Concomitant occurrence of different trigeminal autonomic cephalalgias: A case series and review of the literature

Abstract

Introduction

The trigeminal autonomic cephalalgias (TACs) subsume four primary headache disorders. Hemicrania continua is increasingly regarded as an additional TAC. In rare cases patients may present with two different TACs or a TAC and hemicrania continua.

Cases

We report four patients with two different TACs or one TAC and hemicrania continua. Two patients presented with cluster headache and paroxysmal hemicrania, one patient with cluster headache and hemicrania continua, and one patient suffered from cluster headache and SUNCT.

Discussion

While the International Classification of Headache Disorders (ICHD-II) proposes specific diagnostic criteria, the variability of clinical presentation may make clear diagnosis difficult. All patients fulfilled the ICHD-II criteria. The manifestation of two different TACs or hemicrania continua in one patient is uncommon but possible and should be taken into account especially when chronic headache patients present with changing headache symptoms.

Background

Trigeminal autonomic cephalalgias (TACs) are primary headache disorders characterized by unilateral attacks of facial and head pain accompanied by cranial autonomic symptoms (CAS)-like ptosis, lacrimation, conjunctival injection, rhinorrhea or nasal congestion (1). The prevalence of TACs in population-based studies is low. Regarding the second edition of the International Classification of Headache Disorders (ICHD-II), four primary headache disorders are classified as TACs: cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and probable trigeminal autonomic cephalalgia (2). Hemicrania continua is often considered a member of the TACs group, although it is currently included in Group 4 “Other primary headaches” (3). Short-lasting unilateral neuralgiform headache attacks with CAS is included in the appendix of the ICHD-II (3). Recently the third edition (beta version) was published. The ICHD-III (beta version) now assigns hemicranias continua and SUNCT to the TACs group (4).The specific response to medical treatment may confirm the diagnosis of a TAC, i.e. the elective response to indomethacin is required as one of the diagnostic criteria for paroxysmal hemicrania (5). The response to oxygen confirms the diagnosis of cluster headache, although it is not a diagnostic criterium. The simultaneous occurrence of two different types of TACs or a TAC and hemicrania continua in the same patient is uncommon. So far, very few cases have been reported (6–14).

Methods

All patients first-time referred to the tertiary headache center at the University Hospital Essen, Germany, between January 1, 2009, and May 30, 2011, diagnosed with TAC according to the ICHD-II criteria were prospectively reviewed for co-occurrence of a second TAC or hemicrania continua. All patients underwent diagnostic work-up to exclude secondary headache disorders (prior history, neurological examination, brain magnetic resonance imaging (MRI), and additional investigations if needed). The diagnosis was made by at least two experienced physicians of the headache center (neurologists) based on the patient’s anamnesis, clinical examination and further diagnostic work-up to rule out secondary headache disorder. The diagnosis of paroxysmal hemicranias was confirmed by response to indomethacin.

Results

During the study period, 380 out of 9550 consultations (first and follow-up) first presented with TACs in the headache center. Among those, four patients were diagnosed with two different TACs or the combination of TAC and hemicrania continua. Diagnoses were strictly based on the ICHD-II criteria. All four patients were capable of differentiating between the two headache syndromes. Symptomatic headache syndromes were excluded by cerebral imaging, blood tests and if needed by lumbar puncture.

Case reports

Patient 1

A 38-year-old female presented with left-sided headache attacks occurring for the first time in 2009. She suffered from two to three attacks per day on two to three days during a week over more than a year without pain-free intervals. Each attack lasted 100 minutes on average and was accompanied by left-sided lacrimation and eye redness. The attacks were successfully treated with zolmitriptan nasal spray and/or inhalation of high-dose oxygen. Prophylaxis with lithium (0.6–1.0 mmol/l) and high doses of verapamil (480 mg per day) decreased the pain level and headache frequency, but only in the first month of treatment. Topiramate was not well tolerated and therefore not continued. The patient was diagnosed with chronic cluster headache. Later on, because of ineffective medicinal prophylaxis, the patient underwent bilateral occipital nerve stimulation with unsatisfactory results so far.

