Cluster Headache and Other Trigeminal Autonomic Cephalalgias

Cluster headache (CH) is a primary neurologic disorder characterized by severe unilateral head pain associated with ipsilateral autonomic features such as tearing, rhinorrhea, eyelid edema, and conjunctival injection. It affects about 1% of the population¹ and is the most common of the trigeminal autonomic cephalalgias (TAC). It is considered by many to be one of the most painful headache syndromes. Before modern effective treatments became available, CH caused significant morbidity and was known as the “suicide headache.” Historically, the diagnosis of CH has been something of a catch-all diagnosis owing in part to the fact that the term “cluster” has been used freely to describe patient histories with a pattern of headache symptoms that present in grouped fashion, which would more accurately fall under criteria of other conditions such as migraine, tension-type headache, or one of the other TAC disorders. This past misuse of the term has led to clinical neurologists encountering more incorrect diagnoses of CH in the medical history of their patients than apt diagnoses based on current criteria. A correct and timely identification of CH or its mimics, besides ruling out other differentials, allows clinicians to identify and implement effective treatments and may speed time to relief and remission of severely painful symptoms. This review provides an overview of CH and differentiates it from other primary and secondary headache pain syndromes to aid the clinician in making a prompt determination.

Clinical and Diagnostic Features of Cluster Headache

In The International Classification of Headache Disorders, 3rd edition (ICHD-3), CH is defined as attacks of severe, strictly unilateral pain, which are orbital, supraorbital, temporal, or in any combination of these sites, lasting 15 to 180 minutes and occurring from once every other day to 8 times a day.² In addition to the autonomic symptoms, people also can experience restlessness or agitation in contrast to other headache pain disorders that improve with relative stillness. People with CH may attempt to apply pressure to the head or face, pace around, or adopt different body positions to find relief from pain. People typically report only 1 to 2 attacks during a year, occurring in series lasting weeks to months (the so-called “cluster periods”), separated by remission periods, usually lasting months or years.² These attack periods may be time-locked to certain seasons or months of each year. Alcohol is a known trigger of CH.³ Subclassification of episodic CH is marked by at least 2 cluster periods lasting 7 days to 1 year, separated by pain-free periods lasting 3 months or more. Chronic CH is defined by attacks occurring for more than 1 year without remission or with remission lasting less than 3 months. A diagnosis of probable CH is made when all but one diagnostic criterion are met.²

The pathophysiologic basis of CH is not clearly understood, although it is known that 3 peripheral nervous system structures (trigeminovascular system, parasympathetic nerve fibers, and hypothalamus) interact to activate cortical areas of the central nervous system involved with the perception of head pain.⁴ Parasympathetic fibers project through the sphenopalatine ganglion, inducing autonomic symptoms. Other parasympathetic fibers from the superior salivatory nucleus pass out of the brain in the trigeminal nerve through the otic and carotid miniganglia, mediating vasodilation.⁴ Nitric oxide has been suggested as a mediator of vasodilation in CH as well as in playing an important role in modulation of hypothalamic function.^5,6 It thus stands to reason that direct high-flow oxygen delivery during cluster attacks would be helpful to abort symptoms. Calcium channel blockers (with verapamil as the standard for cluster prevention) decrease calcium influx into smooth muscle, reducing vasodilation. More recent study has led to the Food and Drug Administration approval of galcanezumab (a calcitonin gene-related peptide antagonist) for preventive treatment of CH.⁷

The past 3 decades have seen greater understanding of differences and similarities of CH and CH mimics with other TAC disorders. Table 1 provides an overview of clues to differentiation as well as various acute and preventive treatment options for TACs (Table 1).

Cluster Headache Mimics

Paroxysmal Hemicrania

The ICHD-3 diagnostic criteria for paroxysmal hemicrania (PH) include attacks of severe, unilateral pain that are orbital, supraorbital, temporal, or a combination of these sites, lasting 2 to 30 minutes and occurring several times a day. Symptoms are accompanied by ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, or eyelid edema, and occur with a frequency of > 5 per day.² Although our current understanding of PH dates to literature from the 1970s,⁹ diagnostic criteria are still being refined, as evidenced by changes in the ICHD-3 to include “restlessness or agitation” in lieu of the presence of some autonomic symptoms. This is a common theme in TAC disorders which share hypothalamic stimulation. Attacks are usually spontaneous, although in 10% of people, head turning can trigger an attack.¹⁰ As in CH, alcohol can be a trigger for PH. Similarities between PH and CH are apparent in their diagnostic criteria; however, there are important differences. Whereas CH prototypically presents in men between 20 and 40 years of age,¹¹ PH may affect any age group,¹² with a more balanced female-to-male ratio, from 1:1 to 2.4:1.¹³

