Diagnosis of Trigeminal Autonomic Cephalalgias

Abstract

The trigeminal autonomic cephalalgias (TACs) are defined by several important characteristics. They are all short-lived headaches (except for hemicrania continua, HC) and tend to be severe in intensity. The TACs share a common site of origin in the hypothalamus, but an initial thorough workup for posterior fossa or pituitary pathology is warranted before making the diagnosis of these primary headache disorders. Many of the entities in two groups, the TACs and the other primary headache disorders—with important exceptions—respond to indomethacin; in fact, some of the headaches should be absolutely responsive to indomethacin. TACs often demonstrate ipsilateral parasympathetic hyperactivity and/or sympathetic hypoactivity.

Among the TACs are the indomethacin-sensitive hemicranias, either paroxysmal or chronic depending on the presence, or not, of a full month of remission, and the less common indomethacin-insensitive TACs. The recently introduced third edition of the International Classification of Headache Disorders (ICHD-3) includes new additions to the TACs. HC, the iconic indomethacin-sensitive headache disorder, is now classified as a TAC. The extremely rare short-lasting unilateral neuralgiform headache with conjunctival tearing and injection (SUNCT) and short-lasting unilateral headaches with cranial autonomic symptoms (SUNA) are now included together under the new term, short-lasting unilateral neuralgiform headache attacks (SUNHA). Included with the indomethacin-insensitive headaches in TACs is cluster headache (CH).

Introduction

The trigeminal autonomic cephalalgias (TACs) refer to a specific group of primary headaches characterized by unilaterality, associated cranial autonomic features, and specific duration of pain. The major TACs as listed by the International Classification of Headache Disorders, third edition, beta version (ICHD-3) are listed in Table 2.1 and, to differentiate them, the Other Primary Headache disorders (covered in Chap. 3) are listed in Table 2.2.

Table 2.1 The major trigeminal autonomic cephalalgias (TACs), ICHD-3

Table 2.2 The major Other Primary Headaches, ICHD-3 (covered in Chap. 3)

The term “probable” is used in the ICHD-3 to mean a headache is missing one ICHD-3 criterion to make the diagnosis. Probable TACs are under ICHD number 3.5. The probable headaches are excluded from our tables for simplicity, utility, and clarity .

Remember that if the patient is missing a single criterion, the headache diagnosis becomes “probable.” As discussed in Chap. 1, when a patient is missing a criterion, the possibility of a secondary cause increases, and serious consideration should be given to doing a careful workup for secondary causes. Essentially, a probable diagnosis should raise your suspicions for sinister etiology.

Table 2.3 Clinical pearls on probable headaches

Diagnostic Features of the TACs: How to Make the Diagnosis

As with any other painful condition, making a correct diagnosis is 90 % of the battle and helps direct proper therapy. This is particularly important with the TACs, as some of these headaches can be differentiated by a response to certain medications, such as indomethacin .

Duration of TACs

Wags have stated that the longer the name of the paroxysmal TAC, the shorter the duration. Hemicrania Continua (HC) is continuous. Eighty-five percent of Cluster Headache (CH) attacks last between 15 and 180 min. Paroxysmal Hemicrania (PH) attacks are between 2 and 30 min. And the duration of Short-lasting Unilateral Headache Attacks (SUNHA), including Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT) and Short-lasting Unilateral Neuralgiform headache attacks with cranial Autonomic symptoms (SUNA), is measured in seconds (1-600 s).

Table 2.4 Duration of the TACs

The current ICHD-3 criteria for the diagnosis of the TACs are listed in the subsequent tables. As noted above, the TACs are grouped into Section 3 of the ICHD-3, and while these headaches are similar in many ways, the response to medications can vary markedly. Each will be discussed separately, but not before some points are made. These clinical pearls on TACs are listed in Table 2.5.

Table 2.5 Initial clinical pearls on diagnosis of TACs

In both HC and CH, if the autonomic features are not manifested, an equally important criterion listed is the sense of restlessness and inability to sit still during an attack. There is a minority of patients who, during an HC exacerbation or a cluster attack, will not manifest obvious ipsilateral sympathetic paresis (miosis, ptosis, Horner’s) or parasympathetic discharge (conjunctival tearing, rhinorrhea, etc.). In such cases, the patient must report (or a companion must report) that the patient will rock, pace, or otherwise appear agitated. One of my cluster patient’s wife told me that the patient was groaning and holding his involved eye; next to him on the pillow was a handgun! This degree of agitation is not required or listed for PH or SUNHA .

