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Abstract and Figures

In approximately one-third of cases, patients with mastocytosis can display various disabling general and neuropsychological symptoms. General signs may have a major impact on quality of life. Neurologic symptoms are less frequent. In a majority of cases, the pathophysiology of these symptoms is not known but could be linked to tissular mast cell infiltration, mast cell mediator release, or both. Treatments aiming at reducing mast cell number and/or stabilizating mast cells may be useful. Preliminary results suggest that treatment with kinase inhibitors may improve symptoms of depression and cognitive impairment.
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Neuropsychological Features of
Adult Mastocytosis
Daniela S. Moura, PhD
Sophie Georgin-Lavialle, MD, PhD
Raphaël Gaillard, MD, PhD
, Olivier Hermine, MD, PhD
Neurologic and psychiatric symptoms should be evaluated prospectively on large co-
horts of patients. In addition, they should be evaluated in children populations, which
are poorly studied in this respect.
New research is needed to better understand the pathophysiology of these manifes-
tations. The results of this research could point out the role of mast cells in neurologic
and psychiatric disorders outside mastocytosis.
INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological
Disorders and Therapeutical Implications, Paris, France;
Paris Descartes – Sorbonne Paris Cite
University, Imagine Institute, Paris, France;
CNRS ERL 8254, Paris, France;
Laboratory of
Excellence GR-Ex, Paris, France;
Service d’He
´matologie clinique, Assistance Publique-Ho
de Paris, Ho
ˆpital Necker, Paris, France;
Service de me
´decine Interne, Ho
ˆpital Tenon, Assistance
ˆpitaux de Paris, Universite
´Pierre et Marie Curie, 4 rue de la chine, Paris 75020,
Laboratoire de “Physiopathologie des maladies Psychiatriques”, Centre de Psychiatrie
et Neurosciences, U894, INSERM, Universite
´Paris Descartes, Sorbonne Paris Cite
´, Paris, France;
Service de Psychiatrie, Faculte
´de Me
´decine Paris Descartes, Centre Hospitalier Sainte-Anne,
´Paris Descartes, Sorbonne Paris Cite
´, Paris, France
* Corresponding author. Service d’He
´matologie Adultes et centre de re
´rence sur les mastocy-
toses, Ho
ˆpital Necker-Enfants Malades, 161 Rue des Se
`vres, Paris 75743 Cedex 15, France.
E-mail address:
Mastocytosis Mast cell Kit Depression Anxiety Cognitive impairment
Mastocytosis is associated with several and disabling general and neuropsychological
symptoms, including pain, headache, anxiety, depression, and cognitive impairment.
Cognitive impairment in mastocytosis is not linked to depression.
Anxious and depression symptoms may improve after treatments by tyrosine kinase inhib-
itors aiming at reducing mast cell activation.
Immunol Allergy Clin N Am 34 (2014) 407–422
0889-8561/14/$ – see front matter Ó2014 Elsevier Inc. All rights reserved.
Mastocytosis is defined as an excessive accumulation of mast cells in several organs or
tissues. In most cases, the disease is indolent and does not reduce life expectancy. The
disease is associated, however, with an underestimated chronic disability, presumably
linked to the release of mast cell mediators by abnormal mast cells that includes flushes
and the well-defined gastrointestinal symptoms, cardiovascular instability, and skin
involvement, in particular pruritus and esthetic concerns. In addition, it is well recognized
that in almost one-third of the patients, general symptoms, including fatigue and muscu-
loskeletal pain, could also have a major impact on the quality of life. Although less recog-
nized and less attributed to mediators released from abnormal mast cells, symptoms,
such as headache, anxiety, mood, and cognitive impairment, are frequent and should
be specifically evaluated because they may require specific therapies and are associ-
ated with significant impairment of social life and professional activities. In this review,
in addition to the authors’ studies on psychiatric and neurologic disorders, the major
recent findings concerning neuropsychological symptoms in mastocytosis are reviewed
and data supporting the hypothesis that abnormal mast cell activation and to a less
extent mast cell accumulation are involved in these disorders are discussed.
Neurologic Features
Few studies are focused on neurologic symptoms associated with mastocytosis
(Table 1). In earlier studies of a large cohort of patients, some investigators reported
frequent acute or chronic headache; more rarely, syncope and acute-onset back
pain; and, in a few cases, clinical and radiological features resembling or allowing a
diagnosis of multiple sclerosis.
