Neuroimaging in Trigeminal Autonomic Cephalgias

Arne May

Peter J. Goadsby

Primary short-lasting headaches broadly divide themselves into those associated with prominent cranial autonomic symptoms, so-called trigeminal autonomic cephalgias (TACs), and those where autonomic symptoms are minimal or absent. The group of TACs comprises cluster headache (CH), paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT syndrome) (35). The concept of trigeminal autonomic cephalgias underlines a possibly shared pathophysiologic basis for these syndromes that is not shared with other primary headaches, such as migraine or tension-type headache (24). As thus far findings in functional imaging of primary headache syndromes are specific to the disease (60,54), these techniques may be helpful in unravelling the degrees of relationship between clinically analogous headache syndromes.

TACs are relatively rare when compared to migraine or tension-type headache, which is likely to be why they are poorly recognized in primary care. The most remarkable of the clinical features of CH is the striking rhythmicity or cycling of the attacks and bouts. CH is probably the most severe pain syndrome known to humans, with female patients describing each attack as being worse than childbirth. The syndrome is well defined from a clinical point of view (35) and despite the fact that it has been recognized in the literature for more than two centuries (41), its pathophysiology has been hitherto poorly understood. Neuroimaging has made substantial contributions in recent times to understanding this relatively rare but important syndrome best illustrated by the advances in understanding CH.

THE ISSUE OF VASCULAR VERSUS NEUROGENIC MECHANISMS

In contrast to migraine, where at least two experimental models have been developed and tested in clinically relevant settings by pharmacologic means, CH has not been well studied in experimental animals and developments have come directly from human studies. A comprehensive model for CH has to explain the unilateral headache as well as the sympathetic impairment and parasympathetic activation. Recent functional imaging data may allow such a model to be developed.

Despite the large number of investigations in recent years, the issue of peripheral (e.g., vessel or perivascular inflammation) versus central nervous system (e.g., hypothalamic or parasympathetic) mechanisms is still unresolved. The pathophysiologic concept of vascular headaches is based on the idea that changes in vessel diameter or gross changes in cerebral blood flow would trigger pain and thus explain the mechanism of action of vasoconstrictor drugs, such as ergotamine (85).

CH specifically has been attributed to an inflammatory process in the cavernous sinus and tributary veins (33,64). Inflammation has been thought to obliterate venous out-flow from the cavernous sinus on one side, thus injuring the traversing sympathetic fibers of the intracranial internal carotid artery and its branches. According to this theory, the active period ends when the inflammation is suppressed and the sympathetic fibers partially or fully recover. This theory is based substantially on abnormal findings using orbital phlebography in CH patients (31,28,77) and on the fact that nitroglycerin (NTG) and other vasodilators can induce an acute CH attack (13).

However, in a study on CH patients using magnetic resonance imaging (MRI), no definite pathologic changes were found in the area of the cavernous (78). Using single photon emission computerized tomography (SPECT), parasellar hyperactivity was present in 50 (episodic) to 80% (chronic) of CH patients and in 70% of migraineurs (76). Similar findings on orbital phlebography can be seen in the cavernous region in patients with Tolosa-Hunt syndrome (29), hemicrania continua (3), SUNCT
syndrome (32,44), and chronic paroxysmal hemicrania (3,29), suggesting the changes are not specific for CH. Moreover, given the circadian rhythmicity of attacks and cycling of bouts (34,48,47), a purely vasogenic cause cannot easily explain the entire picture of CH (23). In view of the striking relapsing-remitting course (48), its seasonal variation (48), and the clockwise regularity (14), the concept of a central origin of CH needs consideration (14,45).

TABLE 90-1 Doppler Studies of Different Headache Types

*Author*	*Year*	*Diagnosis*	*Study Population*	n	*BFV Changes*
Afra et al. (1)	1995	CH	Attack/interval	19	↓
Dahl et al. (10)	1990	CH	Attack	25	↓
Kudrow (46)	1979	CH	Attack/interval	26	↓
Schroth et al. (72)	1983	CH	Attack	6	↑
Shen (75)	1993	CPH	Attack	3	↓
Shen et al. (73)	1993	CH	Attack/interval	14	↓
Shen et al. (74)	1994	SUNCT	Interval	4	Ø
BFV = blood flow velocity, CH = cluster headache; CPH = chronic paroxysmal hemicrania; SUNCT = short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
↑ = increase; ↓ = decrease; Ø = no change.

