Continuing Education Activity

Chronic paroxysmal hemicrania is a primary headache syndrome characterized by recurrent unilateral episodes of headache associated with cranial autonomic symptoms. Headaches are sharp and stabbing in nature and occur more than 5 times per day, up to 40 times per day in some cases. Chronic paroxysmal hemicrania is a rare but under-diagnosed headache syndrome. Accurate diagnosis and timely treatment of chronic paroxysmal hemicrania can limit patient disability from this headache syndrome. This activity reviews the diagnosis, evaluation, and treatment of chronic paroxysmal hemicrania and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of chronic paroxysmal hemicrania.
• Review the appropriate evaluation of chronic paroxysmal hemicrania.
• Outline the management options available for chronic paroxysmal hemicrania.
• Discuss interprofessional team strategies for improving care coordination and communication to advance chronic paroxysmal hemicrania diagnosis and treatment and improve outcomes.

Introduction

Chronic paroxysmal hemicrania (CPH) is a primary headache syndrome characterized by recurrent unilateral episodes of headache associated with cranial autonomic symptoms. Headaches are sharp and stabbing in nature and occur greater than 5 times per day, up to 40 times per day in some cases. Associated cranial autonomic features include ipsilateral lacrimation, conjunctival injection, nasal congestion, rhinorrhea, facial flushing, eyelid edema, miosis or mydriasis, diaphoresis or aural fullness.[1] The mean duration attack is 26 minutes, with a range of 2 minutes to nearly two hours.[2] Attacks occur both daytime and nighttime in most cases. CPH occurs on the same side in greater than 95% of patients.[1][3] CPH differs from episodic paroxysmal hemicrania in that there is no remission or remission that lasts less than three months. Paroxysmal hemicrania responds well to indomethacin, with complete resolution in most patients. 

CPH is in a family of headache syndromes called the trigeminal autonomic cephalgias (TACs). TACs are characterized by unilateral trigeminal nerve distribution pain that occurs in tandem with ipsilateral cranial nerve autonomic symptoms. The TACs include paroxysmal hemicrania, cluster headache, hemicrania continua, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).

The International Classification of Headache Disorders 3rd Edition defines chronic paroxysmal hemicrania as follows:[4]

A. At least 20 attacks fulfilling criteria B to E without a remission period, or with remissions lasting less than 3 months, for at least one year:

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

C. Either or both of the following:

1. 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

2. A sense of restlessness or agitation

D. Occurring with a frequency greater than 5 per day

E. Prevented absolutely by therapeutic doses of indomethacin

F. Not better accounted for by another ICHD-3 (International Classification of Headache 3rd edition) disorder

Etiology

The etiology of chronic paroxysmal hemicrania is unknown.

Epidemiology

Chronic paroxysmal hemicrania is a rare, although likely underdiagnosed condition. One Norwegian study estimated the prevalence of 1%.[5] A review of several headache studies found that 1.7% of patients followed in a neurology headache clinic have a diagnosis of paroxysmal hemicrania.[6] Episodic paroxysmal hemicrania has been shown to affect males and females equally, whereas chronic paroxysmal hemicrania is more common in females. Chronic paroxysmal hemicrania can begin at any age, with a mean of onset of 37 years demonstrated in one study of 84 patients.[1][3]

Pathophysiology

The pain and autonomic symptoms are seen in chronic paroxysmal hemicrania are the result of communication via neuropeptides between hypothalamic nuclei and the trigeminal and facial nerves. The pain in paroxysmal hemicrania is mediated by trigeminovascular pathways via activation of the ophthalmic division of the trigeminal nerve, with cranial autonomic symptoms mediated by activation of facial nerve parasympathetic fibers.[7] Positron electron tomography (PET) and functional magnetic resonance imaging (fMRI) have shown contralateral hypothalamic activation in paroxysmal hemicrania.[8] Hypothalamic nuclei are integral in modulating pain pathways. The hypothalamus releases neuropeptides orexin-A (antinociceptive properties) and orexin B (pronociceptive properties), which relay pain signals to the trigeminal nerve.[9] 

History and Physical

A thorough history is key to diagnosing chronic paroxysmal hemicrania. Headache quality (sharp, stabbing), duration (2 to 30 minutes), and associated cranial autonomic features are the key features that suggest a diagnosis of CPH. Attacks are commonly spontaneous, although in 10% of patients head turning can trigger an attack.[3] Neurologic exam during a paroxysmal hemicrania attack may reveal unilateral autonomic features such as lacrimation, conjunctival injection, eyelid edema, ptosis, miosis, mydriasis, and/or diaphoresis. Tenderness to palpation in the periorbital and temporal region may be present unilaterally during an attack. Neurologic exam should otherwise be normal; if any other deficits are identified on neurologic examination, further evaluation with neuroimaging should be considered.