In addition, several case reports discussed rare asso-
ciations between mastocytosis and various neurologic conditions, including chorea,
encephalopathy, and strokes.
From these studies, it is difficult, however, tolink these
neurologic manifestations with abnormal mast cell activation and they may have been
more fortuitous than causal. Two recent studies, however, reported neurologic symp-
toms on large cohorts of adult patients with mastocytosis.
First, they investigated
the occurrence of headache by sending questionnaires to 171 patients with systemic
mastocytosis. They received 64 responses, and 36 patients (56.2%) complained of
These patients displayed headaches, which were classified as migraines
(37.5%) or tension-type headaches (17.2%). Second, they tried to identify which
complication of the disease could have an impact on the nervous system in a retrospec-
tive study of 223 adult patients with mastocytosis.
The most frequent symptoms they
found were headache (n 578; 35%), followed by syncope (n 512; 5.4%), acute back
Table 1
Main neuropsychological features in mastocytosis
Neuropsychological Features Percentage (%) Reference
Depression and anxiety 40–60 Moura et al,
Headache 35–56 Smith et al,
Including migraine 37.5 Smith et al,
Cognitive impairment 38.6 Moura et al,
Syncope 5 Smith et al,
Back pain 4 Smith et al,
Multiple sclerosis 1.3 Smith et al,
Moura et al
pain (n 59; 4%), and clinical and radiological features, allowing a diagnosis of multiple
sclerosis (n 53; 1.3%). The frequency of all these symptoms seems higher than might
be expected in the general population of the country in which the study was performed
(0.1%), suggesting that mast cell activation may be involved in these disorders.
In mastocytosis, although mood disorders are clinically observed and are one of the
main complaints of patients, specific descriptive literature reports are rare
concern small number of patients. Quantitative and qualitative descriptions of these
symptoms in larger cohorts are still missing. In a seminal study by Rogers and col-
leagues in 1986,
depression frequency and features were investigated. In this study,
depression was diagnosed after psychiatric interview in 40% of patients (n 510). In
2008, the authors further reported a prevalence of 75% of depression symptoms among
88 patients with indolent mastocytosis, including cutaneous and systemic forms of the
The authors’ first descriptive study looked at a large sample of 288 subjects.
The results of this first study showed a prevalence of depression in mastocytosis at
approximately 60%, which confirmed the results of previous studies of a smaller num-
ber of patients.
The higher prevalence reported in the authors’ study could be explained
by the different methods of assessment and largely by the choice of a low cut-point of
the Hamilton depression rating scale used to consider patients as depressed.
Cognitive Impairment
Soter and colleagues
were the first to report cognitive impairment in mastocytosis in
the 1970s. In this study, they reported neuropsychiatric symptoms among patients
with mastocytosis as “attention and concentration disorders, irritability, fatigue, head-
ache, socio-relational difficulties and poor motivation” in 5 patients of 8.
about memory impairment in mastocytosis have only been specifically studied in 1986
in 10 patients with an old version of the clinical Wechsler Memory Scale.
According to
the investigators, most patients presented disorders of cognition affecting memory
and attention that fluctuated with the disease and were in some cases improved by
histamine antagonists used to control the activity of mast cells. The authors have
confirmed these results and shown in 57 patients with mastocytosis that cognitive
impairment is a common symptom (38.6%). The prevalence of memory impairment
in the authors’ sample was high but not as much as suggested by Rogers and col-
leagues (70% in a sample of 10 patients). In addition, the authors’ study provided ev-
idence that memory impairment in mastocytosis was not related to age or level of
education of patients (mean age 42 years and high level of education [32%] in the
group with disorders). The prevalence of cognitive impairment in the authors’ sample
was significantly higher than reported in the literature in younger populations (45–59
years) suffering from chronic diseases, such as diabetes, or in the elderly (65 years
and over) where the prevalence of cognitive impairment without dementia is approx-
imately 15% to 40%.
The prevalence of cognitive impairment in the authors’ sam-
ple was similar to that observed in multiple sclerosis, an inflammatory disease in which
mast cell activation (without mastocytosis) may play a role and in which the prevalence
of cognitive impairment is estimated between 40% and 60%.