HEMODYNAMICS

Transcranial Doppler

Since CH was regarded as a vascular headache and since CH attacks may be provoked by the vasodilators histamine, NTG, and alcohol, several Doppler studies have been carried out to examine possible diameter changes in large intracerebral arteries (Table 90-1). Most studies demonstrated a bilateral decrease in blood flow velocity (BFV) in the middle cerebral artery and the anterior cerebral artery during the attack compared to the headache-free interval (1,10,46,72,74). Three studies used the elegant combination of Doppler and blood flow measurement using SPECT. Dahl et al. (10) and Afra et al. (1) demonstrated a decrease in BFV during the acute CH attack in frontal arteries but failed to show any blood flow changes. Gawel et al. (20) measured CO2 reactivity of the major intracranial vessels and demonstrated that the CO2 reactivity was significantly lower during the cluster period, but only in the ipsilateral anterior cerebral artery to the headache side. Using gallium SPECT, they described in three out of six patients during the active cluster period a lesion in the region of the cavernous sinus that faded as the patient moved out of the active period. They suggested that this finding may represent the cavernous sinus plexus lesion postulated as the central defect in CH. In summary, transcranial Doppler studies have shown decreased velocity in the middle cerebral artery after NTG administration and in the acute CH attack. It was also shown that this vasodilation did not alter brain blood flow.

Cerebral Blood Flow

Studies of cerebral blood flow in CH are relatively few. Most have been done with SPECT, and the results of this semiquantitative method have been quite heterogeneous, probably due to methodologic differences (Table 90-2), some reporting an increase (42,65,67,70,84), some a decrease (65,84), and some no differences in cortical blood flow (1,10,37,38,43,63,71). Di Piero and co-workers (12) studied CH patients out of the active period and normal volunteers using the cold water pressor test. They demonstrated changes in pain transmission systems, which bear more detailed examination. The fact that the alterations are also present out of the active period of the disease suggested a possible involvement of central tonic pain mechanisms in the pathogenesis of CH.

FUNCTIONAL NEUROIMAGING

Positron emission tomography (PET) may represent the best currently available technique for visualising in vivo changes in regional cerebral blood flow (rCBF) in humans when activations in the brain with a relatively long time constant, such as those in most headache syndromes, are to be investigated. Modern high-resolution PET scanning allows the detection of subtle changes in rCBF during defined behavioral tasks and provides an index of synaptic activity relating networks of regions to tested brain functions (17,18). CH attacks can be elicited with NTG during the active cluster period without significant side effects (13). Clinical and experimental data show NTG-provoked and spontaneous cluster attacks to be comparable (16,22), and NTG does not alter rCBF significantly (40,43). The headache can be rapidly and effectively aborted with sumatriptan. This approach therefore allows detection
of brain regions with increased blood flow during NTGinduced cluster attacks, focusing interest on the hypothalamic region (Table 90-3).

TABLE 90-2 Single Photon Emission Computerized Tomography Studies in Cluster Headache

*Author*	*Year*	*Diagnosis*	*Method*	n	*CBV Changes*
Afra et al. (1)	1995	CH	99mTC-HMPAO	19	Ø
Dahl et al. (10)	1990	CH	133Xenon	25	Ø
Henry et al. (37)	1978	CH	135Xenon	3	Ø
Hering et al. (38)	1991	CH	99mTC-HMPAO	14	Ø
Kobari et al. (42)	1990	CH	133Xenon	5	↑
Krabbe et al. (43)	1984	CH	133Xenon	18	Ø
McHenry et al. (62)	1978	CH	133Xenon	3	Ø
Nelson et al. (65)	1980	CH	133Xenon	26	↑↓
Norris et al. (67)	1976	CH	133Xenon	1	Ø
Sakai et al. (70)	1978	CH	133Xenon	9	↑
Schlake et al. (71)	1990	CH	99mTC-HMPAO	5	Ø
Wesseling et al. (84)	1989	CH	99mTC-HMPAO	8	↑↓
CBV = cerebral blood flow; CH = cluster headache. ↑ = increase; ↓ = decrease; Ø = no change.