Case

A 26-year-old woman presents to clinic with symptoms of episodes of severe headache. She describes the headache as a sharp, throbbing, stabbing pain behind her right eye that can last several hours. The episodes occur with associated nausea and vomiting. She notes laying down in a dark room with a compress over her eye can help the pain. She describes tearing in both of her eyes and her boyfriend has told her that her eye turns red during the episodes. These episodes occur up to four times a month and are triggered by her menses and sleep deprivation. They do not seem to occur at a particular time of day, but can be more frequent in the summer, she feels in relation to the heat.

Introduction

Autonomic dysfunction can be associated with a variety of headache disorders. Seen most often as associated eye tearing, redness, nasal congestion, rhinorrhea, ptosis, miosis, or facial sweating, autonomic dysfunction in headache can present a challenge for appropriate diagnosis. It can be commonly seen in the trigeminal autonomic cephalalgias (TACs) such as cluster headache, or paroxysmal hemicranias, but can also be present with migraine and with secondary headache disorders such as headaches associated with pituitary dysfunction, intracranial aneurysm, and sinus headaches. Often times, unless directly asked, patients may not report associated autonomic symptoms with their headaches. Symptoms may be mild, as often in the case of autonomic symptoms associated with migraine, or may be more severe and a predominant feature of the headache, as can be seen in cluster headache.

This article will discuss autonomic dysfunction in headache disorders and how to differentiate different headache types with associated autonomic dysfunction.

Pathophysiology of Autonomic Dysfunction in Headache

In order to appreciate autonomic craniofacial phenomenon in pain, it is important to recognize where cranial autonomic symptoms (CAS) arise from. Brain pathways that produce autonomic symptoms with headache have been well elucidated in experimental animal studies and neuroimaging studies in humans [1], and have been termed the trigeminal-autonomic reflex [2]. Cranial nociception pathways involve the trigeminal nerve. Trigeminal nerve afferents provide nociceptive innervation to cranial structures that course through the trigeminal ganglion and trigeminal sensory root. They then project to the trigeminal nucleus. Pain input from cranial structures goes through the descending tract of the trigeminal nucleus caudalis and dorsal horns of the spinal cord at the C1 and C2 level. This is called the trigeminocervical complex [3]. With activation of the trigeminocervical complex, a reflex activation of cranial parasympathetic outflow can occur [1]. Simultaneous activation in the brainstem of the trigeminal nerve and craniofacial parasympathetic nerve fibers in the superior salivary nucleus has been termed the trigeminofacial reflex [4]. Activation of this reflex occurs in patients with cluster headache and other TACs [5••]. CAS in TACs may be due to central disinhibition of the trigeminal-autonomic reflex [1].

Autonomic activation can also occur in patients with migrain-producing CAS, with reports of both hypo and hyperfunctioning of the autonomic nervous system in patients with migraine [6,7].

In addition to the trigeminal system, the hypothalamus likely plays a role in CAS. The hypothalamus is involved in regulating autonomic functions and maintaining homeostasis. Hypothalamic dysfunction is linked to both TACs and migraine [5••,8]. Neuroimaging studies in TACs have shown ipsilateral posterior hypothalamic activation [9–12]. The hypothalamus modulates nociceptive and autonomic pathways. In TACs, an abnormality in the hypothalamus may activate cranial autonomic and trigeminovascular nociceptive pathway [13]. Newer studies looking at autonomic response to the head-up tilt table test have shown that patients with cluster headache have a decreased autonomic response [14••]. This adds further evidence to dysregulation in the posterior hypothalamus possibly contributing to autonomic responses in patients with cluster headache.

Hypothalamic activation occurs in migraine as it does in cluster headache and other pain disorders [15]. In 2014, neuroimaging studies of patients with migraine reported enhanced functional connectivity between the hypothalamus and brain areas that regulate autonomic functions [16]. What is not well understood is if hypothalamic activation leads to CAS in both migraine and TACs, and if so, why are CAS often unilateral in TACs and more often bilateral in migraine? The trigeminal autonomic reflex does have a minor contralateral component due to crossover in the brainstem [17]. It has been theorized that in TACs, such as cluster headache, the contralateral trigeminal autonomic reflex may be suppressed due to some unknown mechanism [18]. Why this would occur in a small portion of patients with migraine, and not occur in a small portion of patients with cluster headache who have bilateral CAS is unknown at this time.

Primary Headache Disorders with Cranial Autonomic Symptoms

The TACs are a group of headache disorders that are characterized by severe pain in the trigeminal distribution with associated autonomic features (Table 1). Pain is unilateral, often in V1-V2, though the pain can travel into V3. Pain is often severe and disabling. Patients with cluster headache may consider suicide due to the nature of attacks. Headache episodes in the TACs are usually of short duration, lasting seconds and up to 3 hours. Attacks often repeat numerous times through the day, sometimes at regular and predictable intervals (such as soon after falling asleep in cluster headache). Autonomic symptoms can vary but are a prominent part of TACs. An example of this is seen in the syndrome LASH, long-lasting autonomic symptoms with hemicranias (LASH) [19, 20, 21••]. In this syndrome, patients with hemicrania can have CAS occurring hours prior to unilateral head pain. CAS can appear for days and may continue for hours after headache resolves. LASH syndrome is an interesting phenomenon that may imply a greater activation of the trigeminal-autonomic reflex vs. indicate greater dysfunction in the autonomic pathways in these patients.