Neurologic Symptoms
Neurologic symptoms can be acute, related to mast cell mediator release, such as
headache and syncope, or permanent, related to mast cell infiltration, such as back
Neuropsychological Features of Adult Mastocytosis 409
pain, in cases of vertebral infiltration with or without fracture. Headaches were
frequently reported in 35% of patients in a large cohort of 223 patients.
In a second
study by the same group based on a smaller number of patients (36 patients) using a
questionnaire, it was shown
that 25% of patients displayed chronic daily headache,
37.5% presented migraine, and 17.2% complained of tension-type headache, mostly
episodic. Among the patients with migraine, two-thirds reported an associated aura,
most frequently visual. Typical aura could be reported with or without migraine among
39% of the patients of the cohort. Symptoms that are clearly associated with abnormal
mast cell activity, such as flushes, pruritus, and/or diarrhea, were more common in pa-
tients with either tension-type headache or migraine than in patients not reporting
headache. Beurey and colleagues
reported syncope as early as in 1971, and this
symptom has been more extensively reported by Smith and colleagues
in 12 patients
of 223 with mastocytosis.
The patients reported by Smith and colleagues had been
referred to a neurologist for indeterminate spells with episodic loss of consciousness.
When performed, cerebral MRI, electroencephalograms (EEGs), and cardiac evalua-
tions were considered normal. When reported, the spells evolved over the course of
several minutes, culminating with a brief syncopal episode. The most commonly asso-
ciated symptoms were loose stools, abdominal cramps, nausea, hot flushing, light-
headedness, palpitations, and diaphoresis, suggesting a role of acute mast cell
mediator release. Smith and colleagues
identified 3 patients with clinical and radio-
logical features compatible with the diagnosis of multiple sclerosis. In this report, 1
man 25 years old and 2 women 57 and 64 years old, respectively, met the revised
McDonald clinical criteria for multiple sclerosis. Finally, several case reports were pub-
lished reporting rare neurologic features associated with mastocytosis, including
chorea (n 52), encephalopathy (n 52), cerebral infarction (n 51), coma (n 51),
and strokes with cervical artery dissection (n 52).
Such isolated case reports
may be fortuitous associations and were not confirmed on the large cohort of Smith
and colleagues in 2011.
Psychological Symptoms
Depression characteristics and assessment
Although psychological symptoms (depression and disorders of attention and me-
mory) are part of chronic manifestations of mastocytosis, patients suffering from
mastocytosis and concerned by these disorders express great suffering linked to
the misunderstanding and lack of recognition of their symptoms by themselves but
also by physicians or relatives. As discussed previously, no reports in the literature
have studied extensively depression characteristics in a large group of patients
with mastocytosis. In an attempt to better characterize depression based on a ques-
tionnaire, the authors performed, in a large cohort, a detailed analysis of symptoms in
patients complaining of mood disorders. The data suggest that depression associ-
ated with mastocytosis comprises mainly affective-cognitive aspects (depressed
mood, guilt, feelings of failure, and poor motivation [loss of interest in the work
and activities]) and anxiosomatic aspects (somatic and psychic anxiety and middle
and late insomnia).
Symptoms like psychomotor slowing and insight problems
are rare and are considered atypical symptoms in this population. It is also important
to consider the limitation of depression assessment using questionnaires instead of a
structured interview diagnosis based on Diagnostic and Statistical Manual of Mental
Disorders criteria.
Although the Hamilton Depression Rating Scale is still the gold
standard for evaluating depression in clinical trials, it may not be the best choice
for mastocytosis patients because of the over-representation of somatic items that
may overlap with symptoms of the disease.
By studying in detail the Hamilton
Moura et al
score, however, the authors could demonstrate that a high-level score was associ-
ated with core depression symptoms, such as sadness and loss of motivation.
The use of a more accurate clinical depression scale, the Beck Depression Rating
Scale, led to similar results but with a slightly lower rate of depression.
use of more than one scale and/or scales less biased by somatic symptoms should
be preferred to screen for depression in mastocytosis. Regardless of the type of
questionnaires used, however, it is also important to complete the assessment of
patients presenting with more severe symptomatology detected by questionnaires
using a psychiatric interview to confirm diagnosis and provide, if necessary, proper
Cognitive impairment characteristics and assessment
Among mastocytosis patients, cognitive symptoms were mostly characterized by
attention impairment.
