Chronic Paroxysmal Hemicrania 

Updated: Jun 12, 2019
Author: Monica Saini, MD, MBBS;

Overview

Background

Chronic paroxysmal hemicrania (CPH), also known as Sjaastad syndrome, was first described in 1974, by Sjaastad and Dale.[1] In 1976, the term CPH was proposed by Sjaastad on the basis of the first 2 patients, who had daily (ie, chronic), solitary, limited attacks (ie, paroxysmal) of unilateral headache that did not shift sides (ie, hemicrania).[2]

CPH falls under the Trigeminal Autonomic Cephalalgias (TACs); it accounts for about 3%–8% of TACs and is much less common than cluster headache (CH).[3] (See Presentation.)

The short-lasting primary headache syndromes may be divided into (1) headaches with autonomic activation and (2) headaches without autonomic activation. Headaches with autonomic activation include chronic and episodic paroxysmal hemicrania, CH, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome). (See Etiology and DDx.)

Diagnostic criteria

In the current International Classification of Headache Disorders (ICHD-3), TACs include cluster headache (CH), paroxysmal hemicrania (PH), and the short-lasting unilateral neuralgiform headache attacks (SUNHAs).[4]

ICHD-3 diagnostic criteria for PH include the following:

A. At least 20 attacks of headache fulfilling criteria B–E

B. Severe unilateral orbital, supraorbital and/or temporal pain lasting 2–30 minutes

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 rhinorrhoea, c) eyelid oedema, d) forehead and facial sweating, e) miosis and/or ptosis
  2. a sense of restlessness or agitation

D. Occurring with a frequency of >5 per day

E. Prevented absolutely by therapeutic doses of indomethacin

F. Not better accounted for by another ICHD-3 diagnosis

Chronic versus nonchronic

PH may be present in nonchronic or chronic form, although the chronic type is 4 times more common. Approximately 65%–85% of patients with PH have the chronic form.[5]

Nonchronic attacks are similar to chronic ones but tend to be less severe and less frequent. (See Prognosis.)

Before the development of chronic symptoms, many patients (42%) pass through a nonchronic stage, with attacks separated by intervals of complete remission.

The term pre-CPH stage or prechronic was preferred initially on the basis of the assumption that all patients would develop chronic symptoms. However, approximately 20% of patients appear to remain in the nonchronic stage for long periods.

ICHD-3 diagnostic criteria for CPH are as follows:[4]

A. Attacks fulfilling criteria for Paroxysmal hemicrania, and criterion B below

B. Occurring without a remission period, or with remissions lasting < 3 months, for at least 1 year

Etiology

The mechanisms responsible for pain in CPH remain unknown. The past medical history in patients with CPH is usually unremarkable. A history of head or neck trauma is reported in about 20% of cases, but these findings are similar to those for CH or migraine.

Occasionally, attacks may be provoked mechanically by bending or rotating the head and by applying external pressure against the transverse processes of C4-C5, C2 root, or the greater occipital nerve.

No familial disposition is known for CPH; families of affected individuals do not have higher incidences of CH or migraine than does the general population.

Discussion of important features, such as intense, unilateral headache; autonomic abnormalities; and effectiveness of indomethacin, may help in understanding the pathogenesis.[6]

Trigeminal, sympathetic, and parasympathetic involvement

The release of trigeminal and parasympathetic neuropeptides during headache has been described.[7] Activation of the ipsilateral trigeminovascular system may explain sudden, unilateral headache and may lead to miosis, increased intraocular pressure (IOP), and other autonomic abnormalities.

Increased sweating and decreased salivation during attacks and the ability of an alpha-blocking agent or a stellate ganglion blockade to inhibit an increase in IOP suggest sympathetic involvement.

Increased tearing, nasal secretion, and miosis may be due to parasympathetic stimulation. Trigeminoparasympathetic activation during CPH attacks has been suggested; increases in the vasoactive intestinal peptide (ie, parasympathetic peptide) level have been reported. levels of calcitonin gene-related peptide also are reported to be high during CPH attacks.

Pain and pressure threshold, nociceptive flexion reflex, and blink and corneal reflexes have been studied in patients with CPH. The corneal reflex thresholds have been found to be decreased bilaterally during CPH attacks. Increases in corneal temperature on the symptomatic side also have been reported; this finding may be due to increased ocular blood flow.

