Abstract
We report headache induced BOLD changes in an atypical case of trigeminal autonomic cephalgia (TAC). A 68-year-old patient was imaged using fMRi during three attacks of a periorbital head-pain with a average duration of 3 min. During the attacks, left sided conjunctival injection, rhinorrhea, lacrimation, facial sweating and hypersalivation were apparent. These attacks were usually partly responsive to oxygen administration but otherwise refractory to any drug. The patient described either attacks with a duration of one minute or less or longer attacks persisting for maximum of 20 min with headaches occurring up to 100 times a day. When considering the symptoms, frequency, duration and therapeutic response of the patient's headache, no clear-cut classification to one of the subtypes of trigeminal autonomic cephalgias (cluster headache, paroxysmal hemicrania, SUNCT) or trigeminal neuralgia was possible. The cerebral activation pattern was similar but not identical to those previously observed in cluster headache and SUNCT with a prominent activation in the hypothalamic grey matter. This case study underlines the conceptual value of the term TAC for the group of headaches focusing around the trigeminal-autonomic reflex. Our results emphasize the importance of the hypothalamus as key region in the pathophysiology of this entity.
Introduction
Trigeminal autonomic cephalgia is a relatively new term, first proposed by Goadsby and Lipton (1) for a group of primary headaches with pain and autonomic involvement in the facial area of the trigeminal nerve. Although the headache syndromes of this group, namely cluster headache, paroxysmal hemicrania, and SUNCT, clearly share typical clinical features, in most cases a subclassification is mandatory as therapeutical regimen and response differ. Therefore, the intensity, localization, frequency and duration of the pain, autonomic involvement, age and gender of the patients as well as triggering factors have to be considered. Cluster headache is characterized by the most intense pain, continuing for 15–180 min, with one to eight attacks per day and predominance in males (4 : 1) (2). In episodic and chronic paroxysmal hemicrania, headache periods are shorter (2–45 min), more women are affected, and this disorder typically shows a good response to indomethacin administration (usually between 100 and 150 mg per day). Finally, short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a syndrome with very short headache attacks (15–60 s), but a high daily frequency, and is often refractory to any medical and surgical treatment (3).
A typical differential diagnosis for SUNCT is trigeminal neuralgia, where pain also occurs in the distribution of the trigeminal nerve, however, mostly in the area of the second or third branch and usually lacking autonomic symptoms. The incidence of daily attacks in trigeminal neuralgia is sometimes up to 100 per day and therefore even higher than in SUNCT (1).
Despite unquestionable differences between the mentioned syndromes, some patients show a mixture of symptoms, more than one clinical presentation on different occasions (e.g. cluster headache and trigeminal neuralgia in the same patient) or a shift of symptoms, respectively, attributed diagnosis with time.
During the last decade, substantial progress has been achieved in the understanding of the pathogenesis of TAC and other primary headache disorders. Participation of the trigemino-parasympathetic reflex, which has been first described in cats (4), in the pathological process is now well accepted. Moreover, there is growing evidence of the hypothalamic grey being also involved in the pathogenesis of TAC as PET activation studies revealed ipsilateral hypothalamic activation in cluster headache (5). The cerebral activation detected in the study by May et al. (6) was not found in experimental pain studies and therefore seems to be specific to cluster headache. These results were taken further using voxel based morphometry, suggesting an increased grey matter density in the homolateral hypothalamus. Finally, hypothalamic activation near to the one in cluster headache was also found in an imaging case study of a patient suffering from another TAC, namely SUNCT attacks (7).
We present the clinical characteristics and functional imaging data of an interesting patient with TAC. In this patients case we felt, that no further classification was feasible, with the patient showing hallmarks of cluster headache, SUNCT, but also trigeminal neuralgia.