Due to their characteristics, cognitive impairment in masto-
cytosis seems to meet the criteria for an “unspecified cognitive disorder” as described
in the DSM (Fourth Edition).
These disorders were not linked to depression, age,
level of education, or clinical subcategories. Moreover, no correlation was found be-
tween these cognitive disorders and the provision of antihistaminic drugs. In addition
to cognitive impairment, lack of motivation is an important symptom to consider in this
group of patients. Although difficult to quantify, this symptom shares some links with
fatigue and could help understand the primary pathways and mechanisms involved
with cognition impairment. Fatigue is a complex symptom composed of both psychic
(motivational) and somatic dimensions. The psychic dimension of fatigue is often
associated with symptoms, such as pain and affective and cognitive alterations,
and is more difficult to characterize.
Its behavioral expression (motivation and
reward responsiveness), however, has a specific neural circuit involving dopaminergic
subcortical structures, such as putamen and anterior cingulate cortex, that could be
implicated in difficulties to sustain attention and/or to engage in even simple actions
among these patients.
Assessment of cognitive impairment in mastocytosis should
be more systematic in patients with complaints and should focus on attention and
auditory memory and executive functions as well.
Although the pathophysiology of infiltrative complications, such as spinal cord
compression, is easy to understand by a mechanical role of mast cell infiltration of
vertebral bone, the pathophysiology of fatigue, cognitive dysfunction, psychiatric
symptoms, and headache remains unclear (Fig. 1).
Mast Cells in the Brain
Mast cells are present in variable quantities in all tissues and organs, especially along
vessels, including the brain, which is rich in mast cells. In this organ, they are prefer-
entially located near blood vessels at the level of the blood-brain barrier and also at the
nerve endings of sensory and sympathetic fibers.
In addition, mast cells are found
particularly and in high density in certain structures of the diencephalon, especially
in the hypothalamus, which is involved in systems of stress response, emotion, and
cognition, and also in amygdales, in the ventral portion of the median eminence,
near the pituitary gland at these anterior and posterior sides as well as in the hippo-
campal formation and surrounding leptomeninges and meningeal spaces at the level
of the olfactory bulb.
A large number of mast cells reside in the thalamus, which
lesions or stimulation of the dorsomedial portion and earlier kernels have been asso-
ciated with changes in emotional reactivity and pain.
Neuropsychological Features of Adult Mastocytosis 411
Mast Cells, Stress Response, Cognition, and Emotionality
Because of their particular distribution and density in related brain structures, mast
cells’ overactivity may interfere with brain function and adversely affect stress
response, cognition, and emotionality.
In a previous work, the authors
showed that patients with mastocytosis displayed high levels of perceived stress
linked to lower telomere length.
Perceived stress results from cognitive and
emotional evaluation of situations by individuals. The brain structures involved in phys-
iological stress response are also implicated in cognitive appraisal as well as emotion
and behavioural responses to adversity. In mastocytosis, in line with other studies in
the field of stress, chronic hyperactivation of the stress response system has been
hypothesized to explain the high prevalence of neuropsychological symptoms as
well as a high tendency to perceive stress in conventional situations.
The path-
ologic variation of the number and the activation of mast cells in the brain could lead to
a dysfunction of these systems. In line with these observations, negative emotion
expressed in mastocytosis could also result from conditioning process involving re-
sponses to stress. Mast cells could be recruited through aversive conditioning.
Once conditioning is obtained, psychological cues could lead to mast cell activa-
which could maintain aberrant responses to stress.
Mast Cell Neuroinflammation and Depression
The cytoplasm of mast cells contains many granulations of preformed mediators,
such as histamine, tryptase, serotonin, cytokines, and chemokines (interleukin
[IL]-3, IL-4, IL-5, IL-6, IL-8, granulocyte macrophage–colony-stimulating factor, and
which, in cases of abnormal release, may explain part of all the symp-
toms found in patients with mastocytosis, including olfactory hypersensitivity, head-
ache and migraines, pain, and probably mood, anxiety, and cognitive disorders.
