Our current study indicates that mastocytosis patients have a high prevalence of potentially disabling symptoms. Among patients not receiving anti-depressant therapies, some 49% were depressed according to an analysis based on the Hamilton score. Headaches were also noted in one out of two patients of our cohort and were associated to anti-histamine treatment. Episodes of vertigo were noted in one out of every three patients. Cognitive and sexual impairment were also prevalent, affecting up to 50% and 25 % of patients, respectively. No association between the latter symptoms and anti-histamine treatment was noted. In addition, one in four patients reported a negative impact on their professional life.
Depression was associated with cognitive, sexual, urinary, gastro-intestinal symptoms and fatigue. However, no associations were detected between depression and cutaneous, respiratory, and cardio-vascular symptoms. As the majority of patients were receiving anti-histamines, and montelukast treatment at the time of completing the questionnaire, this may have reduced our ability to detect an association.
The prevalence of neurological, cognitive, sexual, and psychiatric symptoms (including depression) was similar in patients with cutaneous and systemic mastocytosis. Symptoms were not influenced by indicators of total MC burden such as serum or medullar tryptase level [9-11]. There were not associations between symptoms and the presence of KIT mutations.
There is limited data about the frequency of neuro-cognitive, psychiatric, and sexual impairment in mastocytosis patients. Two previous studies reported the prevalence of neurological symptoms in mastocytosis patients [12, 13]. Headaches were the most prevalent symptom affecting some 35 to 56% of patients. Experiencing a headache was associated with an increased prevalence of other MC mediator-related systemic symptoms .
Cognitive impairment was first reported by Soter et al. in five out of eight mastocytosis patients . In another small study, ten patients underwent psychiatric interviews and a battery of psychological testing. Out of these, eight presented with cognitive and affective changes categorised as mixed organic brain syndrome . In another study 22 out of 57 mastocytosis patients (38.6 %) presented with memory/concentration impairment. This cognitive impairment was not related to depression, age or the type of mastocytosis . Our current study, of a larger cohort (n=139), reports a higher prevalence of cognitive impairments such as memory loss and difficulty concentrating in 52 % and 40 % of patients, respectively. We also observed an association between cognitive symptoms and depression, urinary and gastro-intestinal symptoms, and fatigue but not with age. Although depression and cognitive impairments are common co-morbidities, understanding their relationship remains limited .
In terms of mood disorders, Roger et al. diagnosed depression from psychiatric interviews in four mastocytosis patients out of ten . This was further investigated in two other studies. The first of these studies calculated a HAMILTON score for 88 patients and found that 75% of patients had scores of ≥ 10 . The second study, involving 288 patients, reported 56% of patients with a HAMILTON Score between 8 and 22 which was categorised as mild-moderate depression based on the cut-offs used in that study . In contrast to our study, these two previous studies did not assess associations between depression and other mastocytosis symptoms. The Moura et al. study showed that mastinib treatment, a tyrosine kinase inhibitor which decreases disease burden, also improved depression scores. Interestingly, this improvement was unrelated to the improvement in overall quality of life. This is also consistent with a phase 2a multicentre study which evaluated the effect of masitinib treatment in 25 mastocytosis patients and showed a >50% improvement in Hamilton scores compared to baseline . Improvement in depression could be related to the inhibitory effect of masitinib on MC activation which would support the assumption that depression is a systemic manifestation of the disease .
The frequency of depression in mastocytosis patients appears to be higher to what might be expected in the general population (7%) and in patients with advanced chronic conditions such as cancer (10-15%) and diabetes (14-25%) [21-24].
This raises the question of whether neurological, affective, and cognitive impairment is the result of primitive MC infiltration of the brain or the effects of MC mediators.
Boddaert et al reported morphological brain abnormalities consisting on abnormal punctuated white matter hyper signals in 49% of mastocytosis patients with psycho-cognitive complaints. As no histological diagnosis was done in this study, no evidence of MCs infiltration of the brain could be found. The authors suggested the implication of MC mediators without MC infiltrates in the recruitment and the proliferation of inflammatory cells resulting in neuroimaging abnormalities and neuro-cognitive symptoms .
Indeed some experimental evidence suggests that MC mediators may contribute to headaches, depression, and cognitive impairment.
Degranulation of dural mast cells induces activation of the trigeminal pain pathway believed to underpin migraine headaches . Histamine, leukotrienes, TNF-alpha, IL-6 and endothelin-1 released from MCs have been implicated in the pathophysiology of migraines [26-28].
A study of fifty-four mastocytosis patients has also suggested a role for MCs in the tryptophan catabolic pathway which is involved in depression. Alterations in tryptophan and serotonin metabolism, which are implicated in depression pathogenesis, have also been demonstrated in mastocytosis patients 
The implication of pro-inflammatory cytokines and MC-derived inflammatory mediators in neuro-inflammation and neurodegeneration could also explain the cognitive impairment in mastocytosis . The degranulation of MCs and the release of histamine  activate microglia through histamine receptors H1 and H4 and release neurotoxic mediators such as IL-1b, TNF-alpha, IL-6, and nitric oxide (NO) . These pro-inflammatory mediators directly induce neuronal death in the brain. Inflammatory cytokines such as IL-1b are known to induce neurodegeneration .
We therefore suspect that these symptoms are the result of mast cell activation and the systemic release of mediators rather than due to the proliferation or infiltration of MCs. This hypothesis is also sustained by the lack of impact of the type of mastocytosis (cutaneous or systemic) on these symptoms.
Regarding the impact of the disease on patients’ professional lives (which affects 26% of patients in our study), it appears to be noticeably higher than what had been reported in one previous study (15%) . This emphasises the importance of disease burden in mastocytosis patients. In our cohort, this impact was associated with psycho-cognitive impairment, gastro-intestinal, cardiovascular, and urinary symptoms, and fatigue.
The patient's perception of disability was assessed in a cohort of 62 patients with a confirmed mastocytosis diagnosis. Perceived handicap was noted in 87% of patients and was scored as moderate to severe in 52% of patients. In the same study, psychological, sexual, cognitive and neurological symptoms were found to be key contributors to disability in mastocytosis .
Our study is the first, to our knowledge, to simultaneously evaluate the neurological, cognitive, and emotional impacts of mastocytosis, which highlights the high degree of patient distress. There is an urgent need for physicians to recognise and treat neuro-psychiatric and cognitive symptoms associated with mastocytosis and to better understand the impact of such symptoms on the lives of their patients.
Our study has some limitations which are essentially due to its retrospective and monocentric nature. The available clinical data also did not allow us to assess the different headache subtypes. To assess depression, we used a validated measure and not a structured diagnostic interview which is generally considered the gold standard to detect depression.
We also only assessed subjective cognitive impairment and did not use objective instruments to evaluate this type of impairment in our mastocytosis patients.