Chronic Paroxysmal Hemicrania

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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, which has been included in the International Headache Society (IHS) classification system since 1988, is much less common than cluster headache (CH). (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

IHS diagnostic criteria for CPH include the following (slightly modified from the Headache Classification Committee criteria, 1988) (see Presentation, Workup, Treatment, and Medication)[3] :

Chronic versus nonchronic

CPH may be present in nonchronic or chronic form, although the chronic type is 4 times more common. Nonchronic attacks are similar to chronic ones but may 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.

Dividing CPH into unremitting and remitting forms may be appropriate. The unremitting form is the chronic form, which either is unremitting from the onset or evolves from the remitting form

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.[4]

Trigeminal, sympathetic, and parasympathetic involvement

The release of trigeminal and parasympathetic neuropeptides during headache has been described.[5] 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.[6, 7]

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.

CPH can occur at any age, with the mean age of onset being 34 years.[8] Patients as young as age 6 years have been described in the literature, while the oldest known patient with CPH was age 81 years.[9, 10] 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.[11]

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:

History

The pain in chronic paroxysmal hemicrania (CPH) is unilateral, always affects the same side, and is generally oculofrontotemporal in location. The literature does contain reports of a few unusual cases; for example, patients with bilateral symptoms and a possible shift in the side of the headache when the CPH progresses from the nonchronic to the chronic stage.

The pain is usually most severe in the oculotemporal area, the forehead, and above or behind the ear. Occasionally, pain can radiate and involve the ipsilateral shoulder, arm, and neck.

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

During severe attacks, excruciating pain that is throbbing, boring, pulsating, or clawlike in character has been described. In contrast to patients with CH, patients with CPH usually sit quietly or may curl up in bed between attacks.

The attack frequency usually is 10-20 attacks daily, but it may range from 2-40 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 can 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 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:

Approach Considerations

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

Perform lab studies to evaluate structural, metabolic, and other secondary causes of headache and facial pain. 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.

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.[13]

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.

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.

Other medications that may provide relief include the following:

The results of one prospective, open trial conducted with 10 patients experiencing CPH suggested that acetylsalicylic acid (and probably naproxen and diclofenac) and verapamil (for prophylaxis) are the most effective second-line drugs.

In another report, 2 teenaged girls who demonstrated dramatic, yet incomplete, improvement with indomethacin had nearly complete relief with verapamil monotherapy.[14]

Uncertain or ineffective treatments

The efficacy of sumatriptan in CPH is still controversial.[15, 16, 17] 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 Summary

The drug of choice in the treatment of chronic paroxysmal hemicrania (CPH) is indomethacin.[12] 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.

About 10% 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.

An article suggested that topiramate--a sulfamate-substituted monosaccharide that potentiates the inhibitory activity of the neurotransmitter gamma-aminobutyric acid (GABA) and may block glutamate activity--could be helpful as a preventive agent.

Indomethacin (Indocin)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

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

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.

Verapamil (Calan, Verelan, Covera-HS)

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

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.

Prednisone

Clinical Context:  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)

Clinical Context:  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.

Class Summary

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

Acetazolamide (Diamox)

Clinical Context:  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.

Class Summary

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

Topiramate (Topamax)

Clinical Context:  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.

Class Summary

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

Author

Manish K Singh, MD, Assistant Professor, Department of Neurology, Teaching Faculty for Pain Management and Neurology Residency Program, Hahnemann University Hospital, Drexel College of Medicine; Medical Director, Neurology and Pain Management, Jersey Institute of Neuroscience

Disclosure: Nothing to disclose.

Coauthor(s)

Jashvant Patel, MD, Medical Director, Department of Pain Medicine and Comprehensive Rehabilitation, Medical College of Pennsylvania Hahnemann University

Disclosure: Nothing to disclose.

Additional Contributors

Howard A Crystal, MD Professor, Departments of Neurology and Pathology, State University of New York Downstate; Consulting Staff, Department of Neurology, University Hospital and Kings County Hospital Center

Howard A Crystal, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Nothing to disclose.

Jorge E Mendizabal, MD Consulting Staff, Corpus Christi Neurology

Jorge E Mendizabal, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, National Stroke Association, and Stroke Council of the American Heart Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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