Evaluation

Primary chronic paroxysmal hemicrania is diagnosed by taking a thorough history and response to indomethacin. There is not a single imaging or laboratory test that is diagnostic of CPH, rather laboratory and imaging can be used to rule out alternative diagnoses. Cranial imaging is normal in primary chronic paroxysmal hemicrania. Imaging with magnetic resonance imaging or computed tomography can rule out a structural cause of secondary chronic paroxysmal hemicrania. Serum erythrocyte sedimentation rate and C-reactive protein are elevated in giant cell arteritis and are typically normal in CPH. Secondary paroxysmal hemicrania can occur due to vascular malformation, stroke, tumor, trauma, elevated intracranial pressure, or collagen vascular disease. 

Treatment / Management

Indomethacin, a nonsteroidal anti-inflammatory drug, is the first-line treatment for chronic paroxysmal hemicrania. Indomethacin dosed either 25 mg or 50 mg orally three times a day is typically effective for preventing attacks in CPH. Indomethacin is effective for preventing headaches in paroxysmal hemicrania, hemicrania continua, primary cough headache, and primary stabbing headache. Prolonged indomethacin use can predispose to peptic ulcers; for this reason, gastrointestinal prophylaxis with a proton pump inhibitor is recommended while taking indomethacin and limiting treatment with indomethacin to as short a duration as possible is ideal for preventing side effects. Indomethacin should be avoided in patients with renal insufficiency, prior stroke, or myocardial infarction. Calcium channel blockers, acetazolamide, topiramate, melatonin, and corticosteroids can also be used for preventing CPH, although they are less effective than indomethacin. Pericranial nerve blocks do not appear to be effective in treating chronic paroxysmal hemicrania.[10]

Differential Diagnosis

Trigeminal neuralgia involves paroxysms of pain in the trigeminal distribution; however, it does not have the associated autonomic features seen in chronic paroxysmal hemicrania. Temporal arteritis manifests as a temporally predominant headache with tenderness to palpation, monocular visual changes and laboratory workup classically shows an elevated sedimentation rate and C-reactive protein. The trigeminal autonomic cephalgias, including CPH, are characterized by headache associated with cranial autonomic features - cluster headache differs from CPH in its frequency of every 1 to 8 days and response to sumatriptan and high flow oxygen and lack of response to indomethacin. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection (SUNCT) also presents with unilateral headache and associated autonomic features, although attacks occur more frequently than CPH, with shorter duration and response to lidocaine infusion and lack of response to indomethacin. 

Toxicity and Side Effect Management

Indomethacin is the most effective treatment for chronic paroxysmal hemicrania. Indomethacin can exacerbate renal insufficiency and peptic ulcer disease. Indomethacin can cause cardiovascular thrombotic effects and should be used with caution in patients with prior stroke or myocardial infarction. Patients should be screened for renal impairment with a basic metabolic profile before initiating indomethacin treatment. Indomethacin should be avoided in patients who have a history of peptic ulcer disease. For patients with risk of peptic ulcer disease who would benefit from indomethacin treatment, gastrointestinal prophylaxis with a proton pump inhibitor can be given concurrently with indomethacin to minimize the risk of gastrointestinal irritation. Bleeding risk is increased when antithrombotic medications are taken with indomethacin.

Prognosis

The prognosis for recovery from CPH is excellent when patients are correctly diagnosed and treated with indomethacin. Intolerance or contraindications to indomethacin limit definitive treatment and may result in a more disabling headache course.

Complications

Exacerbation of peptic ulcer disease and renal insufficiency as well as an increased risk of cardiovascular thrombotic events can be seen in patients treated with indomethacin.

Deterrence and Patient Education

Patients should be educated on the signs and symptoms of the trigeminal autonomic cephalgias, including CPH as the specific time course, headache qualities, and associated autonomic symptoms can help guide the clinician to an accurate diagnosis and appropriate treatment. The various TACs, including CPH, respond to different medical therapies, so differentiating between these headache syndromes is important to achieve symptom relief.

Pearls and Other Issues

Chronic paroxysmal hemicrania is a significant headache syndrome for medical practitioners to be aware of because it can cause significant disability if left untreated, and it generally responds very well to treatment with indomethacin. Taking a thorough history, including headache frequency and duration, as well as the presence of associated cranial autonomic symptoms, is the key to diagnosing CPH. Cranial imaging and laboratory workup can help to rule out alternative diagnoses. A trial of indomethacin is appropriate for patients who meet criteria for CPH and do not have contraindications to treatment such as peptic ulcers, prior stroke or myocardial infarction, or renal insufficiency. Gastrointestinal side effects can be seen with indomethacin, it is essential to monitor patients for GI side effects and to consider GI prophylaxis with a proton pump inhibitor while taking indomethacin.

Enhancing Healthcare Team Outcomes

An interprofessional team that provides a holistic and integrated approach to chronic paroxysmal hemicrania can help achieve the best possible outcomes. The diagnosis of CPH can be made by any medical provider by taking a thorough headache history. Treatment of CPH with indomethacin requires consideration of any risk factors for peptic ulcer disease, cardiovascular disease, concurrent antithrombotic medications, and renal function. Primary care doctors and neurologists who most commonly diagnose and treat CPH may consult with a pharmacist regarding dosing schedule, a gastroenterologist regarding gastric safety of indomethacin, a cardiologist in the setting of a history of cardiovascular events and/or a nephrologist to guide the safety of using indomethacin in the setting of renal insufficiency.