Never underestimate the severity of the pain of CH! CH is called the “suicide headache” for good reason.

As many as 50 % of patients with TACs will refer their symptoms of photophonophobia to the ipsilateral, painful side, in contrast to migraineurs, who usually complain of bilateral light and sound sensitivity. HC, in particular, manifests unilateral photophonophobia in at least half of patients, and ipsilateral photophonophobia should make the clinician think seriously about a TAC diagnosis.

The diagnosis of a TAC should provoke a workup for a hypothalamic or pituitary lesion; as many as 10% of patients with TACs, in particular SUNHA, will have an abnormality of this region or the posterior fossa on a good imaging study, in particular SUNHA. If the clinician has not visualized a magnetic resonance imaging (MRI) with and without contrast as part of the workup, repeating one should be considered.

SUNA is simply a SUNHA without the red eye or tearing, so SUNA and SUNCT are very similar. Neither is indomethacin responsive; both tend to respond to antiepilepsy drugs such as lamotrigine or gabapentin.

Trigeminal neuralgia (TN) does not manifest autonomic features and is only rarely in V1, so location and associated autonomic features distinguish SUNHA from TN, even when the duration of attacks is similar. In addition, SUNHA is usually heralded by stabs of pain, sometimes in a sawtooth pattern, not seen in TN.

A woman with frequent cluster-like attacks, especially if not terribly agitated, should make the clinician think of PH rather than CH, due to gender alone. After ruling out secondary causes, an indomethacin trial may be indicated.

Diagnosis of Cluster Headache

CH, the most common of the TACs, are generally more common in males, starting as early as the second decade. CH can persist well into life, as far as into the seventh decade. They are called clusters because they tend to cluster at the same time(s) of the year, with cycles or periods of daily attacks lasting for weeks to months in the episodic variety, and remissions lasting for months to years. This is considered to be a reflection of the relationship of these headaches with circadian and circannual periods and the effect of light–dark cycles on the suprachiasmatic nucleus of the hypothalamus, by way of the retinal–hypothalamic–pineal pathways .

Approximately 85 % of all CHs are episodic; the cluster period or cycle, as it is called, spontaneously remits, and there will be freedom from CH attacks for a month or longer each year in episodic cluster headache (ECH).

The remaining cluster sufferers have chronic clusters in which they will have headaches daily or near daily and will not be free from a CH attack for any period of a month or more in a given year. Chronic cluster headache (CCH) may start de novo, but generally evolves from the episodic variety.

Most cluster attacks are severe and retro-orbital. They are not throbbing; rather, they are described as burning, boring, stabbing, or tearing. Attacks are short, sharp, and severe (triple S; SSS).

Cluster attacks are manifested by parasympathetic activation (scleral injection, lacrimation, diaphoresis, nasal stuffiness, and/or rhinorrhea). Less common is a Horner’s or partial sympathetic paresis with ptosis and/or miosis. As noted above, agitation is the rule, and cluster attacks are generally shorter than 3 h in duration. Major diagnostic criteria for CH are listed in Table 2.6.

Table 2.6 Diagnostic criteria for cluster headache, ICHD-3

There is a circadian alarm clock periodicity to the attacks, attacks occurring at the same time of day or night, and a circannual periodicity with the cluster periods occurring at the same time of year, often with the changing of the clocks for daylight savings time. The periodicity feature of CH, extremely useful in diagnosis and not usually seen in the other TACs, is not included in the ICHD-3 criteria.

Attacks can be precipitated by alcohol, fumes such as gasoline fumes, excessive exercise, and napping. Cluster patients in cycle rarely, if ever, drink alcohol. Cluster patients are commonly smokers, however .

In about 30 % of cluster and PH patients, a low-level pain can persist ipsilaterally interictally. The patients describe this as a “ghost pain” between attacks. The continuous pain of HC is generally more severe, averaging 6–7/10 in intensity.

Table 2.7 Clinical pearls on diagnosing cluster

Diagnosis of the Paroxysmal Hemicranias

The Paroxysmal Hemicranias (PH) are defined by an absolute response to indomethacin. The headaches are similar in quality to cluster pain, but the pain is shorter lasting and more frequent during any given day.

