Paroxysmal hemicrania

Paroxysmal hemicrania is a rare primary headache disorder that usually begins in adulthood that is characterized by multiple attacks of unilateral pain that occur in association with cranial autonomic symptoms ¹. Patients experience severe throbbing, claw-like, or boring pain usually on one side of the face; in, around, or behind the eye; and occasionally reaching to the back of the neck. This pain may be accompanied by red and tearing eyes, a drooping or swollen eyelid on the affected side of the face, and nasal congestion. Patients may also feel dull pain, soreness, or tenderness between attacks. Attacks of paroxysmal hemicrania typically occur from 5 to 40 times per day and last 2 to 30 minutes. Paroxysmal hemicrania has two forms: chronic, in which patients experience attacks on a daily basis for a year or more, and episodic (nonchronic), in which the headaches may remit for months or years. Episodic (nonchronic) attacks are similar to chronic ones but tend to be less severe and less frequent. 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-chronic paroxysmal hemicrania 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. The chronic paroxysmal hemicrania is 4 times more common with approximately 65%–85% of patients with paroxysmal hemicrania have the chronic paroxysmal hemicrania ². Certain movements of the head or neck or external pressure to the neck may trigger these headaches in some patients. Paroxysmal hemicrania is more common in women than in men. Paroxysmal hemicrania prevalence is estimated to be 1:50,000, with a mean age of onset of 40 years (range 5-68 years).

The hallmarks of paroxysmal hemicrania syndrome are the relative shortness of the attacks and the complete response to indomethacin therapy.

Chronic paroxysmal hemicrania

Chronic paroxysmal hemicrania also known as Sjaastad syndrome, was first described in 1974, by Sjaastad and Dale ³. In 1976, the term chronic paroxysmal hemicrania 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) ⁴.

Chronic paroxysmal hemicrania falls under the trigeminal autonomic cephalalgias; it accounts for about 3%–8% of trigeminal autonomic cephalalgias and is much less common than cluster headache ⁵.

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, cluster headache, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome) ⁶.

International Classification of Headache Disorders, 3rd edition (beta version) ⁷ diagnostic criteria for chronic paroxysmal hemicrania are as follows:

• 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

Chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania was age 81 years ⁹. In one report, chronic paroxysmal hemicrania beginning at age 3 years was described; however, the condition may have been related to ipsilateral occipital hemorrhagic infarction in this patient ¹⁰.

What cause chronic paroxysmal hemicrania?

The mechanisms responsible for pain in chronic paroxysmal hemicrania remain unknown. The past medical history in patients with chronic paroxysmal hemicrania 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 cluster headache 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 chronic paroxysmal hemicrania; families of affected individuals do not have higher incidences of cluster headache 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 ¹¹.

Trigeminal, sympathetic, and parasympathetic involvement

The release of trigeminal and parasympathetic neuropeptides during headache has been described ¹². 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 chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania attacks.

Pain and pressure threshold, nociceptive flexion reflex, and blink and corneal reflexes have been studied in patients with chronic paroxysmal hemicrania. The corneal reflex thresholds have been found to be decreased bilaterally during chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania. Functional neuroimaging studies have demonstrated activation of the hypothalamus in cases of trigeminal autonomic cephalgias ¹³.

Chronic paroxysmal hemicrania symptoms

The pain in chronic paroxysmal hemicrania is characteristically unilateral. However, pain may switch sides between attacks and can rarely be bilateral ¹⁴.

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 ¹⁵.

Headache can develop at any time in patients with chronic paroxysmal hemicrania, in contrast to cluster headache, 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).

The pain is severe in patients with chronic paroxysmal hemicrania, 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 chronic paroxysmal hemicrania 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, 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 chronic paroxysmal hemicrania and trigeminal neuralgia is called chronic paroxysmal hemicrania-tic syndrome; many cases of this syndrome have been reported
• Simultaneous occurrence of ipsilateral cluster headache and migraine headache in patients with chronic paroxysmal hemicrania has been reported
• Paroxysmal hemicrania has been reported to co-occur with primary cough and stabbing headache, which are also indomethacin-sensitive ¹⁶

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

Chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania is important. For example, during severe, frequent attacks, patients may describe a constant headache or persisting tenderness on the symptomatic side.

Chronic paroxysmal hemicrania diagnosis

The diagnosis of chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania, 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 chronic paroxysmal hemicrania, 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 chronic paroxysmal hemicrania.