Two important distinctions exist.¹⁴ First, the distinguishable circadian/circannual periodicity of CH is not observed in PH, as PH attacks can occur day or night with no respect to timing of month or year. Second, PH should respond absolutely to indomethacin,² whereas CH will not respond to this medication as convincingly. Indomethacin response is included as an ICHD-3 diagnostic criterion for PH, and few neurologic pathologies exist with equally definitive or effective remedies. The prescription of indomethacin with timely observation of symptom response can be used to help aid in distinguishing between disorders (given the individual’s tolerance of NSAIDs). Remission periods lasting longer than or less than 3 months help differentiate episodic PH from chronic PH, respectively.

Short-Lasting Unilateral Neuralgiform Headache Attacks

Short-lasting unilateral neuralgiform headache attacks (SUNHA) are attacks of moderate or severe, strictly unilateral head pain lasting seconds to minutes, occurring at least once a day and usually associated with prominent lacrimation and redness of the ipsilateral eye.² Two subcategories of SUNHA are 1) short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and 2) short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). These conditions are differentiated respectively by presence of both conjunctival infection and tearing versus simply one or neither. SUNHA differentiates itself from the other TAC disorders by the brief nature of the “stabbing” attacks, in which attacks occur as a single stab, a series of stabs, or recurrent stabs in a “sawtooth” pattern if viewed on a frequency graph.² The super-short duration of the painful stimuli can be a telling diagnostic clue when present, although a more prolonged sawtooth pattern of pain could be interpreted as a single consistent painful attack, leading to confusion with other TAC or headache/pain disorders.¹⁵

SUNHA shares a similar sex profile with PH, with a male predominance of 1.5:1.¹⁶ As with PH, SUNHA does not follow the same circadian/circannual time course as CH, despite known hypothalamic activation. Initiation of treatment with observation of responsiveness can be a helpful diagnostic tool for SUNHA. Preventive medications include more neuropathic or antiepileptic drugs, such as lamotrigine or topiramate. Gabapentin, carbamazepine/oxcarbazepine, or duloxetine are secondary options. Intravenous lidocaine can be used acutely for rescue.¹⁵

Hemicrania Continua

Hemicrania continua (HC) is a persistent, strictly unilateral headache associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, or eyelid edema, or with restlessness or agitation.² Similar to PH, early literature shows that HC was thought to be a “cluster headache variant” until 1981. Medina and Diamond¹⁷ reported a case series in which the majority of people achieved remission with indomethacin treatment. Further research used PET scans to show that disinhibition of the trigeminal autonomic reflex through activation of structures such as the dorsal rostral pons and posterior hypothalamus was similar to known pathophysiology in CH and SUNHA.¹⁸ The differentiating clinical feature of HC as compared with PH, SUNHA, or CH is the persistent nature of the pain, whereas PH exhibits more periodic symptoms marked by interictal relief; ergo, the names “continua” and “paroxysmal” are fitting. Some individuals also report a sensation of a “foreign body” in the ipsilateral eye, such as sand or itchiness.¹⁹

As with the other TAC disorders, the persistent nature of HC is distinct from the cluster timing of CH and can be a useful diagnostic clue among CH, PH, and SUNHA. Similar to PH, HC responds absolutely to indomethacin,² and trial of this medication with adequate response helps narrow the differential. Although “persistent” headache refers to the duration of pain, which is unremitting, people with HC typically present with a baseline unilateral headache with episodic painful exacerbations and associated autonomic symptoms.²⁰ These periods of exacerbation may mimic PH, and it may not always be clear if background pain outside of severe attacks constitutes HC or another headache disorder, such as tension-type headache or chronic migraine. Both PH and HC respond to indomethacin treatment, and as long as reduction of pain is achieved, the importance of distinction between the 2 pathologies may be secondary. If people cannot tolerate indomethacin, then topiramate, celecoxib, corticosteroids, lamotrigine, or lithium can be considered.²⁰ The 2 subtypes of HC, 1) remitting and 2) unremitting, are differentiated by headache pain that remits periodically for >24 hours versus the unremitting presence of daily and continuous symptoms for at least 1 year without any remission period >24 hours.