As with CH and HC, there are both episodic and chronic PH subforms. Episodic Paroxysmal Hemicrania (EPH) occurs in periods lasting 1 week to a year, and its occurrence is separated by pain-free periods lasting 1 month or longer (remissions). When cycles of attacks of PH last more than 1 year without remissions lasting 1 month or longer, the headache qualifies as Chronic Paroxysmal Hemicrania (CPH). This distinction is identical to that in CH .

EPH is more rare than CPH, the opposite of CH, where the episodic subform is more common. In EPH, the disorder occurs equally in males and females, while in CPH there is a female predominance. CH always has a male predominance, regardless of subform.

Attacks of PH can be less severe than CH, but in the same location. The attacks are quite short, up to 30 min only, allowing for 15 min of overlap with CH attacks. The usual duration of a PH attack is 14 min, so it is usually easy to tell from SUNHA or TN. SUNHA attacks are from 1 s to 10 min, but average duration is 50 s. However, there is an overlap of a 2–10-minute duration between SUNHA and PH, so indomethacin can be the important distinguishing feature, as SUNHA does not respond to indomethacin. TN attacks are much shorter, there are no autonomic features, and are usually in V2–3, while PH is in V1.

More than half of the time, PH attacks occur more than five times per day by ICHD-3 criteria, so attacks usually occur more frequently in PH than CH. The frequency of CH attacks can be up to eight times per day, so the frequency of the two disorders can overlap, but this is rare. In general, CH attacks occur one to three times daily, and PH attacks occur with a mean frequency of eight times per day. SUNHA attacks can occur hundreds of times per day.

Patients are less frequently agitated in PH than with CH. Agitation is not a diagnostic criterion for PH, but is for CH.

There is no circadian or circannual periodicity. PH attacks occur at random.

Finally, and most importantly, the diagnosis of PH is made by absolute responsiveness to indomethacin. If you have ruled out secondary causes and think the patient could have PH, try an indomethacin course first before treating as if it is cluster .

Table 2.8 Diagnostic criteria for paroxysmal hemicrania, ICHD-3

Table 2.9 Clinical pearls on diagnosing paroxysmal hemicrania

Diagnosis of SUNHA (SUNCT and SUNA)

In the third edition of the ICHD, the category SUNHA includes the two recognizable forms of SUNCT and SUNA. SUNCT and SUNA are very brief headaches with prominent cranial autonomic features that can deceive the clinician because they can be triggered by cutaneous stimuli, similar to TN . These headaches are characterized by paroxysms of short-lasting (1–600 s) stabbing tic-like pain. Average duration of each attack is around 50 s. The duration of these severe attacks was expanded from 5–240 s in ICHD-2 to 1–600 s in ICHD-3.

The attacks can present with isolated stabs of pain in the orbit or the temporal region or anywhere in the head, and can occur hundreds of times a day. SUNCT/SUNA can alternately present with groups of stabs (sawtooth pattern) separated by complete or incomplete resolution of the pain. A single stab can herald an attack. There may be periods of remission, or there may be no days of remission.

Unlike TN, which as noted above, SUNHA attacks might resemble because of cutaneous triggers and duration, SUNHA attacks generally do not exhibit a refractory period. Also, TN occurs < 5 % of the time in V1; SUNCT/SUNA pain is usually in V1. Time to peak for SUNHA is about 2–3 s. SUNHA attacks are longer in duration (typically 30–120 s) than TN (typically 1–3 s). SUNCT, as the names infers, is associated with both conjunctival injection (redness) and tearing, and there may be other ipsilateral autonomic signs. SUNA may have conjunctival injection or tearing but not both together, and other autonomic features occur .

Secondary headaches may masquerade as SUNHA, including brainstem strokes, arteriovenous malformations, pituitary tumors, arterial dissections of the vertebral artery, or demyelination. It is therefore mandatory to investigate all suspected cases of SUNCT/SUNA or to personally review high-quality imaging if it has been performed.

There have been several small case series of SUNCT being cured by resection of pituitary tumors. The pathophysiology and explanation for these cures is mysterious.

Remember, SUNHA is rare. Be vigilant in a search for secondary causes .

Unfortunately, SUNHA does not respond to indomethacin as do PH and HC. Treatment for SUNCT/SUNA will be discussed in Chap. 11, but is usually lamotrigine or gabapentin .

