Hemicrania Continua

Etiology

Hemicrania continua is a primary headache disorder without a secondary organic cause. Our understanding of the pathogenetic mechanisms of trigeminal autonomic cephalalgias, including hemicrania continua, is limited. Multiple theories have been proposed, including cavernous sinus inflammation, intracranial arterial vasodilation, upregulation of vasopeptides, particularly calcitonin gene–related peptide and vasoactive intestinal peptide, and trigeminal nerve autonomic dysregulation, resulting in the increased cranial parasympathetic outflow. Other intracranial areas are also involved, as pain is not always restricted to the area supplied by the trigeminal nerve. Secondly, trigeminal nerve transection does not relieve symptoms in all patients.[5]

Epidemiology

Hemicrania continua was initially considered a rare headache disorder. Only 18 cases were reported in the first 7 years and about 100 cases in the first 17 years (1984-2001) after its discovery.[6][7] Although large epidemiologic studies are lacking to outline the exact prevalence of this condition, hemicrania continua cases are estimated to constitute about 1% of total headache cases.[8][9] A more recent meta-analysis of patients attending headache clinics estimated a higher number of 1.8% among all headache patients.[10] This number is still considered underreported and underdiagnosed.

Hemicrania continua is more prevalent in young adults in their third and fourth decades, with a mean age of 30. However, the range varies from the first to seventh decades. Hemicrania continua is slightly more common in women compared to men, with a reported female-to-male ratio of 1 to 2.4.[10]

History and Physical

As the name indicates, patients with hemicrania continua present with a continuous unilateral headache lasting at least 3 months. This headache is mild to moderate in severity, dull in character, and often does not affect physical activity. The pain commonly coincides with the territories innervated by the trigeminal nerve's first division, particularly the frontal and periorbital regions, but extratrigeminal areas may also be involved.

The unilateral headache in hemicrania continua is side-locked, meaning it occurs on the same side, with a slight preference for the right side. However, side-alternating attacks have also been reported in the literature.[11] Rare cases of bilateral hemicrania continua have also been documented.[12][13][14] Although the headache in hemicrania continua is unremitting, about 1 in 5 persons (20%) may experience pain-free periods lasting from 1 day to several weeks.[15] The clinical diagnostic criteria based on ICHD-3 are listed in the Evaluation section below.

The background headache often has superimposed fluctuating headache exacerbations, lasting a few minutes to days. These exacerbations are also highly variable, with a frequency ranging from more than 20 attacks daily to 1 attack in 4 months. About half of patients report 1 attack daily. The pain is moderate to very severe in intensity and throbbing or stabbing in character. Some people may label these headache exacerbations as the worst headache of their lives and may also experience suicidal thoughts during these exacerbations. Patients may become restless, agitated, and have difficulty staying still.

The migrainous features of photophobia, phonophobia, nausea, and vomiting may occur during exacerbations, but aura is very uncommon. Stress, alcohol, irregular sleep patterns, and menstruation also trigger exacerbations in some patients.

Similar to other trigeminal autonomic cephalalgias, hemicrania continua is associated with ipsilateral cranial autonomic symptoms, especially during exacerbations. Still, these autonomic symptoms are generally less prominent compared to other trigeminal autonomic cephalalgias, including cluster headaches and paroxysmal hemicrania. The cranial autonomic features reflect parasympathetic overactivity and sympathetic underactivity. These features may include forehead sweating, lacrimation, conjunctival injection and swelling, ptosis, miosis, foreign body sensation in the eye, nasal congestion, rhinorrhea, and aural fullness.

Evaluation

ICHD-3 has proposed the following criteria for the diagnosis of hemicrania continua:

• Unilateral headache fulfilling criteria 2 to 4
• Present for greater than 3 months, with exacerbations of moderate or greater intensity
• Either or both of the following:
  • At least 1 of the following symptoms or signs, ipsilateral to the headache:
    • Conjunctival injection or lacrimation
    • Nasal congestion or rhinorrhoea
    • Eyelid edema
    • Forehead and facial sweating
    • Miosis or ptosis
  • A sense of restlessness or agitation or pain aggravation by movement
• Responds absolutely to therapeutic doses of indomethacin
• Not better accounted for by another ICHD-3 diagnosis

The ICHD-3 diagnostic criteria for hemicrania continua focus on 3 key features: unilateral continuous pain for more than 3 months, the presence of either ipsilateral cranial autonomic symptoms or agitation during exacerbations, and a complete response to indomethacin, which is 1 of the pathognomonic features of hemicrania continua. A complete response to indomethacin is typically noted within 2 hours of indomethacin injection. The headache reappears within 6 to 24 hours of stopping indomethacin. Since indomethacin provides dramatic relief, an indomethacin trial is proposed by a few authors in all chronic unilateral headaches. However, a response to indomethacin does not rule out secondary causes of hemicrania continua.[16]

Secondary conditions that may mimic hemicrania continua include posttraumatic headache, post-craniotomy headache, intracranial space-occupying lesions, poststroke headache, internal carotid artery dissection or aneurysm, idiopathic intracranial hypertension, venous malformation, cerebral venous sinus thrombosis, analgesic rebound headache, paraneoplastic syndromes, sinus pathologies, dental lesions, and temporomandibular joint pathologies.