The effectiveness of indomethacin in CPH may be due partly to reduction of intracranial blood flow (via a nonprostaglandin mechanism) and partly to the drug’s anti-inflammatory effects.

These findings may indicate a primary central mechanism and a secondary involvement of peripheral factors, affecting the sympathetic and parasympathetic systems.

Hypothalamic involvement

Studies have suggested a crucial role by the hypothalamus in CPH. Functional neuroimaging studies have demonstrated activation of the hypothalamus in cases of trigeminal autonomic cephalgias.[8, 9]

Epidemiology

Occurrence in the United States

CPH is a rare syndrome, but the number of diagnosed cases is increasing. The prevalence of CPH is not known, but the relative frequency compared with CH is reported to be approximately 1-3%.

International occurrence

Many cases of CPH have been described throughout the world, in different races and in different countries, including Australia, the Czech Republic, Slovakia, Denmark, Italy, France, Mexico, Canada, Sweden, Germany, Poland, India, Spain, Brazil, South Africa, Norway, New Zealand, the United Kingdom, and the United States.

Sex- and age-related demographics

In the past, because of a female preponderance, CPH was considered a disease of women. However, CPH has been reported in increasing numbers of men. A study conducted in 1979 reported a female-to-male ratio of 7:1, but a review of 84 patients in 1989 reported a female-to-male ratio of 2.3:1. A more recent prospective study of 31 patients found a female-to-male ratio of 1:1.[10]

CPH can occur at any age, with the mean age of onset being 34 years.[11] Patients as young as age 6 years have been described in the literature, while the oldest known patient with CPH was age 81 years.[12, 13] In one report, CPH beginning at age 3 years was described; however, the condition may have been related to ipsilateral occipital hemorrhagic infarction in this patient.[14, 15]

Prognosis

Patients in the nonremitting stage of CPH may need lifelong therapy, possibly with smaller doses of indomethacin.

Long-lasting remission periods usually reflect a nonchronic stage, but they may occur in patients with established chronic disease. In chronic cases, in fact, recurrence of attacks after a drug-free period of 1.5 years has been reported.

The mortality rate and morbidities associated with CPH have not been reported, although the therapy of choice for this condition, indomethacin, is known to be associated with the risk of bleeding.

Factors that may or may not affect the course of CPH include the following:

  • Pregnancy - CPH attacks have been reported to improve during pregnancy; however, they recur after delivery

  • Menstruation - Menstruation may have either a positive or negative effect on attacks

  • Birth control - Birth control pills do not seem to influence attack frequency

  • Menopause - Reliable data do not exist regarding the effects of menopause on CPH

 

Presentation

History

The pain in chronic paroxysmal hemicrania (CPH) is characteristically unilateral. However, pain may switch sides between attacks and can rarely be bilateral.[16]

Patients usually report pain that is severe in intensity and has an abrupt onset and cessation. During severe attacks, excruciating pain that is throbbing, boring, pulsating, or clawlike in character has been described. The location of pain is primarily in the distribution of the ophthalmic division of the trigeminal nerve and C2, followed by the maxillary-mandibular and C3 distributions. Accompanying photophobia and phonophobia has been reported, usually lateralizing to the side of the pain. Occasionally, patients may experience nausea, though vomiting is rare. In 50%–80% of patients, agitation or restlessness may be noted.[10, 17]

Headache can develop at any time in patients with CPH, in contrast to CH, in which the headache usually occurs at night.

The attack frequency usually is 10–20 attacks daily, but it may range from 2 to 40 attacks daily. Attacks usually last 2–25 minutes, but they may last as long as 60 minutes. In a prospective study, mean attack duration was 13 minutes (range 3–46 min). In a retrospective study, the mean duration of attacks was 21 minutes (range 2–120 min).

CPH has been reported to be triggered by various stimuli, including neck movement, external pressure to the neck, or other factors.

CPH attacks are accompanied by autonomic symptoms, mostly on the same side as the pain, such as red eyes, tearing, nasal congestion, and, sometimes, rhinorrhea. Occasionally, photophobia may be present. Gastrointestinal symptoms are very rare.