Table 2.10 Diagnostic criteria for SUNHA (SUNCT/SUNA), ICHD-3

Table 2.11 Clinical pearls on SUNHA

Pathophysiology of the TACs: What you Need to Know

There is now a substantial body of evidence that the spectrum of TACs and the Other Primary Headaches are related in their pathophysiological origin, as one would suspect, since they generally share many clinical features. Recent advances with positron emission tomography (PET) scanning and functional MRI have demonstrated areas of activation in the posterior hypothalamus for all of the TACs during the headache phase. In addition, the expected areas of the cortical and subcortical pain matrix show activity in response to the pain. Table 2.12 displays the areas of hypothalamic activation.

Table 2.12 Areas of hypothalamic stimulation seen with the TACs

HC offers a mirror image of CH and migraine functional imaging. Cluster manifests activation in the ipsilateral hypothalamus, HC the contralateral hypothalamus. Some scientists feel that migraine manifests activation in the contralateral upper brainstem, HC the ipsilateral upper brainstem .

Anatomically, there are reciprocal connections between the posterior hypothalamus and the trigeminal nucleus caudalis (TNC), the site of origin of the second order nociceptive neuron. In the last decade, there have been more than 50 patients who have had implantation of deep brain stimulators (DBS) in the ipsilateral hypothalamus for drug refractory CH and other TACs. There are no controlled studies of DBS for TACs, except to note that turning off working stimulators without patient knowledge has resulted in return of headaches.

For CH, in 60 % of patients there has been a greater than 50 % decrease in the frequency of headaches, and in 30 % there has been a complete response with DBS. However, there has been one death and several transient ischemic attacks (TIAs) and strokes in the course of implanting DBS for CH .

It is now apparent that stimulation of this hypothalamic site promotes the relief of the headache and does not stimulate the pain, suggesting that the posterior hypothalamus is a key area of modulation for cluster and TAC pain. This is discussed further, along with other stimulation approaches, in Chap. 12 on treatment of the TACs and other primary headaches.

The Paroxysmal TACs: Telling Them Apart

CH, PH, and SUNHA constitute the paroxysmal TACs, in that the minority of patients have continuous pain, and the continuous pain is generally not severe. HC, on the other hand, is a continuous TAC. Table 2.13 outlines major points that help differentiate the paroxysmal TACs from one another .

Table 2.13 Differential points among the paroxysmal TACs. (Adapted from Goadsby et al. 2010)

Hemicrania Continua

HC is one of four primary daily headaches, covered in Chap. 4. However, it is a TAC as well, and since ICHD-3 classifies it in the TAC section, it is also covered here. HC is a continuous, side-locked, generally moderate (6/10 intensity) headache associated with cranial autonomic symptoms, with periodic severe intensity exacerbations. By definition, this headache is indomethacin responsive. Because HC has these qualifying autonomic characteristics, it is categorized as a trigeminal autonomic cephalalgia or TAC in ICHD-3, the only TAC that is continuous most of the time. However, as noted above, agitation can substitute as a diagnostic criterion for the autonomic features, or also can occur with them.

The ICHD-3 criteria for HC are quite specific, but there are detailed descriptions of patients with this syndrome suggesting that clinical presentations can be more variable. Still, most have a dramatic indomethacin response.

The official criteria are that the headache be strictly one-sided and continuous for at least 3 months. Periodic exacerbations occur in which the pain becomes moderate to severe (usually severe), and autonomic features such as ipsilateral lacrimation, conjunctival injection, ptosis, miosis, nasal stuffiness, or rhinorrhea occur. The response to indomethacin is incorporated in the diagnosis, and the criteria specify “complete response.”

Table 2.14 Hemicrania Continua (HC), ICHD-3 criteria

Cittadini and Goadsby described in detail 39 patients with HC, and added a number of common clinical features, in addition to the ICHD-3 criteria. The daily baseline side-locked headache of HC can be mild, although they described the continuous headache as averaging 6/10 intensity in their case series.

The exacerbation frequency was daily in about half and 5/7 days in another third, so the step-up to severe is frequent. Severe exacerbation length was from 30 min to 72 h for the most part.

Triggers for exacerbation turned out to be common and were similar to migraine, including stress or let down from stress, and alcohol, the latter also a trigger for CH. More than two-thirds of patients were agitated or restless with severe exacerba- tions, and more than one-fourth were described as aggressive (generally verbally, not physically). These symptoms are also similar to those found in CH.

Many patients with HC have other additional features or variable presentations. First, it is worth remembering that often patients with HC come in complaining about the exacerbations, not the daily headache. Asking about the presence or absence of headache-free time helps find patients with CDH, especially HC. This is a critical clinical point: Ask whether the patient has any truly headache-free days, that is, days without any residual or mild pain.

