Pathophysiology of Headache
Headache has come a long way during the seven editions of this book, in part because of the issues raised by its first author. Understanding headache is a challenging task given the large number of headache syndromes; the current International Headache Society (IHS) classification runs to 96 pages (Headache Classification Committee of the International Headache Society, 1988). However, understanding the mechanisms of headache is time well spent given the common nature of headache problems (Rasmussen, 1995; Stewart et al., 1992) and the expansion of treatments, particularly for migraine, that has taken place in the last few years (Goadsby and Silberstein, 1997). The emphasis in this section is on the primary headache syndromes, which are very common and, while not life-threatening, are lifestyle-disabling. After dealing specifically with migraine and cluster headache, the issues of the blood vessels, so close to Wolff’s interests (Graham and Wolff, 1938, 1966; Ray and Wolff, 1940; Tunis and Wolff, 1953), and tension-type headache will be addressed.
Headache is an excellent example of a problem that spans the breadth of medicine. It can be at once a major symptom, such as in subarachnoid hemorrhage, and the most disabling aspect of a primary syndrome, such as in cluster headache. Headache may be divided into primary headache, in which the headache and any associated features are themselves the disease processes, and secondary headaches, in which the headache is a symptom of an underlying disorder.
Much of the basic anatomy of all types of headache must be shared, since ultimately the trigeminal nucleus transduces nociceptive information from the head prior to its distribution within the brain. The best described anatomy and physiology have been developed in the investigation of migraine, but much of this substrate must be shared. Since secondary headache processes entrain very similar mechanisms for the expression of pain or even trigger primary headache mechanisms, it is not surprising that a secondary headache can mimic a primary headache phenotype and provide a very substantial diagnostic challenge.
Migraine is, in essence, an episodic headache that has certain associated features (Table 5 – 1), which give the clues to its pathophysiology (Table 5 – 2). In addition the term migraine is often used in two ways: first, to refer to the phenotype attacks, and secondly, to imply the underlining biotype of a headache disorder. It is interesting to compare the features of migraine and tension-type headache and to ask “What is quintessentially migrainous?” How can we make the diagnosis based on understanding the elements that contribute to the dysfunction?
The essential aspects to be considered in understanding migraine are as follows:
- Anatomy of the large intracranial vessels and dura mater and their neural connections, which are known as the trigeminovascular system
- The physiology and pharmacology of activation of the peripheral branches of the ophthalmic branch of the trigeminal nerve as marked by plasma protein extravasation and neuropeptide release
- The physiology and pharmacology of the trigeminal nucleus, in particular its caudalmost part, the trigeminocervical complex
- The brain stem and diencephalic modulatory systems, which control trigeminal pain processing
Table 5 – 1 Simplified diagnostic criteria for migraine: comparison with tension-type headache (repeated attacks of headache lasting 4 to 72 hours or 30 minutes to 7 days for tension-type headache, which have these features)
Adapted from the Headache Classification Committee of the International Headache Society (1988). Permission from Goadsby, P.J. and J. Olesen (1996). Diagnosis and Management of Migraine. BMJ 312:1279 – 1282.
At least 2 of the following
At least 1 of the following
Surrounding the large cerebral vessels, pial vessels, large venous sinuses, and dura mater is a plexus of largely unmyelinated fibers, which arise from the ophthalmic division of the trigeminal ganglion and, in the posterior fossa, from the upper cervical dorsal roots. The trigeminal fibers that innervate the cerebral vessels arise from neurons in the trigeminal ganglion which contain substance P (SP) and calcitonin gene – related peptide (CGRP) (Uddman et al., 1985), both of which can be released when the trigeminal ganglion is stimulated in either humans or cats (Goadsby et al., 1988).
Stimulation of the eranial vessels, such as the superior sagittal sinus, is certainly painful in humans (Feindel et al., 1960). In humans, the dural nerves that innervate the cranial vessels consist largely of small-diameter myelinated and unmyelinated fibers which almost certainly subserve a nociceptive function (Fig. 5 – 1).