Table 1 Trigeminal autonomic cephalalgias classification
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Migraine is a moderate to severe headache disorder with associated symptoms of nausea, vomiting, photophobia, and phonophobia, made worse by physical activity [22]. CAS are an often underreported and little known occurrence in migraine. In 2008, Lai and colleagues reported on CAS in migraine [18]. They found that 56 % of patients with migraine have a least one CAS. In migraine, bilateral CAS symptoms are more common than unilateral symptoms (occurring in around 32 % of patients). CAS appears inconsistently with headaches, is unrestricted to headache side, and can occur in mild to moderate headache intensity, though is often seen in more severe headaches and may represent a more severe migraine attack. Forehead and facial sweating is more common than lacrimation. Less than one third of migraine patients had CAS with every headache.

Gelfand and colleagues in 2013 reported on CAS in pediatric patients with migraine [23••]. They found that 70 % of pediatric patients with migraine had at least one CAS with their headaches, though most had more than one. Like Lai et al., Gelfand et al. found that most CAS in migraine is bilateral. In the pediatric population, aural fullness, facial sweating/flushing, and lacrimation were the most common CAS seen.

Secondary Headaches and Autonomic Dysfunction

In the presence of autonomic symptoms with headache, one should always consider secondary headaches on the differential. There are many secondary headaches that present with TAC-like headaches and can be difficult to distinguish from primary TACs without neuroimaging. Secondary causes of headache with autonomic dysfunction include cerebellopontine angle tumors [24], internal carotid artery dissection [25], sphenoiditis [26], sinus disease [27,28], parasagittal hemangiopericytoma [29], moyamoya [30], pituitary lesions [31], and post schwannoma excision [32]. Consider imaging of the brain with magnetic resonance imaging (MRI) and/or magnetic resonance angiography (MRA) in patients with autonomic symptoms and headache, especially in SUNCT or SUNA, or with headache with CAS with headache features that are changed from baseline.

Differentiating Headaches with Autonomic Features

In 2013, Viana and colleagues published a study reviewing the management of TACs [33••]. In their study, they reported continued misdiagnosis of TACs. Primary TACs are often diagnosed as either migraine, trigeminal neuralgia, sinus infections, dental pain, or temporal mandibular disorder. The delay to diagnosis for cluster headache is up to 3 years [34]. Often up to three physicians are consulted prior to the diagnosis of cluster [33••]. Migraine with CAS and cluster headache with migraine features, such as aura, photophobia, phonophobia, make distinguishing cluster headache more difficult. Viana et al. reported after a review of studies on TACs that up to 61.2 % of cluster attacks can be associated with photophobia and phonophobia. Twenty-seven percent of cluster attacks can be associated with nausea and vomiting. One fourth of cluster headache patients had migraine aura prior to attacks. Fourteen percent of cluster headache can side shift during a cluster period, again making differentiation based on diagnostic criteria somewhat difficult.

In order to differentiate cluster headache and TACs from other primary headache disorders, one should consider the following items (Table 2); duration of headache, severity of headache, associated agitation or pacing, timing of headache/headache recurrence, prominence and laterality of CAS symptoms, number of attacks in one day, laterality of photophobia and phonophobia (in cluster headache, these symptoms are often seen unilateral to the headache attack [35]), and nature of rhinorrhea (clear vs. purulent). Taken in consideration together, diagnosis of TAC vs. other primary headache disorder becomes clearer.

Table 2 How to differentiate between TAC, migraine, and other headache disorders
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Return to Our Case

Features That Can Help Differentiate Our Patient’s Headache

Length of headache: Untreated the headache lasts for several hours.

Features of headache: Severe, unilateral, has a component of throbbing, with nausea, vomiting and photophobia that is bilateral. Laying down is helpful.

Autonomic features: Bilateral eye tearing and eye redness, though is not clear if redness is unilateral or bilateral. Symptoms are not always associated with every headache and are often seen in more severe attacks.

Time pattern of headache: Headaches have triggering factors, do not occur a particular time of day or year, though they are more frequent in the summer.

Our patient was diagnosed with migraine without aura.

Conclusion

CAS in association with headache can be seen in TACs, migraine, and a number of secondary causes of headache. The pathophysiology of CAS in headache disorders likely is related to the trigeminal autonomic reflex and activation of the posterior hypothalamus. CAS is more common in migraine that has been recognized in the past, with occurrence in 56 % of adults and 70 % of pediatric migraine sufferers. There are subtle distinguishing features between TACs and migraine. The most helpful features of headache to help differentiate TACs from other primary headache disorders are duration of attacks, associated agitation or pacing, and prominence and laterality of CAS. It is difficult to rule out secondary causes of headache with CAS without neuroimaging, so if clinical suspicion is high based on new onset symptoms, patients age, associated risk factors (history of cancer, pituitary issues in past), or other systemic symptoms, consider pursuing further work-up.