A second headache entity occurred together with the chronic cluster headache. The patient complained of a moderate left-sided headache lacking pain-free intervals that persisted for more than one year. This headache showed up to three pain exacerbations during a week, mostly in the afternoon, that were accompanied by lacrimation, nasal congestion, eye redness and palpebral swelling. The pain exacerbations lasted between 20 minutes and six hours. Indomethacin (200 mg per day) resulted in freedom from the persistent pain, which confirmed the diagnosis of hemicrania continua. However, cluster attacks persisted during this treatment. Etoricoxib did not reduce the pain.

Patient 2

A 47-year-old male presented with left-sided recurrent headache attacks accompanied by nasal congestion, eye redness, ptosis and palpebral swelling. He suffered from six attacks per day, each lasting approximately 60 minutes. Severe attacks could be treated with subcutaneously administered sumatriptan (6 mg) whereas moderate attacks responded to inhalation of high-dose oxygen. Initially steroids reduced attack frequency. This was followed by successful treatment with verapamil (720 mg per day) in addition to lithium (0.6–1.0 mmol/l), whereas treatment with topiramate was terminated because of side effects (mental problems and hallucinations). A diagnosis of chronic cluster headache was made because pain-free intervals did not last longer than two weeks. Contralateral to the cluster headache, periorbital headache attacks occurred five to seven times per day lasting between two to 10 minutes. The pain intensity was moderate, the character stabbing. During pain attacks palpebral swelling was reported as CAS. Steroids had only a minor effect on headache intensity or frequency. Indomethacin (75 mg per day) resulted in freedom from the short-lasting pain attacks while cluster attacks still occurred. Because of indomethacin intolerance, we successfully switched the patient to etoricoxib with satisfying response. Diagnostic criteria of chronic paroxysmal hemicrania were fulfilled for the right-sided headache. Both headaches first occurred in 2002.

Patient 3

A 48-year-old male presented with strictly left-sided headache attacks twice a day occurring mainly at nighttime. The duration of the attacks varied between 60 and 180 minutes, and the attacks were accompanied by left-sided nasal congestion, lacrimation and eye redness. The headache first appeared in 2004 and lasted only three to four months. After a pain-free interval of five years, the headache attacks reappeared in 2009 and lasted for more than one year without pain-free intervals longer than one week when the patient first presented to our headache center. Acute attacks were sufficiently treated with inhalation of high-dose oxygen or nasal application of zolmitriptan or subcutaneous injection of sumatriptan (6 mg). Prophylaxis with 880 mg verapamil per day resulted in a reduction of attack intensity and frequency. Steroids in high dosage led to pain relief for only a few days. Treatment with lithium, topiramate and methysergide was stopped because of side effects. The patient was diagnosed with chronic cluster headache. Five years after the first occurrence of cluster headache a second headache disorder appeared. The patient complained of sharp left-sided periorbital pain attacks radiating to the temple area lasting five to 10 seconds up to 30 times per day. Pain attacks were accompanied by CAS such as conjunctival injection and lacrimation. The diagnostic criteria of SUNCT syndrome were fulfilled. Lamotrigine (400 mg per day) led to freedom from the short-lasting pain attacks while cluster attacks still occurred.

Patient 4

An 80-year-old woman presented with up to six headache attacks per day predominantly during the night, each lasting up to 30 minutes. Pain attacks first occurred in 2001 and then reappeared each year for several months. All attacks occurred on the right side of her head and were accompanied by ipsilateral lacrimation and nasal congestion. Sumatriptan led to acute pain relief while verapamil (120 mg per day) successfully reduced pain frequency. The diagnosis of episodic cluster headache was made. In 2011 the patient presented with a second headache characterized by right-sided pain attacks lasting between 15 and 20 minutes over the last two months. The pain was mainly located around the right eye and accompanied by CAS such as nasal congestion and lacrimation. In contrast to the former cluster attacks, the headache now occurred during daytime and did not respond to either sumatriptan or verapamil. However, treatment with indomethacin (150 mg per day) resulted in immediate freedom from pain. Thus, the diagnosis of paroxysmal hemicrania was confirmed.