Recognizing the various stages and different patterns of CPH is important. For example, during severe, frequent attacks, patients may describe a constant headache or persisting tenderness on the symptomatic side.

Physical Examination

The pain is severe in patients with CPH, and attacks are associated with autonomic features, such as the following:

  • Lacrimation - 62%

  • Conjunctival injection - 36%

  • Ipsilateral nasal congestion - 42%

  • Rhinorrhea - 36%

  • Eyelid edema - 33%

Lacrimation may occur bilaterally but is always more marked on the symptomatic side. Occasionally, mild ipsilateral miosis may be observed during attacks.

Patients with CPH who have had dissociation in pain and autonomic features also have been described. Other points to consider in the physical examination include the following:

  • No definite evidence points to a Hornerlike syndrome, such as that described in cluster headache (CH), but mild miosis and eyelid edema that may mimic ptosis may be observed

  • Forehead sweating may increase on the ipsilateral side, and patients with generalized sweating have been reported

  • The coexistence of CPH and trigeminal neuralgia is called CPH-tic syndrome; many cases of this syndrome have been reported

  • Simultaneous occurrence of ipsilateral CH and migraine headache in patients with CPH has been reported

  • PH has been reported to co-occur with primary cough and stabbing headache, which are also indomethacin-sensitive[18]

  • Perform a careful physical examination to evaluate pathologic secondary headache

 

DDx

Diagnostic Considerations

Differential diagnosis should include other headaches with major autonomic features (eg, SUNCT syndrome) and persistent headaches with milder autonomic features (eg, hemicrania continua [HC]).[19]

HC is a rare disorder characterized by continuous, unilateral, indomethacin-responsive hemicrania of moderate severity.[20] These headaches last from minutes to several days and sometimes are associated with autonomic features. A noncontinuous form also has been described.

Along with HC, several other paroxysmal, indomethacin-responsive headache syndromes have been described, including the following:

  • Jabs-and-jolts syndrome

  • Icepick headache

  • Hypnic headache syndrome

  • Benign cough headache syndrome

  • Benign exertional headache

  • Coital headache

  • Thunderclap headache

Cervicogenic headache, facial neuralgia, and other rare disorders, such as red ear syndrome, also are considered in the differential diagnosis.

Simultaneous occurrences of CPH and other disorders, including CH, trigeminal neuralgia (CPH-tic syndrome), and migraine, also have been reported. The crucial factor in the differential diagnosis is the absolute response to indomethacin.

Cluster headache

The trigeminal-autonomic cephalgias include cluster headache (CH) and paroxysmal hemicranias in which head pain and cranial autonomic symptoms are prominent. CH is the most important differential diagnosis.

CH has male preponderance, unlike CPH. In CPH, the frequency of attacks is higher, usually more than 15 in 24 hours, whereas CH has an attack frequency of 1–4 (maximum 8) in 24 hours. The duration of headaches is shorter in CPH (2–25 min) than in CH (15–60 min). While CH has a nocturnal preponderance, CPH does not demonstrate any circadian rhythm. Autonomic symptoms tend to be more severe in CH. Finally, CPH can be distinguished by its response to indomethacin therapy, which is not seen in CH.

SUNCT syndrome

SUNCT syndrome is a rare, distinctive condition with a male preponderance; it is characterized by less severe pain but also by marked autonomic activation during attacks. The pain, usually in the frontal and periocular area, is intractable to medications, including indomethacin.

LASH

A unique, stereotypical, episodic headache disorder marked by long-lasting autonomic symptoms with associated hemicrania (LASH) has been reported. The autonomic symptoms clearly overshadow the headache as the major component of the syndrome. Both types of symptoms respond to indomethacin.

Other differentials

Other disorders that may mimic CPH include the following[21] :

  • Infarcts

  • Arteriovenous malformation

  • Brain tumor - Eg, frontal lobe tumor, meningioma of the roof of the cavernous sinus, pathologic process in the region of the cavernous sinus, gangliocytoma near the sella turcica, and parasellar pituitary microadenoma

  • Maxillary cyst

  • Collagen vascular disorders

  • Cervical radiculopathy

  • Disk herniation

  • Carotidynia

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of chronic paroxysmal hemicrania (CPH) is extremely important because it may lead to lifelong treatment with a potentially noxious drug.

