Abstract
Introduction
Systemic mastocytosis (SM) is characterized by an increased total burden of mast cells, which can be pathologically demonstrated as multifocal infiltrates of mast cells in either the bone marrow or an extra-cutaneous site. The World Health Organization (WHO) has published criteria for the diagnosis of SM, defining increasingly aggressive subtypes (1). These diagnoses range from the most common and benign form, indolent systemic mastocytosis (ISM), to mast cell leukemia (MCL). A large percentage of patients with ISM possess a specific gain-of-function mutation (D816V) in the mast cell c-Kit receptor, which results in premature mast cell activation (2).
Symptoms in mastocytosis are attributable to paroxysmal mast cell degranulation, either directly into the host tissue or into the bloodstream, and may include flushing, diarrhea, itching, and syncope. A recent case series of individuals with neurological manifestations in mastocytosis has provided additional clinical data to suggest a pathogenic relationship between migraine and mast cell dysfunction (3), building on an earlier detailed case investigation by Ashina (4). Interestingly, other authors have commented on a cluster-like headache phenomenology, but without reference to International Headache Society (IHS) criteria (5,6). While headache in general is known to be a significant contributor to disability in patients with mastocytosis (7), a dedicated study has not been carried out to define the headache sub-types and clinical features in this population.
Mast cells have been most closely studied with respect to the pathophysiology of migraine (8,9), although they have also been implicated in cluster headaches (10,11). Mast cells are found in varying densities throughout the dura mater, in association with connective tissue, neural, and vascular structures (12,13). A variety of stimuli implicated in migraine pathogenesis have also been associated with mast cell degranulation, including pituitary adenylate cyclase-activating peptide (14), substance P (15), calcitonin gene-related peptide (15), corticotropin-releasing factor (16), and the parasympathetic nervous system (17). More direct evidence comes from the landmark observation that dural mast cell degranulation results in sustained meningeal nociceptor activation, in addition to activation of second order neurons within the trigeminal nucleus caudalis, as measured by c-Fos expression (18).
With the aim of better understanding the clinical relationship between primary headache syndromes and mast cell activity, we obtained detailed survey information from 64 patients with systemic mastocytosis regarding their experience with headaches, if any.
Participants and methods
Patient identification
With Mayo Clinic Institutional Review Board (IRB) approval, the Mayo Medical Index Registry was searched between January 1999 to December 2008, to identify all participants 18 years of age or older who had been assigned a diagnosis of systemic mastocytosis. One-hundred-and-seventy-one consecutive cases of systemic mastocytosis were identified, all meeting WHO consensus criteria (1). A retrospective chart review of neurologic referral across this population has previously been reported (3).
Data collection
All patients were sent a detailed headache survey by mail, designed to assess cross-sectional primary headache diagnoses, according to International Headache Society (IHS) International Classification of Headache Disorders-2 (ICHD-2) criteria (19). The survey further ascertained information regarding the underlying mast cell disease, with attention to current mast cell mediated symptoms. Participants were asked questions regarding the temporal association of their headaches with flairs of their mastocytosis. Patients contradicting themselves in different survey questions, or with unclear answers, were subsequently interviewed by telephone by the primary investigator (JHS) to ensure accurate documentation of the clinical features.
To more completely define the clinical phenotypes, all survey participants were asked to complete the Headache Disability Inventory (HDI), a self-report inventory (20). The HDI is a 25-item questionnaire which assesses both the emotional (E) and the functional (F) impact of headache. We considered the total composite score of both components (E + F) in our analysis, which is scored as a fraction out of a maximal possible score of 100.
Statistical analysis
All analyses were carried out using the JMP statistical software package (Version 8, SAS Institute Inc, Cary, NC, USA). Descriptive statistics were used to describe the cohort. Continuous variables were described as means with standard deviations, and nominal variables as counts and percentages. Groups were compared using Kruskal-Wallis tests to compare continuous variables among three groups, followed by post-hoc pairwise comparisons using Wilcoxon Rank Sum tests when the overall p-value for the three-group comparison was significant. For dichotomous variables, a strategy was applied using chi-square or Fisher's exact tests, as appropriate. Adjustments were not made for multiple comparisons. Results were considered to be statistically significant for p ≤ 0.05.
Results
Comparison of survey responders and non-responders
Disease duration defined as the time from tissue diagnosis to either survey return or send date (for non-responders). Abbreviations: ISM = indolent systemic mastocytosis, SM-AHNMD = systemic mastocytosis with an associated hematologic non-mast cell disorder, ASM = aggressive systemic mastocytosis.
Distribution of headache diagnoses among survey respondents (n = 64)
Combined subgroups of both infrequent and frequent episodic TTH.
Clinical features by headache diagnosis
Abbreviations: HA = headache, TTH = tension-type headache, MC = mast cell, FH = family history.
Multiple comparisons abbreviated as a: TTH differs from no HA, b: Migraine differs from no HA, c: Migraine differs from TTH.
Headache reported to be concurrent with at least 50% of mastocytosis flair.