Migraine and Trigeminal Neuralgia

Although the differential diagnosis of unilateral cephalgia with prominent autonomic symptoms should include the TAC disorders, migraine headache also can present with autonomic symptoms. The presence of these findings should not preclude a diagnosis of migraine.

Migraine headache is one of the most common complaints in medicine, affecting more than 1 billion people worldwide during their lifetime.²¹ The astute clinician will always have a suspicion that recurrent and disruptive headache symptoms could be attributable to migraine headache, despite variable presentation. Based on prevalence alone, the majority of the headache complaints seen in both the outpatient and emergency settings will end up diagnosed as migraine. Many clinical features are shared between migraine and CH; however, recognizing differences between the two can aid in reaching the correct diagnosis.

Migraine prevalence among women may be as high as 25%, conferring a 2:1 to 4:1 risk in women as compared with men.^22,23 In contrast, male compared with female predominance of CH is from 3:1 to 7:1.¹¹ The ICHD-3 diagnostic criteria for migraine include nausea or vomiting or photophobia and phonophobia in attacks lasting 2 to 4 hours with no particular attention to timing of recurrence of episodes.² Episodic migraine is differentiated from chronic migraine based on the number of monthly days with symptoms (< 15 days vs > 15 days per month of “background” headache, with 8 of those days including migraine features). Clues to differentiation also may be found in a review of family medical history. Both migraine and CH have been shown to have convincing patterns of heritability, with migraine’s penetrance much more pronounced.²² If a person reports a strong family history of either migraine or CH, this could be an important clue for differentiation.

The Danish Blood Donor Study, started in 2010, included a questionnaire about migraine and associated symptoms. Of 128,802 study participants surveyed, 57% reported presence of at least 1 autonomic symptom during migraine, and 31% reported at least 2 autonomic symptoms,²⁴ demonstrating that these symptoms are associated prevalently with migraine headache. A practical approach to migraine differentiation from the TAC disorders should not be based solely on the presence of autonomic symptoms.

The description of short-lasting unilateral pain in a periorbital, temporal, or maxillary distribution is suspicious for SUNHA; however, trigeminal neuralgia (TN) should be considered in the differential. TN is defined by severe recurrent paroxysms of unilateral facial pain in the distributions of one or more divisions of the trigeminal nerve, lasting from a fraction of a second to 2 minutes, with an electric shock-like, shooting, stabbing, or sharp quality of pain.² In addition to episodes of pain, a proportion of people also experience persistent background pain, which along with autonomic signs and prolonged disease duration represent predictors of worse treatment outcomes.²⁵ TN traditionally has responded to carbamazepine/oxcarbazepine or other neuropathic or antiseizure medications; however, repair of a structural lesion (commonly vascular compression of cranial nerve V) can yield findings amenable to surgical repair. Favoni et al¹⁶ published a case series in which 16 individuals diagnosed with SUNHA underwent microvascular decompression with 12 of them (75%) reporting effectiveness in symptoms reduction. These results could lead to further investigation of surgical intervention for SUNHA. TN should not be discounted as a possibility even if signs of TAC disorders predonimate.

Secondary headache (any headache pain caused by a secondary source) is common, and a full description of all secondary factors that could cause headache would be impossible. The ICHD-3² serves to differentiate among many of these secondary causes, including compression from space-occupying lesions, illnesses, neuropathies, substance use or withdrawal, musculoskeletal disorders, and psychiatric disorders, to name a few. Secondary headaches can mimic any primary headache disorder, including migraine and the TAC disorders. A thoughtful and complete history of concurrent medical conditions, associated symptoms, and risk factors always should be obtained. The diligent clinician can save lives by identifying dangerous pathology masquerading as a more common and rudimentary complaint.

Summary

TAC disorders and other primary and secondary headaches can be extremely painful and disruptive to people’s lives. Modern diagnostic modalities and understanding of the TAC disorders have allowed us to implement targeted therapy. Expanding classification to 5 cephalalgias with autonomic features helps decrease the overdiagnosis of CH, and allows clinicians and individuals to experience the benefits of an effective (and sometimes curative) therapy. With a sound understanding, the confident clinician can bring rapid and substantial quality of life improvements to patients.