A detailed clinical history in regards to headache characteristics is crucial for diagnosis. Lab studies to evaluate structural, metabolic, and other secondary causes of headache and facial pain are indicated where atypical features are noted. Baseline routine blood tests may be needed to exclude contraindications to certain drugs and to avoid complications from long-term use of various medications.

The INDOTEST (indomethacin 50mg intramuscular [IM] test dose) may be a useful tool in assessment of unilateral headache. Perform this test in a standardized manner. Intramuscular indomethacin 50 mg should result in freedom of attacks within 30 minutes. Oral indomethacin in a daily dose of up to 200 mg is reported to be completely effective, and provides diagnostic certainty.

No characteristic electrocardiographic patterns have been found during attacks of CPH, but marked variations in heart rate and rhythm abnormalities, including bradycardia, sinoatrial block, bundle branch block with episodes of atrial fibrillation, and multiple extrasystoles, have been observed.

Orbital phlebography may be abnormal in some patients, but the significance of this finding has not been established.

In a study of 3 patients with CPH, a slightly lower cerebral vasomotor reactivity was observed in the medial and posterior cerebral arteries on both sides and in the anterior cerebral artery on the symptomatic side than has been found in healthy subjects. These observations may imply an abnormal vascular reactivity in CPH.

In another study, as compared with cluster headache (CH), CPH attacks did not demonstrate any changes in visually evoked event-related potentials (ERPs), latencies, and amplitudes.[22]

Perform ophthalmic evaluation, if needed, to assess ocular pathology such as glaucoma or orbital pseudotumor.

Imaging studies

Computed tomography (CT) scanning or, preferably, magnetic resonance imaging (MRI) of the brain may be needed to rule out structural pathology. Neuroimaging study findings, including those from MRI, are usually normal in patients with CPH.

Consider obtaining an MR angiogram or arteriogram, if necessary, for atypical presentations. Electroencephalography, brain mapping, and other radiologic studies are not required for patients with typical presentations.

Procedures

Consider lumbar puncture, if necessary, for atypical presentations.

 

Treatment

Approach Considerations

The treatment of choice for chronic paroxysmal hemicrania (CPH) is indomethacin, which has an absolute effect on the symptoms. Episodic cluster headache (CH) and CPH respond well to this agent. Take precautions to prevent serious gastrointestinal and renal complications secondary to long-term use of indomethacin. Indomethacin should be administered in three or more doses per day because of its short half-life time of 4 hours.[3]

Approximately 30% of patients report dose-limiting side effects with indomethacin and about 20% may discontinue indomethacin due to side effects. The evidence for other medications is available from only open studies.[23] The best evidence amongst these medications is for verapamil. Other medications with reported benefits include acetazolamide, topiramate, piroxicam, and aspirin.[24]

Emerging treatments

Non-invasive vagus nerve stimulation (nVNS) has been reported to be benificial in small cohorts of patients.[25, 26]

Occipital nerve stimulation was demonstrated to be effective in one patient, with a follow-up of more than 10 years. Patient reported a sustained efficacy of >50% reduction in attack frequency, with complete resolution at final follow-up such that indomethacin could be discontinued.[27]

Deep brain stimulation (DBS), targeting the posterior hypothalamus, has been used to treat patients with chronic, medically refractory TACs (CH, PH and SUNCT), achieving a response rate of around 60%.[28]

Uncertain or ineffective treatments

Subcutaneous sumatriptan is ineffective.[3]

Anaesthetic blockades of pericranial nerves are said to be ineffective.

Oxygen, lithium, carbamazepine, and other anticonvulsants are ineffective in patients with CPH.

Anesthetic blockade of the occipital nerves and supraorbital nerve has not provided significant relief. Occipital nerve blockade helps in distinguishing CPH and HC from cervicogenic headache. Supraorbital nerve blockade may help in distinguishing hemicrania continua (HC) and supraorbital nerve neuralgia (in which nerve block is markedly effective).

Reliable evidence for the efficacy of chiropractic manipulation, acupuncture, or surgical management in the treatment of CPH does not exist.

Consultations

Consult with an ophthalmologist to evaluate ocular pathology such as glaucoma or orbital pseudotumor.