Histamine has a modulator effect in some mnemonic systems, but its exact function
in memory remains controversial.
In their study of memory disorders in
Fig. 1. How mast-cells might be involved in the etiology of neuropsychiatric symptoms asso-
ciated to mastocytosis? (Adapted from Selvier Medical Art.)
Moura et al
mastocytosis, Roger and colleagues
suggested that histamine might be responsible
for memory disorders in mastocytosis. Their hypothesis was based on the fact that
their patients improved their neuropsychiatric symptomatology with antihistamine
drugs. Serotonin produced by mast cells contributes to hippocampal function.
mastocytosis, Kushnir-Sukhov and colleagues
have shown that patients display-
ing gastrointestinal and neuropsychological symptoms presented low levels of serum
serotonin. In line with these studies, it could be hypothesized that an abnormal devi-
ation of the metabolism of the serotonin produced by mast cells may interfere with
normal function of the hippocampus and may be involved in the memory loss
observed in patients with mastocytosis. In addition, it is not excluded that inflamma-
tory mast cell cytokines, like TNF-a, could also trigger depression in mastocyto-
Several studies have shown that inflammation related to mediator
release by mast cells is linked to depression.
Moreover, inflammation could
lead to activation of indoleamine 2,3-dioxygenase (IDO), which breaks down trypto-
phan into kynurenine, explaining fatigue
and cognitive impairment
accumulation of kynurenic acid and quinolinic acid and possibly the reduced levels
of serotonin in mastocytosis patients.
Mast Cells and Headache
In migraine, mast cells might be involved through their interactions with peptidergic
and cholinergic neurons.
At this level, presynaptic endings may capture mediator
release by mast cell granules.
In agreement with this hypothesis, some studies
have suggested a direct role of mast cell degranulation in headache
and found that
symptoms reflective of mast cell activity were significantly greater in individuals
reporting headaches.
Vascular instability in periphery may result in poor perfusion
of the brain but could also be related to prostaglandin and histamine release at the
brain level.
Mast Cells and Multiple Sclerosis
The role of mast cells in the pathophysiology of multiple sclerosis is extensively sug-
gested in the literature. Mast cells are detected in human multiple sclerosis lesions and
increase mast cell activity, as assessed by a high level of tryptase, is detectable in the
cerebrospinal fluid of patients with active multiple sclerosis.
Furthermore, several
studies have found an association between mast cell burden and susceptibility to
experimental autoimmune encephalitis.
Neuropsychiatric symptoms are thus frequently associated with mastocytosis and
may present as various clinical features. Clinicians may face 2 situations.
Mastocytosis Was Not Previously Diagnosed
In patients with cognitive and/or mood complaints in which mastocytosis was not pre-
viously diagnosed, associated clinical symptoms and signs in favor of this diagnosis
should be looked for. In the presence of skin lesions, the diagnosis of mastocytosis
is easy and a usual clinical investigation should be made that may include skin
biopsies, bone marrow aspiration and biopsy, and measurement of tryptase levels.
Tryptase levels and eventually bone marrow aspiration and biopsies should be per-
formed in cases of the presence of unusual psychiatric features or symptoms compat-
ible with mast cell activation, including mainly gastrointestinal symptoms, flushes,
pruritus, bone and musculoskeletal pains, and osteoporosis. In these cases,
Neuropsychological Features of Adult Mastocytosis 413
a diagnosis of mastocytosis could be made following the standard World Health Or-
ganization criteria but in some cases no evidence of mast infiltration may be found
and the diagnosis of mast cell activation syndrome could be proposed. Mast cell acti-
vation syndrome has recently been described and diagnostic criteria have been writ-
ten and include patients presenting with symptoms suggesting mast cell
degranulation without any diagnostic criteria for a specific entity.
The absence of
a clonal mast cell population suggests that in this entity, mast cells are quantitatively
normal but qualitatively abnormal, probably with a lower threshold of activation. Some
studies suggest that this not well-defined entity is genetically determined. Overall, sta-
bilizing mast cells or inhibiting effects of mast cell degranulation with therapeutics,
such as antihistamine or cromolyn sodium, is effective for some symptoms, such as
pruritus or GI tract disturbances, but, except for a few case reports,
their impact
on psychiatric symptoms is not known.
