Our data can be summarized as follows. 1) The prevalence of CA is highest in TM and episodic migraine, intermediate in PM, and lower in S-ETTH and O-CDH. CA appears to map onto migraine biology and to the migraine spectrum (TM, migraine, PM). Within a headache type, attack frequency is certainly one determinant of CA, but it is not the most important across headache types; otherwise, the prevalence of CA in O-CDH would be higher than in the episodic headaches (episodic migraine and PM). 2) The severity of CA is also highest in TM and migraine followed by PM and lower in S-ETTH and O-CDH, even after adjustments that account for the severity of the headache. Therefore, it is not that compared with migraine, the lower severity of ETTH attacks account for the lower severity of CA seen in the later group. Once more, this finding supports that CA maps onto migraine biology. 3) In logistic regression, CA is more common in women than in men for all primary headaches. Therefore, sex (female) and CA are associated. 4) In migraineurs, CA is associated, after adjustments, with female sex, high attack frequency, long disease duration, and obesity. The relative frequency of CA decreases with age. 5) Depression is independently associated with higher CA scores for all headache types.
Identifying factors that map onto disease biology as well as risk factors for clinical and anatomic progression for diseases have emerged as a very important public health priority because it may provide a foundation for more aggressive preventive intervention.24
Furthermore, identifying risk factors that are specifically related to one disease progression (e.g., from migraine to transformed migraine or from episodic tension-type headache to chronic tension-type headache) may provide valuable insights into disease pathophysiology.24-26
Although available evidence is limited, risk factors for headache progression can be divided into nonmodifiable and modifiable based on the prospects for addressing them with behavioral or medical interventions.27
For migraine, examples of factors nonmodifiable by medical intervention include age, sex, and socioeconomic status. Medically addressable risk factors include frequency of migraine attacks, obesity, acute medication overuse, caffeine overuse, stressful life events, depression, and sleep disorders.28,29
Our data suggest that CA maps onto the migraine biology. Although the first neurologic event leading to migraine pain is a matter of debate, it has been suggested that dysfunction of brainstem involved in the modulation of craniovascular afferents may lead to activation of ascending and descending pathways with initiation of a perimeningeal vasodilatation and neurogenic inflammation.30
In this context, the pain is understood as a combination of altered perception (as a result of peripheral or central sensitization) of stimuli that are usually not painful as well as the activation of a feed-forward neurovascular dilator mechanism in the first (ophthalmic) division of the trigeminal nerve. Alternative view proposes that cortical spreading depression, the presumed substrate of migraine aura, is the first neurologic event that would lead to inflammation of meningeal blood vessels and activation of the trigeminal nucleolus caudalis.31
Cortical spreading depression would also be modulated by brainstem structures.
CA is a frequent symptom experienced with migraineurs,4-7
reflecting central sensitization at the level of the trigeminal nucleus caudalis, a structure that is in close relation with the periaqueductal gray area.32-34
Speculating on the progression of migraine, it may be hypothesized that repetitive activation of trigeminovascular neurons and consequently repetitive activation of modulatory pain pathways involving the periaqueductal gray may lead to impairment of function or partial neuronal cell damage, through the liberation of free radicals, in the periaqueductal gray (involved with migraine modulation) or eventually in areas involved with migraine generation.30,31
If that is true, CA would be associated with the migraine spectrum, but not with all primary headache disorders, which was the primary hypothesis of our study.
Female sex and depression seem to be nonspecific proallodynic factors. For the first, the importance of sexual hormones may be speculated. In a human model of capsaicin-induced trigeminal sensitization, pain area significantly changed across the menstrual cycle from a maximum at the menstrual and a minimum at the luteal phase (p
< 0.001). The areas of pain were significantly larger in both phases for females compared with males. Area of brush-evoked allodynia was also larger at the menstrual phase compared with the luteal phase (p
< 0.0001) and males (p
For depression, to our knowledge, this is the first study to report it as being independently associated with CA throughout a gamut of headache disorders. Because several antidepressants act in the substantia nigra pars compacta and ventral tegmental area,36
suggesting the importance of these structures that are closely related with the trigeminal nucleus caudalis,37
in the etiology of depression, this may at least partially explain our findings.
Our data also suggest that CA increases with increased weight and decreases with age. Obesity is associated with increased plasmatic concentration of several proinflammatory mediators and of calcitonin gene-related protein.38,39
Furthermore, relative to normal weight, obese migraineurs have attacks of increased frequency and severity,29
which may explain the higher prevalence of CA in obese individuals. Of note is the age-related decrease in CA. The reasons for this are unknown, but previous studies have shown that migraine attack frequency and severity decreases with age.40
Perhaps the activation of pain pathways declines as attacks become less frequent and severe. Perhaps headaches improve with age as a result of involution of the neurotransmitter systems that mediate head pain.41,42
Our data must be interpreted with caution. First, although we used a questionnaire that has been validated for the assessment of CA in the population, the validation happened in migraineurs only.10
Although we have no reasons to assume that the psychometric properties of the questionnaire would be substantially different in the other headache groups, analogous problems were seen with other headache questionnaires such as MIDAS and HIT-6 that have been validated for migraine but are often used for the assessment of other primary headaches such as chronic daily headaches or cluster headaches.43-45
Second, the ASC classification of severity of CA has not been compared with classification based on QST. Although QST is the gold standard for determining whether a patient has allodynia at a particular point in time, it is subject to temporal sampling error.1,2
Finally, although our data suggest that the prevalence and severity of allodynia varies among different primary headaches, we have not yet determined if allodynia as measured by ASC predicts headache progression. Strengths of our study include the robust sample size and the use of validated questionnaires in a cohort of subjects previously identified and representative of the US population.