 

Medication

Medication Summary

The drug of choice in the treatment of chronic paroxysmal hemicrania (CPH) is indomethacin.[21] When a patient experiences frequent, unilateral headaches (ie, >4 attacks in 24 h), a drug trial with indomethacin should be considered. The dose of indomethacin should be increased to at least 150 mg/day for 3-4 days. A beneficial effect is seen usually within 48 hours but may take as long as 5 days.

In one study, indomethacin effect was complete within 24 hours in most patients, and frequently the effect was seen within 8 hours. Maintenance dosage is usually 25-100 mg/day but may range from 12.5-300 mg/day. After discontinuation of medication, symptoms usually reappear within 12 hours to a few days. However, remission periods lasting years have been described.

A significant proportion of patients may experience adverse effects of indomethacin, including dyspepsia, nausea, vomiting, vertigo, gastric bleeding, purpura, and other conditions. To prevent adverse gastric effects, antacids, misoprostol, or an H2 antagonist or proton pump inhibitor may be coadministered when indomethacin is being used for longer periods. An indomethacin suppository is another option for gastric intolerance or when a higher dose (eg, 300 mg/day) is needed.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Class Summary

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Indomethacin (Indocin)

Indomethacin has absolute effect on symptoms of CPH. It is available as an immediate-release preparation, a sustained-release preparation, a suppository, and an oral suspension.

Naproxen sodium (Aleve, Anaprox, Naprelan, Naprosyn)

Naproxen sodium is used for the relief of mild to moderately severe pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Ibuprofen (Motrin, Ibuprin, Addaprin, Ibu, Caldolor)

Ibuprofen is the drug of choice for patients with mild to moderately severe pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Piroxicam (Feldene)

Piroxicam is used for the relief of mild to moderately severe pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Celecoxib (Celebrex)

Celecoxib primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, GI toxicity may be decreased. Seek the lowest dose of celecoxib for each patient. It is extensively metabolized in liver primarily via cytochrome P450 2C9. Celecoxib is approved by the FDA to treat osteoarthritis and rheumatoid arthritis.

Although increased cost can be a negative factor, the incidence of costly and potentially fatal GI bleeds is clearly less with COX-2 inhibitors than with traditional NSAIDs. Ongoing analysis of cost avoidance of GI bleeds will further define the populations that will find COX-2 inhibitors the most beneficial.

Aspirin (Ascriptin, Bayer Aspirin, Bufferin, Ecotrin, Halfprin)

Aspirin treats mild to moderately severe pain. It inhibits prostaglandin synthesis, preventing the formation of platelet-aggregating thromboxane A2.

Calcium Channel Blockers

Class Summary

These agents inhibit calcium ions from entering slow channels, select voltage-sensitive areas, and vascular smooth muscle. Verapamil may be an effective calcium channel blocker for the prophylaxis of CPH.

Verapamil (Calan, Verelan, Covera-HS)

During depolarization, verapamil inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle.

Corticosteroids

Class Summary

These agents may be effective in the treatment of CPH. Pain relief may occur via inhibition of prostaglandin synthesis.

Prednisone

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. A high dose is prescribed for the first few days, followed by a gradual taper.

Prednisolone (Pediapred, Prelone, Orapred)

Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is a commonly used oral agent. A high dose is prescribed for the first few days, followed by a gradual taper.

Carbonic Anhydrase Inhibitors

Class Summary

These agents may be used to provide relief in patients with CPH.

Acetazolamide (Diamox)

Acetazolamide is a carbonic anhydrase inhibitor that blocks HCO3 reabsorption in the proximal renal tubules. It causes increased renal excretion of sodium versus chloride, causing a net increase in serum chloride. Acetazolamide is also a diuretic and, therefore, may help decrease extracellular fluid (ECF) volume that frequently accompanies chloride-resistant metabolic alkalosis. Acetazolamide may provide relief in patients experiencing CPH.

Anticonvulsants, Other

Class Summary

Agents with state-dependent sodium channel–blocking action and inhibitory activity of the neurotransmitter GABA may have prophylactic effects on CPH.

Topiramate (Topamax)

Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic activity that may have state-dependent sodium channel–blocking action. This agent potentiates the inhibitory activity of the neurotransmitter GABA and may block glutamate activity. It is not necessary to monitor plasma concentrations to optimize therapy.