Case report and methods
Patient
A 68-year-old caucasian male construction engineer with a 12 years history of TAC and without history of migraine was imaged. He presented with recurrent strictly left sided stabbing head-pains, being most severe between November and March, but occurring throughout the whole year with a frequency of 4–100 attacks per day. The pain maximum was located retro- and peri-orbitally with ipsilateral conjunctival injection and lacrimation as well as ipsilateral nasal rhinorrhoea and hypersalivation. During the attacks swelling of the eyelids and left sided facial sweating was evident. Usually, the attacks occurred in the second part of the night or in the early morning. These late night episodes started mostly spontaneously, but at other daytimes multiple triggers were also able to provoke the same pain episodes. Potential triggers were cold wind on the left eye, light touch to the left facial side and gaping, but also chewing and speaking. Beginning and cessation of the headache were always abrupt. The patient described two similar pain manifestations, which differed only in their duration. On the one hand short episodes with a maximum duration of 1 minute, therefore resembling SUNCT attacks, and on the other hand longer episodes of up to 20 min being more compatible with paroxysmal hemicrania or cluster headache. Whereas predominantly the longer attacks occurred during the months before and after the fMRI scanning, the patient's clinical presentation had then shifted to the shorter attacks thereafter. The response to medication was frustrating. Oxygen administration results in a slight to medium relieve of symptoms, which is usually only seen in cluster headache. All other medications which were investigated in the course of the long-lasting illness, such as indomethacin (up to 150 mg/day per os), cortisone, lithium, carbamazepine, amitriptyline, ergotamine, metamizol, tramadol and acupuncture were all without effect on the pain.
The neurological examination was completely normal and cranial CT and MRI were repeatedly unremarkable.
During the fMRI scanning, the patient provoked 3 of the above described pain episodes by touching of a buccal triggerpoint with his tongue. The first with a length of 4 min, the second lasting 1.5 min and the third 5 min.
Methods
Functional magnetic resonance imaging was performed on a 1.5 Tesla Philips Gyroscan NT scanner. The patients head was positioned comfortably inside a receive-only birdcage head coil, supplied with ear plugs, heavily padded and secured with a strap across the forehead in order to minimize head motion. Echo Planar Imaging was used for the acquisition of the functional data. Acquisition parameters were TR: 6000 ms; TE: 50 ms; flip angle: 90°; Matrix: 128 × 128; FOV: 230 × 230 mm; 25 slices (thickness 5 mm). The resulting voxel size was 1.8 × 1.8 × 5.0 mm. 300 functional images were acquired with 101 images during the pain. The patient indicated the beginning and end of the pain attacks by pressing buttons on a nonmagnetic button-box.
Preprocessing and statistical analysis of the fMRI data was conducted using SPM99 (8). FMRI data series were realigned and resliced with sinc interpolation to correct for motion artifacts. Subsequently, the image series were transformed into standard stereotactic space to allow comparisons of stereotactic coordinates with published data on idiopathic headache syndromes. The resampled voxel volume of the normalized images was 2 × 2 × 2 mm. Data were then smoothed with an isotropic Gaussian kernel of 4 mm full-width at half maximum to reduce high frequency noise. Condition-specific effects (pain vs no pain) were estimated in SPM with the General Linear Model using a boxcar approach convolved with the haemodynamic response function (8). A statistical parametric map was generated as t-contrast at a threshold of P < 0.001. Activation was considered significant at a threshold of 0.05 corrected for multiple comparisons.
Results
During the scanning, no head motion greater than 1 mm was detected with and without pain. When comparing the pain attacks with the pain free state using fMRI, we detected significant cerebral activation increases (BOLD signal increases) in the hypothalamic grey matter. This hypothalamic activation extended laterally from a medial peak (Fig. 1). Additionally, with a less conservative threshold of P < 0.001 uncorrected, trends of activation were observed in the cingulate cortex, insula, temporal cortex, and frontal cortex (Table 1).
Statistical comparison of an fMRI study of three triggered trigeminal autonomic headache attacks and rest (no pain) in one patient. The pain induced activations are shown as statistical parametric maps of significant BOLD increases (P < 0.001 uncorrected for descriptive purposes) superimposed on a T1-weighted anatomical reference MR image in (a) coronal, (b) sagittal and (c) axial planes. The images are displayed in radiological convention.