Discussion

The underlying pathophysiological mechanism of TACs, in particular cluster headache, is considered to be a dysfunction or hypersensitivity of the hypothalamus (15–19). This dysfunction may cause a combined appearance of two different TACs in one patient or even a change from one TAC entity to another. The sequential presence of two TACs in a patient leaves open the question whether the primary cause of the disease remains the same while clinical manifestation may differ. This is probably why TACs are sometimes difficult to distinguish in daily clinical practice although the ICHD-II suggests a clear differentiation. However, some overlap syndromes might be possible. Differentiation between cluster headache and paroxysmal hemicrania might be difficult because of an overlap in the time pattern of the pain attack. However, all of the patients were able to differentiate between the different types of headaches and could report response to different treatments for each headache diagnosis. On the other hand, varying responses to treatment with steroids, triptans, indomethacin, verapamil, or lamotrigine remain effective additional criteria to differentiate between the TACs (20,21). However, only the response to indomethacin in paroxysmal hemicrania and hemicrania continua is considered a diagnostic criterion by the ICHD-II (2). In all our patients the specific reaction to certain medical substances was a helpful instrument for finding or at least confirming a diagnosis. Pathophysiology of TACs shares the posterior hypothalamic activation in several imaging studies. Matharu et al. conducted a positron-emission tomography (PET) study to determine the brain structures involved in mediating the pain of hemicrania continua. The study showed a significant activation of the contralateral posterior hypothalamus and brain stem areas. Both may reflect the overlap of symptoms of TACs and migrainous features. However, this activation pattern is different from the disorders currently assigned as TACs in the ICHD-II (19,22). Three of our four patients presented with chronic cluster headache. It might be these patients who are more likely to develop a second form of TACs perhaps due to the chronic activation of their pain matrix (23). However, cluster headache is still the most frequent of all TACs with prevalence between 0.2%–0.3%, which qualifies the statement (24,25).

Hemicrania continua is presumably the continuous form of paroxysmal hemicrania based on the accompanying autonomic features and the response to treatment with indomethacin. Hemicrania continua is classified as a TAC in the recently published ICHD-III (beta version) although patients present with continuous pain (4).

An extensive literature search revealed 10 additional case reports (6–14) with concomitant occurrence of TACs or hemicrania continua (see Table 1). In 12 of the 14 patients both headache disorders occurred on the same side of the head, whereas in only two patients the second disorder occurred on the contralateral side. The combination of two of these disorders might be due to the shared pathophysiology. In our case series three out of four patients presented with ipsilateral pain manifestations. In two patients the headache disorders occurred simultaneously, while the other patients developed a second headache entity several years after the first TAC had occurred. Considering the overlap in clinical presentation, the TACs more likely represent a clinical spectrum than completely different disorders. On the other hand, specific response to diagnosis-specific treatment allows the clear differentiation between the entities.

Table 1.

Concomitant occurrence of different trigeminal autonomic cephalalgias.

Case report (first author)	Year of publication	Gender of patient	Age of first TAC/ hemicrania continua diagnosis (years)	Start of second headache	Cluster headache	Paroxysmal hemicrania	SUNCT	Hemicrania continua	Side of pain
Jotkowitz et al. (8)	1978	Male	41	Subsequent	x	x	Ipsilateral
Pearce et al. (11)	1987	Male	48	Subsequent	x	x	Ipsilateral
Tehindrazanarivelo et al. (14)	1992	Male	27	Subsequent	x	x	Ipsilateral
Tehindrazanarivelo et al. (14)	1992	Male	35	Subsequent	x	x	Ipsilateral
Centonze et al. (6)	2000	Male	37	Subsequent	x	x	Ipsilateral
Lisotto et al. (10)	2003	Male	24	Subsequent	x	x	Contralateral
Saito et al. (13)	2005	Male	<36	Subsequent	x	x	Ipsilateral
Lambru et al. (9)	2008	Male	51	Subsequent	x	x	Ipsilateral
Cosentino et al. (7)	2010	Male	45	Subsequent	x	x	x	Ipsilateral
Robbins et al. (12)	2010	Female	34	Simultaneous	x	x	Ipsilateral
Our cases:
Patient 1	Female	35	Simultaneous	x	x	Ipsilateral
Patient 2	Male	38	Simultaneous	x	x	Contralateral
Patient 3	Male	41	Subsequent	x	x	Ipsilateral
Patient 4	Female	69	Subsequent	x	x	Ipsilateral

TAC: trigeminal autonomic cephalalgias; SUNCT: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

Overall the combined or sequential presentation of two different TACs in one patient is rare but possible and should always be taken into account for diagnosis and choice of treatment.

Clinical implications

Patients suffering from trigeminal autonomic cephalalgias (TACs) or hemicrania continua bear a high burden, thus adequate diagnosis and treatment are essential.

In rare cases patients may present with two different TACs or a TAC and hemicrania continua.