Headache patients were divided into two groups consisting of those who had reported headache concurrently with at least 50% of mastocytosis flairs (n = 15), and those who had not noted an association (n = 20). Patients who experienced headache with at least half of their flairs were more likely to be male (p = 0.002), have higher HDI scores (p = 0.02), and to report itching (p = 0.02), runny nose (p = 0.03), and unilateral cranial autonomic symptoms (p = 0.04). Comparison of all other clinical features, including headache diagnosis, syncope, diarrhea, and flushing, were non-significant.
Discussion
In patients with systemic mastocytosis we find through use of cross-sectional survey-based data that primary headache syndromes are common, disabling, and associated with clinical mast cell activity. We also demonstrate headaches occurring in temporal association with mastocytosis flairs to be associated with greater disability, independent of the headache sub-type. A limitation of this study includes the referral bias possible in the study of a tertiary center cohort, necessitated by the inherent difficulty obtaining a large cohort size in the study of an uncommon disorder. The purpose of this protocol was not to establish whether various primary headache syndromes are comorbidities of mastocytosis, and this conclusion should not be inferred from our data as a control group was not used. A low survey response rate of 43.2% represents an additional potential limitation to our study. However, survey responders more accurately reflected a general mastocytosis population than did survey non-responders, as more aggressive subtypes seemed to be over-represented in the latter group (Table 1) (2). Finally, multiple comparisons were performed, which increases the chance that some of the observed statistically significant relationships could be due to chance.
In our survey, patients with both migraine and TTH more frequently experienced symptoms reflective of mast cell activity than individuals not reporting headache. In other words, the likelihood of having headache in our study cohort was related to the clinical activity of the underlying mast cell disorder. Dural mast cell activity may be a nonspecific means for generating pain in both headache conditions; however, the mechanisms underlying our findings will need to be addressed in further studies (16,21,22). A direct temporal relationship between headache and clinical mast cell activity was reported by only 44% of those with headaches, implying that systemic degranulation alone may not be sufficient to trigger headache. Along these lines, headache is recorded by only a minority of individuals (<4%) during an anaphylactic reaction (23). A more protracted exposure to an increased mast cell burden may contribute to headache susceptibility and chronification. However, headache and abdominal pain are also common symptoms of mast cell activation syndrome (MCAS), which is not associated with tissue infiltration (24). Future study of individuals with mastocytosis may yield insights into the relative contributions of dural versus peripheral mast cell populations.
With regard to the known functions of mast cells, it is of interest that primary cough headache was found to be over-represented in our cohort (4.7%), in comparison with the 1% prevalence observed in both a population and clinic-based study (25,26). This high prevalence needs to be confirmed in a controlled population-based protocol. Although the pathogenesis of cough headache has not been well defined, transient increases in intracranial pressure transmitted from Valsalva maneuvers are certainly an important component (27). The dura has long been appreciated to be sensitive to mechanical stimuli (28). However, it has only recently been demonstrated that mast cell degranulation can persistently sensitize meningeal nociceptors to mechanical stimulation, an effect mediated at least in part by serotonin, prostaglandin I2, and histamine (29). Proteinase-activated receptor 2 (PAR2), which can be activated by mast cell tryptase, may also contribute to meningeal mechanosensitization (30). Increased dural sensitivity to mechanical stimuli in our patients with systemic mastocytosis may have been pathogenic in the development of a pain response to coughing.
An unexpected result of our study was the common occurrence of aura either with or without typical migraine headache (39%), representing an approximate fivefold excess of what would be expected from the sum lifetime prevalence of aura in a general population (2.3% for migraine aura without headache and 5% for migraine with aura) (31,32). Whether meningeal or systemic mast cell-derived products influence the development or propagation of cortical spreading depression (CSD) is not known, but if proven to be true, this would represent a novel insight into the current model of migraine aura (33–37).
Patients in our cohort who experience headache during flairs are more likely to be male, have histaminergic symptoms, and unilateral cranial autonomic features. This may account for the confusion in the literature that patients with mastocytosis may experience cluster-like headaches (5,6). Using standardized IHS criteria, we do not find evidence for cluster headache or other trigeminal autonomic cephalalgias in this population. Interestingly, that these headaches with autonomic features occur in association with mastocytosis flairs further implicates mast cells at the crossroads of pain and autonomic dysfunction (38).
In conclusion, we have described the distribution of primary headache syndromes among a cohort of individuals with systemic mastocytosis, in an effort to broaden our understanding of the contributions of mast cells to headache pathophysiology. Our findings will require confirmation, but are hypothesis generating, in that we implicate for the first time mast cells in the pathogenesis of primary cough headache and provide intriguing new data suggesting a fivefold increase in the occurrence of migraine aura in patients with mastocytosis.
Footnotes
Funding
This research was partially supported by the Center for Translational Science Activities (CTSA) at Mayo Clinic. This center is funded in part by a grant from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) (RR024150 PI: Rizza). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of CTSA, NCRR, or NIH.