BOLD-signal increases during an attack of trigeminal autonomic cephalgia compared with the pain-free state, P < 0.001 uncorrected. Coordinates are displayed in radiological convention
Significant after correction for multiple comparisons.
Discussion
Previous neuroimaging studies have shown significant activation of multiple brain areas in patients with cluster headache (5, 9). Although most of these areas have also been shown to be involved in general pain processing by studies using experimental pain stimulation paradigms such as tonic heat (10) or laser pain (11), ipsilateral posterior hypothalamic activation was exclusively observed in TAC. Based on clinical grounds, a role of the hypothalamus had already before been proposed in the pathology of cluster headache. Especially the seasonal pattern of bout periods and the neuroendocrine changes (12) led to this assumption.
A new and very convincing hint is the clinical observation of continuous long-term electrostimulation of the ipsilateral infero-posterior hypothalamus leading to pain reduction or even complete pain cessation in patients with severe chronic cluster headache (13, 14).
In other forms of TAC, not as much evidence for a central or hypothalamic pathological participation is available, but at least in SUNCT, one case study showed activation of a hypothalamic area nearby (laterally) the one reported in cluster headache (7). Despite the lack of imaging studies in paroxysmal hemicrania, similarities in the pathophysiology of all TAC’s, namely a hypothalamic involvement, are likely, as they share many clinical features.
Before the emergence of studies pointing towards a central mechanism in TAC, a mainly vascular pathogenesis was assumed. Today, a trigemino-vascular activation in the course of a TAC attack is still unquestioned, but this parasympathic reflex is thought to be mediated secondary to a central pain triggering (9). Therefore, these headaches are now referred to as neurovascular headaches.
We presented a case with TAC evidencing clinical features of SUNCT, paroxysmal hemicrania, cluster headache, but also trigeminal neuralgia. Whereas the patients age and sometimes short duration of attacks fit the definition of SUNCT, the frequent occurrence during the night, the response to oxygen administration and the sometimes longer attacks point more towards the diagnosis of cluster headaches or paroxysmal hemicrania. The very high frequency, and possibility to trigger attacks by stimuli in the distribution of the trigeminal nerve are best explained by trigeminal neuralgia. The lack of clinical improvement by indomethacin medication argues against chronic paroxysmal hemicrania. Although the patient described two different types of headaches, in terms of their duration, we think, that because of the otherwise completely identical clinical presentation and intensity of the head-pain, a differential classification of the shorter vs longer attacks the patient described, to different subtypes of TAC is not justified. Rather, we think that a pathophysiologically identical pain may be sometimes abortive in this patient's case. Taking into account these considerations, one possible description for the patients pain would be as an ‘atypically duration SUNCT’.
However, our fMRI results show headache induced activation of the hypothalamic grey matter in a position almost identical to the one shown in cluster headache. This medially localized activation peak extends laterally and overlaps with the one previously reported in SUNCT (7). Therefore, it may be speculated that the mixed fMRI activation pattern reflects the curious clinical presentation our patient shows, where no clear classification is applicable. These results suggest that there is sometimes not only considerable clinical overlap between certain of the primary cranial pain syndromes (15), but that these overlaps may actually be substantiated by imaging techniques. Although this case sheds more light on the assumed pathophysiology of TAC, it needs to be emphasized that there is a strong need to investigate more and clinically clearly defined TAC syndromes to substantiate considerations of the pathogenesis of TAC as well as to explain differences in phenotype.
In conclusion, our new data provide more evidence for a central origin of TAC. The hypothalamus seems to be a key region not only in cluster headache, but also in other forms of TAC. Although a subclassification within the TAC group is desirable, as therapeutic responses to medication differ within this group of primary headaches, it is not feasible in all patients. Therefore, we strongly support the integration of the term trigeminal autonomic cephalgia into the now published revision of the classification system of the International Headache Society (16).
Footnotes
Acknowledgements
We would like to thank Dr Arne May for his very helpful advice during the preparation of this manuscript. This study was supported by the ‘Irmgard und Gerhard Schulz Fond’ and the SFB 391 C9.