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 five times per day, up to forty 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 evaluation and management of chronic paroxysmal hemicrania and highlights the role of the interprofessional team in evaluating and improving care for 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.
• Identify interprofessional team strategies for improving care coordination and outcomes in patients with chronic paroxysmal hemicrania.

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 five times per day, up to forty 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 of the attack is 26 minutes, with a range of two 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 third edition (ICHD-3) 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 three months, for at least one year:

B. Severe unilateral orbital, supraorbital, 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 or lacrimation
   • Nasal congestion or rhinorrhea
   • Eyelid edema
   • Forehead and facial sweating
   • Miosis or ptosis
2. A sense of restlessness or agitation

D. Occurring with a frequency greater than five per day

E. Prevented absolutely by therapeutic doses of indomethacin

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

Etiology

The etiology of chronic paroxysmal hemicrania (CPH) is unknown. Past history of head or neck trauma is reported in few cases but it is similar in migraine as well. Familial disposition for CPH has not been reported. Attacks of CPH are provoked by bending or rotating the head and also by applying external pressure against the transverse processes of vertebrae C4-C5, C2 root, or the greater occipital nerve.

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 seen in chronic paroxysmal hemicrania are the results 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 emission 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 a 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, 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 (CPH) 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] Non-invasive vagal nerve stimulation has proved to be beneficial in a small cohort of CPH patients.[11][12]

Differential Diagnosis

Chronic paroxysmal hemicrania (CPH) mimics other chronic headaches, it is essential to differentiate as treatment modalities are different for different headaches. Following differentials should be considered when assessing a patient of CPH:

• 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.
• 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 Adverse 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 a 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 chronic paroxysmal hemicrania (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. Mortality or morbidities associated with CPH have not been reported. Pregnancy, menstruation, menopause, or birth control pills do not influence the course of CPH.

Complications

Chronic paroxysmal hemicrania (CPH) is a severely debilitating unilateral headache. The complications mostly arise from the treatment of CPH with indomethacin which is the drug of choice in these patients. 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 chronic paroxysmal hemicrania (CPH) as the specific time course, headache qualities, and associated autonomic symptoms can help guide the provider 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 (CPH) is a significant headache syndrome for medical providers 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 the 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 (CPH) 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 providers 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 a nephrologist to guide the safety of using indomethacin in the setting of renal insufficiency.