What then is the source of pain in migraine? It must be borne in mind that the pain process is likely to be a combination of direct factors, i.e., activation of the nociceptors of pain-producing intracranial structures in concert with a reduction in the function of the endogenous pain-control pathways that normally gate that pain (Goadsby et al., 1991). If the carotid artery is occluded ipsilateral to the side of headache in migraineurs, two-thirds of them will experience relief, although this does not account for the other one-third (Drummond and Lance, 1983).
Physiology of Peripheral Connections
Plasma Protein Extravasation
Moskowitz (1990) has provided an elegant series of experiments to suggest that the pain of migraine may be a form of sterile neurogenic inflammation. These are covered here briefly for continuity but are addressed in greater detail here. Neurogenic plasma extravasation can be seen during electrical stimulation of the trigeminal ganglion in the rat (Markowitz et al., 1987). Plasma extravasation can be blocked by ergot alkaloids, indomethacin, acetylsalicylic acid, and the serotonin [5-hydroxytryptamine (5HT)]-1-like agonist sumatriptan (Moskowitz and Cutrer, 1993). In addition, structural changes in the dura mater are seen with trigeminal ganglion stimulation; these include mast cell degranulation and changes in postcapillary venules, including platelet aggregation (Dimitriadou et al., 1991).
While it is generally accepted that such changes, particularly the initiation of a sterile inflammatory response, would cause pain (Burstein et al., 1998; Strassman et al., 1996), it is not clear whether this is sufficient or requires other stimulators or promoters, with some recent clinical data demanding that the role of plasma protein extravasation be reexamined. Moreover, although the plasma extravasation in the retina that is blocked by sumatriptan is seen after trigeminal ganglion stimulation in the rat, no changes are seen with retinal angiography during acute attacks of migraine or cluster headache (May et al., 1998c).
Figure 5 – 1 Craniovascular innervation by trigeminal, sympathetic, and cranial parasympathetic nerves. The large cerebral vessels, pial vessels, large venous sinuses, and dura mater are surrounded by a plexus of largely unmyelinated fibers that arise from the trigeminal ganglion and in the posterior fossa from the upper cervical dorsal roots. Fibers innervating cerebral vessels arise from within the trigeminal ganglion from neurons that contain substance P and calcitonin gene – related peptide (CGRP). (Reproduced with permission from Neurology Ambassador Programme, American Headache Society.)
Clearly, blockade of neurogenic plasma protein extravasation is not completely predictive of antimigraine efficacy in humans, as evidenced by the failure in clinical trials of SP, neurokinin-1 antagonists (Connor et al., 1998; Diener, 1996; Goldstein et al., 1997; Norman et al., 1998), specific plasma protein extravasation blockers, CP122, 288 (Roon et al., 1997), 4991w93 (Earl et al., 1999), an endothelin antagonist (May et al., 1996), and a neurosteriod ganaxolone (Data et al., 1998).
Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood flow and local release of both CGRP and SP (Goadsby et al., 1988). In the cat, trigeminal ganglion stimulation also increases cerebral blood flow by a pathway traversing the greater superficial petrosal branch of the facial nerve, again releasing a powerful vasodilator peptide, vasoactive intestinal polypeptide (Goadsby and Duckworth, 1987). Stimulation of the more specifically vascular pain-producing superior sagittal sinus increases cerebral blood flow (Lambert et al., 1988) and jugular vein CGRP levels (Zagami et al., 1990).
Human evidence that CGRP is elevated in the headache phase of migraine (Gallai et al., 1995; Goadsby et al., 1990), cluster headache (Fanciullacci et al., 1995; Goadsby and Edvinsson, 1994), and chronic paroxysmal hemicrania (Goadsby and Edvinsson, 1996) supports the view that the trigeminovascular system may be activated in a protective role in these conditions. Furthermore, CGRP infusion will trigger headache, some clearly migrainous, in humans (Lassen et al., 1998). It is of interest in this regard that compounds that have not shown activity in human migraine, notably the conformationally restricted analogue of sumatriptan CP122, 288 (Knight et al., 1999b) and the conformationally restricted analogue of zolmitriptan 4991w93 (Knight et al., 1999a), were ineffective inhibitors of CGRP release after superior sagittal sinus stimulation in the cat.
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Peter J Goadsby
Editors: Silberstein, Stephen D.; Lipton, Richard B.; Dalessio, Donald J.