In another study, as compared with cluster headache, chronic paroxysmal hemicrania attacks did not demonstrate any changes in visually evoked event-related potentials (ERPs), latencies, and amplitudes ¹⁷.

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 chronic paroxysmal hemicrania.

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.

Chronic paroxysmal hemicrania treatment

The treatment of choice for chronic paroxysmal hemicrania is indomethacin, which has an absolute effect on the symptoms. Episodic cluster headache and chronic paroxysmal hemicrania 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 ⁵.

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.

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 ¹⁸. The best evidence amongst these medications is for verapamil. Other medications with reported benefits include acetazolamide, topiramate, piroxicam, and aspirin ¹⁹.

Emerging treatments

Non-invasive vagus nerve stimulation has been reported to be benificial in small cohorts of patients ²⁰.

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 ²¹.

Deep brain stimulation, targeting the posterior hypothalamus, has been used to treat patients with chronic, medically refractory trigeminal autonomic cephalalgias (cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing [SUNCT syndrome]), achieving a response rate of around 60% ²².

Uncertain or ineffective treatments

Subcutaneous sumatriptan is ineffective ⁵.

Anaesthetic blockades of pericranial nerves are said to be ineffective.

Oxygen, lithium, carbamazepine, and other anticonvulsants are ineffective in patients with chronic paroxysmal hemicrania.

Anesthetic blockade of the occipital nerves and supraorbital nerve has not provided significant relief. Occipital nerve blockade helps in distinguishing chronic paroxysmal hemicrania and hemicrania continua from cervicogenic headache. Supraorbital nerve blockade may help in distinguishing hemicrania continua 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 chronic paroxysmal hemicrania does not exist.

Chronic paroxysmal hemicrania prognosis

Patients in the nonremitting stage of chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania include the following:

• Pregnancy – chronic paroxysmal hemicrania 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 chronic paroxysmal hemicrania

What cause paroxysmal hemicrania?

Paroxysmal hemicrania cause remains unclear. Trauma, arteriovenous malformations (AVMs) and pituitary adenomas may play a causative role.

Paroxysmal hemicrania symptoms

Most patients (>60%) describe the pain as severe to very severe, rating it at 10 on a verbal rating scale of 0-10. The pain has a temporal, orbital or supraorbital localization. In rare cases, the pain may involve other areas of the face, head or neck. Accompanying ipsilateral autonomic features include lacrimation, conjunctival injection, rhinorrhea, nasal congestion, ptosis and facial flushing. Unilateral phono- and photophobia are frequent. Osmophobia, nausea or vomiting during the attacks has been reported. The attacks are triggered by stress or relaxation after stress, agitation, exercise, alcohol, neck movement, environmental temperature changes, and dietary products (cheese, chocolate, and coffee). The duration of attacks ranges from 2-30 minutes. Attacks usually have a frequency of above five per day (with a mean of 20 attacks per day). In 80% of patients, the disease is described as chronic (when patients have daily attacks without remission for at least one month). As a rule, patients with paroxysmal hemicrania have normal neurological tests. paroxysmal hemicrania has been reported in association with migraine, cluster headache, trigeminal neuralgia and cough headaches.

Paroxysmal hemicrania diagnosis

Paroxysmal hemicrania diagnosis is clinical.

Diagnostic criteria

In the current International Classification of Headache Disorders  – International Classification of Headache Disorders, 3rd edition (beta version) ⁷, trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania and the short-lasting unilateral neuralgiform headache attacks (SUNHAs).

International Classification of Headache Disorders, 3rd edition (beta version) diagnostic criteria for paroxysmal hemicrania 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 rhinorrhea, 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 International Classification of Headache Disorders, 3rd edition (beta version) diagnosis

Paroxysmal hemicrania treatment

A complete response to indomethacin confirms the diagnosis of paroxysmal hemicrania. Treatment with indomethacin with a median dose of 150 mg/day (ranging from 30-300/day) results in dramatic relief of the disabling symptoms caused by paroxysmal hemicrania. Other less effective nonsteroidal anti-inflammatory drugs (NSAIDs), calcium-channel blocking drugs (such as verapamil), and corticosteroids may be used to treat the disorder. Patients with both paroxysmal hemicrania and trigeminal neuralgia (a condition of the 5th cranial nerve that causes sudden, severe pain typically felt on one side of the jaw or cheek) should receive treatment for each disorder.

Paroxysmal hemicrania prognosis

Many patients experience complete to near-complete relief of symptoms following physician-supervised medical treatment. Paroxysmal hemicrania may last indefinitely but has been known to go into remission or stop spontaneously.

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