this dose can be increased to tw'o tablets (50 mg) three times a day if there is not total relief of pain. Most individuals will respond by 150 mg a day, and the response can be dramatic, with quick dissipation of headache symptoms regardless of how long the patient had suffered with head pain. A beneficial effect will normally be seen within 48 hours after the correct dosage has been found. Some individuals need a dose as high as 300 mg of indomethacin per day, but there is a true safety issue w'ith this high of a dose, so going above 225 mg per day is not suggested. If there is no response at 150 mg a day, and the physician still suspects CPH or HC, an extra 25 mg dose of indomethacin can be added every 3 days, to a total of 225 mg a day or the onset of side effects. If the patient does not respond at 75 mg three times a day, one should consider an alternative diagnosis. There are both gastrointestinal and renal potential side effects with chronic indomethacin usage. After 3 months of doing well on indomethacin the medication should be tapered to see if still needed. Many patients cannot come off indomethacin without headache recurrence, however.

Other Potential Non-Indomethacin Treatments78

• COX-2 inhibitors: both CPH and HC have shown some positive response to celecoxib. The dosing is typically high from 200 mg BID to QID. At these doses the gastrointestinal protection these agents afford may be lost. In addition, the safety of COX-2 inhibitors when used on a continuous basis is in question.

  • • Melatonin: melatonin has a similar chemical structure to indomethacin and has been shown to have anti-inflammatory and anti-nociceptive properties. The pain-relieving mechanisms of melatonin are not completely understood, but reports have suggested that melatonin can increase the release of endogenous beta-endorphins and its anti-hyperalgesic effect appears to involve both nitric oxide and opiate pathways. Melatonin has now been shown to help alleviate the pain of hemicrania continua and primary stabbing headache, and in some cases patients become pain-free on melatonin. Melatonin should be tried on all patients with indomethacin-sensitive headaches, including those who are doing well on indomethacin, to try and either lower the indomethacin dose or come off indomethacin entirely or in those who have contraindications to indomethacin. Recently the author did a larger study of melatonin in patients with CPH and HC.78 Less than 20% achieved pain freedom on melatonin alone, but as an add-on therapy about 45% had substantial reduction in pain with the ability to reduce their baseline indomethacin dose. Melatonin dosing: start at 3 mg at bed for 5 nights, then increase every 5 nights by 3 mg up until 5 tabs (l5 mg at bed) and re-assess with physician. Can continue dosing up to 30 mg if tolerated.
  • • The author and colleague have documented the long-term efficacy of radiofrequency lesioning of the C2 dorsal root ganglia, C2 ventral ramus, and/or sphenopalatine ganglia in indomethacin-responsive headaches. Post-procedure most patients can come off indomethacin without pain recurrence.79

SUNCT Syndrome

ICHD-3 diagnostic criteria:

  • • At least 20 attacks fulfilling criteria B-D
  • • Moderate or severe unilateral head pain, with orbital, supraorbital, temporal, and/or other trigeminal distribution, lasting for 1-600 seconds and occurring as single stabs, series of stabs, or in a saw-tooth pattern
  • • At least one of the following five cranial autonomic symptoms or signs, ipsilateral to the pain:

° Conjunctival injection and/or lacrimation ° Nasal congestion and/or rhinorrhea ° Eyelid edema ° Forehead and facial sweating ° Miosis and/or ptosis

• Occurring with a frequency of at least one a day

The syndrome of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is one of the rarest of the primary headache disorders. SUNCT is comprised of brief attacks of moderate to severe head pain with associated autonomic symptoms of conjunctival injection, tearing, rhinorrhea, or nasal obstruction. SUNCT pain is normally localized to an orbital or periorbital distribution, although the forehead and temple can be the main site of pain. Head pain can radiate to the temple, nose, cheek, ear, and palate. The pain is normally side-locked and remains unilateral throughout an entire attack. In rare instances SUNCT pain can be bilateral. Pain duration is extremely short, lasting between 1 and 600 seconds, with an average duration of 10 to 60 seconds. This extremely brief pain duration sets SUNCT apart from other primary headache syndromes (e.g., cluster headache, chronic paroxysmal hemicrania, and migraine). Pain onset is abrupt, with maximum intensity being reached in 2 to 3 seconds. SUNCT pain normally plateaus at a maximum intensity for several seconds and then quickly abates. SUNCT can occur at any time of the day and does not show a tendency toward nocturnal attacks. Attack frequency varies greatly between sufferers and within an individual sufferer. The usual attack frequency ranges anywhere from 1 to more than 80 episodes a day. Individuals can experience from fewer than 1 attack an hour to more than 30 an hour. Most SUNCT patients will be pain-free between attacks, although there are isolated reports of patients experiencing low background pain interictally. SUNCT is an episodic disorder that presents in a relapsing or remitting pattern. Each symptomatic period can last from several days to several months, and a person with SUNCT will typically have one to two symptomatic periods a year. SUNCT can arise spontaneously, but many sufferers have identified triggering maneuvers, including mastication, nose blowing, coughing, forehead touching, eyelid squeezing, neck movements (rotation, extension, and flexion), and ice cream eating. In SUNCT there is no refractory period between pain attacks, so if a trigger zone is stimulated during the ending phase of a previous attack, a new one can begin immediately. This is unlike the refractory period of trigeminal neuralgia. There may indeed be an overlap between trigeminal neuralgia and SUNCT. SUNCT has recently been linked to trigeminal nerve/vessel compression which has been a known etiology for trigeminal neuralgia. All patients with SUNCT should have neuroimaging to look for vessel/nerve contact near the trigeminal root entry zone. In addition, looking for an underlying secretory pituitary tumor (growth hormone, prolactin) is also mandatory by lab work and imaging. Suggested treatments that have shown efficacy in SUNCT include lamotrigine, gabapentin, topira- mate, and clomiphene citrate in refractory cases. Decompression of a nerve contact point may also have efficacy.80-81

Pathogenesis: data suggest that there is indeed posterior hypothalamic activation in many SUNCT patients on functional neuroimaging and this is bilateral in many even though headaches are one-sided, but it also can be ipsilateral or contralateral to the side of the pain.

 
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