Additional features of HC include a foreign body sensation in the ipsilateral eye. This is variously described as like an eyelash or grit or sand. Sometimes, patients will complain that they can never get their contact lens comfortable on that side, and the sensation is also described as “itchy eye.”

Ice-pick pains or primary stabbing headaches, also indomethacin responsive, frequently occur on the same side as the HC. Primary stabbing headaches are covered in Chap. 3, Other Primary Headaches. It is useful to ask a patient with HC-associated features about ice-pick pains, although they do occur in 40 % of migraineurs as well.

The use of a daily nonsteroidal anti-inflammatory drug (NSAID) is frequently seen in patients with indomethacin-responsive syndromes. Thus, a patient coming in with side-locked daily headaches taking daily ibuprofen should raise suspicion for HC. Ibuprofen and other NSAIDs are close enough to indomethacin to provide some HC patients with partial relief, better than alternatives. The same behavior can be seen in patients with PH.

In ICHD-2, the severe exacerbations in HC were described as CH-like with autonomic features. However, HC exacerbations may mimic migraine, not cluster, in some patients, and the exacerbations may be triptan responsive, so in ICHD-3 the cranial autonomic symptoms are included in the criteria for HC diagnosis, but the exacerbations are described as “moderate or greater intensity” and not otherwise characterized.

Cittadini and Goadsby reported photophonophobia in around 75 % of their HC patients, ipsilateral in about half. As previously noted, in case of unilateral photophonophobia a clinician should start thinking about a TAC, and if the pain is continuous and at least moderate, specifically about HC.

Many patients with HC reported by Cittadini and Goadsby had personal or family histories of migraine, often with histories of motion sickness.

However, if a patient with a history of migraine presents with chronic daily headache (CDH) which is side locked and is taking large daily quantities of NSAIDs, especially when mixed with caffeine, the diagnosis of medication overuse headache (MOH), chronic migraine, or transformed migraine with rebound becomes possible.

An indomethacin trial is often the only way to distinguish between chronic migraine with medication overuse and HC with migrainous exacerbations. Indomethacin will work completely in HC patients before they are weaned from the overused NSAIDs or other medications.

The required indomethacin dose is frequently high. In about one-third of the Cittadini and Goadsby series, 300 mg/day was necessary; one patient required 500 mg daily dosing. As noted, the ICHD-3 recommends at least a trial up to 225 mg/day. It is worth trying to lower the daily dose months after stability and headache suppression is achieved.

Indomethacin responsiveness is not diagnostic. Diagnostically, secondary headaches mimicking HC can be indomethacin responsive. Because HC is somewhat uncommon, a baseline MRI is necessary to exclude secondary causes, as in all of the TACs.

In ICHD-3, HC is subdivided into remitting and nonremitting subtypes. These subtypes correspond to chronic and episodic cluster and other TACs, but the criteria are a bit different. For cluster and other TACS, 1 month of no headaches per year is required for ECH, otherwise it is chronic. For HC, the remitting subtype manifests a pattern of pain that is not continuous but is interrupted by remission periods of ≥ 1 day without treatment. The HC unremitting subtype manifests a pattern of continuous pain without remission periods of ≥ 1 day for ≥ 1 year. The ICHD-3 notes that the majority of HC is the unremitting subtype.

Clinical pearls on diagnosing HC are summarized in Table 2.15.

Table 2.15 Clinical pearls on diagnosing HC

Conclusions

There are four primary types of TACs: CH, PH, SUNHA, and HC. The first three are paroxysmal; HC is continuous. However, the first three paroxysmal TACs can have continuous lower-level headaches as well.

Two of the TACs are indomethacin responsive, PH and HC.

All of the TACs generally manifest autonomic features, usually parasympathetic activation, occasionally sympathetic paresis with a partial Horner’s. Two of the TACs are associated with significant agitation, CH and HC.

All TACs require careful imaging before deciding that they are primary. This involves an MRI without and with contrast and a special look at the sella and posterior fossa.

CH and PH are subdivided into episodic forms with remissions of at least a month a year and chronic forms with no remissions. HC is subdivided into a remitting form with remissions of at least a day a year and a chronic form with no remissions. SUNHA is subdivided into a form with both conjunctival tearing and injection, SUNCT, and a form with other autonomic features, SUNA.

Table 2.16 Final clinical pearls on the TACs