The success rate of preventing migraine attacks prophylactically using BTX-A was associated with the type of headache individual patients had. Patients who testified to ‘imploding’ or ‘ocular’ headache were likely to experience a drastic decline in the number of migraine days per month between weeks 4 and 12 after a single treatment session. In contrast, patients who testified to ‘exploding’ headache were unlikely to respond to BTX-A treatment. Thus, migraine perceived as exploding headache appears to be fundamentally different in pathophysiology from migraine perceived as imploding or ocular headache, suggesting that the subjective perception of pain be incorporated into migraine diagnosis.
Considering that migraine prophylaxis may be associated with a placebo effect (Binder et al. 2000
; Dodick et al. 2005
; Evers et al. 2004
; Ondo et al. 2004
), we examined whether the incidence of migraine could be selectively reduced by placebo injections in patients with imploding or ocular headache, but not in those with exploding headache. Retrospective analysis indicated that the mean number of migraine days per month remained unchanged after placebo injections in 6 patients with imploding/ocular headache, as well as in 6 patients having exploding headache. Patient-by-patient analysis indicated that 4 out of 12 patients (33%) experienced a 21–45% drop in migraine days/month. It should be noted, however, that the definition of response to BTX-A in the current study was much higher (>80% drop in migraine days/month), suggesting that the selective response to BTX-A treatment in our patients with imploding/ocular headache was unlikely to be due to a placebo effect. Using a lower threshold for response to BTX-A (e.g., >50% rather than >80% drop in migraine days/month), as in other studies, would slikely increase the size of the placebo effect.
Migraine patients typically describe their headache using familiar terms such as throbbing, pounding, pressing or tightening (Olesen et al. 2005
). In recent years, we have become aware that some patients perceive their pain as pressure buildup inside their head (exploding headache) while others perceive their pain to be inflicted from the outside (imploding headache). Subjective accounts of exploding headaches often consisted of phrases such as: “My head is exploding”, or “my brain feels so swollen that there isn’t enough room inside”, or “I wish someone would drill a hole in my head to let the pressure out”. Subjective accounts of imploding headaches included phrases such as: “someone is tightening a vise around my head and it is going to crush”, or “an elephant is sitting on my head”, or “someone is stubbing a knife in my head”. We must admit that this novel delineation of the type of headache according to its directionality may not be a simple task for either the interviewing physician or the patient. So far, we have employed a three-tier approach in the interview: first, allow the patients to volunteer their own answer to the best of their recollection; second, ask the patients to choose between inward and outward headache; third, present a sample of common testimonies () and ask the patients which fits best their perception of migraine pain. To minimize inter-observer variability, it will first be necessary to optimize a standardized line of questioning presented to the patient and, second, apply the standardized interview in different clinics in order to validate the consistency of the diagnosis.
Although we do not understand the pathophysiological difference between exploding and imploding headaches, we have made it a routine to ask patients to describe their headache and its directionality. We found that the proportion of migraineurs with imploding headache was 42 and 44% in the prospective and retrospective study, respectively. Exploding headache was found in 54% of the patients in the prospective study and 33% of the patients in the retrospective study. While the relative prevalence of exploding and imploding headaches remains to be determined in the general population of migraineurs, our preliminary survey of 50 patients in BIDMC headache clinic suggests that 70% have exploding and 30% imploding or ocular migraine headache.
A number of factors proved unrelated to the prophylactic action of BTX-A. Symptoms such as aura, photophobia, phonophobia, osmophobia, nausea, vomiting or throbbing, were equally prevalent among responders and non-responders. Also unrelated to the prophylactic action of BTX-A is the frequency of migraine attacks: among responders 54% of the patients were ‘episodic’ and 46% were ‘chronic”. Given that medication overuse often renders patients refractory to common migraine therapy, the finding that medication overuse was equally prevalent between responders and non-responders suggests that medication overuse does not interfere with the prophylactic action of BTX-A.
The finding that migraine prophylaxis was unrelated to concurrent muscle tenderness suggests that the effect was independent of the inhibitory action of BTX-A at the level of the neuromuscular junction. The notion that migraine prophylaxis may be achieved through direct inhibition at the level of the central nervous system did not gain support either. The responsiveness to BTX-A was not associated with any centrally-mediated migraine symptoms such as aura and cutaneous allodynia. Considering that cutaneous allodynia is driven by sensitized central trigeminovascular neurons (Burstein et al. 2000b
), it is worth noting that BTX-A proved virtually ineffective in blocking allodynia during migraine in both responders and non-responders.
Rather than acting centrally, BTX-A may exert its prophylactic action on migraine through inhibition of peripheral sensory neurons (Aoki 2005
). That BTX-A can inhibit sensory neurons is consistent with evidence that the toxin inhibits release of substance P from embryonic dorsal root ganglion neurons in vitro
(Welch et al. 2000
), or CGRP from trigeminal ganglion neurons in vitro
(Durham and Cady 2004
), or glutamate from peripheral nociceptors terminating in the dorsal horn in vivo
(Cui et al. 2004
). Using quantitative sensory testing, however, Blersch et al (2002)
showed that subcutaneous injection of BTX-A did not change pain thresholds to local cold, heat and electrical stimulation, and concluded that BTX-A may block pain through chemodenervation or anti-inflammatory action, rather than by direct peripheral anti nociceptive effect.
Regardless of the exact peripheral mechanism of BTX-A action, at issue here is whether the peripheral action is exerted intracranially or extracranially. The finding that exploding headache was impervious to extracranial BTX-A injections is consistent with the general view that migraine pain is mediated by intracranial
nociceptors innervating the meninges and sinuses of the dura. Such a concept may also be tested in the future using patients whose headache stems from a clear intracranial pathophysiology. On the other hand, the amenability of imploding and ocular headaches to BTX-A treatment suggests that these types of migraine pain also involve extracranial
sensory fibers adjacent to the injection sites. Involvement of extracranial tissue in the pathophysiology of certain migraine patients has been proposed some five decades ago (Selby and Lance 1960
; Wolff et al. 1953
). If so, it is tempting to speculate that imploding headache involves activation of extracranial nociceptors that innervate scalp tissues, such as bone and periostium.
The dramatic difference between responders and non-responders in the incidence of migraine after BTX-A treatment suggests that previous studies that pooled data from all treated patients without such distinction (Binder et al. 2000
; Dodick et al. 2005
; Evers et al. 2004
) may have missed the full magnitude of the prophylactic effect of the toxin at the level of the individual patient. Of the 42 subjects that participated in our prospective study, only 14 (33%) were clear-cut responders, while 13 (31%) were clear-cut non-responders. It remains to be determined what types of headache are present in patients whose attack frequency after BTX-A dropped between 33 and 80% (‘partial responders’).
Finally, we would like to emphasize that the present study does not intend and cannot be used to recommend the use of BTX-A as prophylactic migraine therapy. The only goal of this study was to explore for neurological markers that might single out migraine patients who respond to BTX-A treatment from those who do not.