Secondary causes of hemicrania continua should be excluded based on clinical features and appropriate investigations. All patients should be asked about any history of recent trauma. Brain magnetic resonance imaging (MRI) is recommended for all patients presenting with hemicrania continua–like headaches.[17] An angiography, such as magnetic resonance, computed tomography, or digital subtraction angiography, of the head and neck should be advised if a vascular pathology, such as internal carotid artery dissection or aneurysm, is suspected. The clinical features suggesting a vascular pathology include the short-term duration of symptoms, frequent exacerbations, neck pain, neck tenderness, focal neurological symptoms, Horner syndrome, and a history of trauma.

Treatment / Management

Indomethacin

A complete response to indomethacin is 1 of the pathognomonic features of hemicrania continua. Indomethacin is a nonsteroidal anti-inflammatory drug that reversibly inhibits prostaglandin-forming cyclooxygenase (COX) enzyme, similar to ibuprofen and naproxen. Indomethacin is more effective compared to other nonsteroidal anti-inflammatory drugs, probably because it exhibits the greatest central nervous system penetration, central serotonergic effects, inhibition of nitrous oxide-dependent vasodilation, and effects unrelated to COX inhibition.[18] Indomethacin may abort an acute exacerbation of hemicrania continua. This drug is also effective in hemicrania continua prophylaxis, another reason its effect may not be purely related to COX inhibition.[19](B3)

Indomethacin is started at a low dose of 25 mg 3 times a day with meals and titrated slowly, depending upon the response. Patients typically respond within 24 hours, but some may take up to a week.[20] If no clinical response is observed within 48 to 72 hours, the dose is typically increased until either a complete response is achieved or a maximum dose of 500 mg/d is given. The mean dose is typically lower than 200 mg/d.(B3)

Keeping the patient on a minimal long-term therapeutic dose of indomethacin is reasonable to mitigate potential adverse effects, including abdominal discomfort, heartburn, nausea, vomiting, life-threatening gastrointestinal hemorrhage, hypertension, renal failure, and liver failure. Most of the adverse effects of indomethacin are dose-dependent, and maintaining the lowest possible therapeutic dose is recommended. The treatment is often long-term, if not lifelong. Successful indomethacin tapering has been reported in multiple patients without headache recurrence.

Other Noninvasive Treatments

Other noninvasive treatment options should be tried if a patient cannot tolerate indomethacin due to its side effects. These alternatives include melatonin; topiramate; COX-2 inhibitors, such as rofecoxib and celecoxib; gabapentin; corticosteroids; lamotrigine; lithium; amitriptyline; valproate; and naproxen. These drugs are not as effective as indomethacin for treating hemicrania continua, but they should be tried before invasive interventional options are considered. Melatonin has a structure similar to indomethacin and may also be combined with the nonsteroidal anti-inflammatory drug to lower the latter's dose and prevent adverse effects.[21] High-dose oxygen and sumatriptan are typically not effective in managing hemicrania continua. A calcitonin gene–related peptide inhibitor, galcanezumab, has been reported to be successful in aborting pain in patients with hemicrania continua.[22](B3)

Invasive Treatments

Vagus nerve stimulation is an invasive neuromodulation technique used to treat hemicrania continua. Although available data are limited, a positive response has been reported in some studies.[23][24]

Botulinum toxin-A is a treatment approved by the Food and Drug Administration for chronic migraines. Many clinicians also consider it for treating hemicrania continua when noninvasive treatment fails or cannot be tolerated.[25]

Occipital nerve stimulation, such as botulinum toxin, is primarily used for resistant cases of chronic migraine. This modality is currently being investigated for treating hemicrania continua with varying results.[26][27][28](B3)

Sphenopalatine ganglion blockade is another invasive treatment used for managing hemicrania continua. This intervention cuts the parasympathetic outflow of the trigeminal nerve, an important pathophysiologic response in patients with hemicrania continua.

Deep brain stimulation is another invasive method that may be used to treat medically refractory trigeminal autonomic cephalalgia, including hemicrania continua. The posterior hypothalamus is the target in patients undergoing this treatment.[29]

Differential Diagnosis

The differential diagnosis of hemicrania continua includes the following:

• Secondary hemicrania continua, as outlined above, including ophthalmic herpes zoster [30]
• Chronic migraine
• Cluster headache
• Paroxysmal hemicrania
• Medication-overuse headache

A meticulous clinical investigation and appropriate use of diagnostic tests can differentiate these conditions and determine the best treatment option.

Prognosis

Hemicrania continua is not life-threatening, although it is often a lifelong condition. Chronic headaches, even treatable ones, affect patients' quality of life. A complete response to indomethacin treatment is 1 of the pathognomonic features of this condition.

Complications

Most complications of hemicrania continua are treatment-related. Most patients require long-term indomethacin treatment and are thus at risk of developing adverse effects, including abdominal discomfort, heartburn, nausea, vomiting, life-threatening gastrointestinal hemorrhage, hypertension, and renal and liver failure.