Mastocytosis Was Previously Diagnosed
When a diagnosis of mastocytosis is already known, because of their high frequency,
neuropsychiatric symptoms should be systematically investigated. Unfortunately,
both by patients and physicians, they are still not linked to mastocytosis in a significant
number of cases. When confronted with neurologic and psychiatric symptoms, spe-
cialists in neurology and psychiatry should perform a specific and extensive work-
up. Then, in some cases, more specific examinations should be performed, including
cerebral scan or MRI. In cases of neurologic deficits and/or headaches, cardiac
testing with ECG and Holter ECG rule out cardiac rhythm dysfunction; neurologic
assessment with EEG to eliminate seizure in case of syncope should be performed.
Acute back pain should prompt neuroimaging of the spine to look for vertebral fracture
with the risk of spinal cord compression. If a diagnosis of multiple sclerosis is sus-
pected, cerebrospinal MRI and lumbar puncture should be performed.
Treatment of indolent mastocytosis aims to relieve symptoms and requires a thera-
peutic adjustment tailored to each patient profile. Therefore, the treatment is essen-
tially symptomatic.
Until recently, the treatment was intended mainly to prevent
and limit degranulation and/or its consequences. Only in aggressive forms does the
treatment aim to control the proliferation of tumor mast cells. New therapeutic ap-
proaches are being developed, including tyrosine kinase inhibitors, aimed at blocking
the tyrosine kinase activity of KIT or other kinases involved in mast cell activation, like
Lyn. Aspirin has been thought efficacious in the prophylaxis against syncope in
Psychotherapeutic Interventions
Although depression symptoms in mastocytosis seem related to systemic aspects of
the disease, the implication of mast cells in stress response, behavior, and emotion
regulation has been suggested by several studies.
Health psychology focuses on
the impact of physical illness on emotions and cognitions. The concept of emotional
adjustment is often used to understand how an individual negotiates emotionally
with the impact of physical illness and its symptoms. In this process of psychological
adaptation to the disease, patients may develop specific cognitions that reflect the
way they build their understanding of what is happening to them. The concept of
“sense of coherence,” developed by Antonovsky in the 1970s, describes an under-
standing of events by individuals (sense of comprehensibility), feeling that they can
Moura et al
manage (sense of manageability) and feeling they have a sense (sense of meaningful-
ness). The sense of coherence promotes better emotional adjustment to dis-
Therefore, a cognitive-behavioral approach with pragmatic strategies
and information to improve understanding of the disease and the development of per-
sonal emotional management strategies of certain symptoms may be of greater
benefit to these patients than psychodynamic approachs. Besides this general
approach to psychological consequences of the disease, methods focusing on
emotion and stress management, such as mindfulness meditation,
could also pro-
mote better cognitive and psychological adjustment. They might even contribute to
interrupting the stress–mast cell activation interplay by reducing both psychological
stress as a mast cell activation promoter and biologic stress as a mast cell activation
Psychotropic Drugs
According to general guidelines,
patients with a formal diagnosis of moderate to se-
vere depression should benefit from an antidepressant prescription with well-tolerated
antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). Moreover, it
has been shown that SSRIs can reduce endotoxin-induced fatigue
and even pre-
vent depression induced by high-dose interferon-alpha, another condition related to
Considering noradrenaline and dopamine involvement in motivation
and lack of energy,
other classes of antidepressants, such as monoamine oxi-
dase inhibitors, the noradrenaline and dopamine reuptake inhibitor bupropion, and
serotonin-norepinephrine reuptake inhibitors or tricyclics, could also be prescribed.
In another condition with debilitating fatigue, multiple sclerosis (MS), amantadine
has shown efficacy in approximately one-third of patients.
The wake-promoting
agent modafinil could also be prescribed if required. Alternatively, antidepressants
with hypnotic properties, such as mianserin or mirtazapine, alone or in association,
could target insomnia and decrease central histamine effects. Finally, in line with anti-
histamine drugs use, further studies could assess the benefits of blockade of media-
tors released by mast cells. Neurokinine-1 antagonists, such as aprepitant, showed
promise in animal studies and early clinical trials as novel antidepressants.
if larger clinical trials did not confirm this property, aprepitant might target cognitive
impairment and/or depression in mastocytosis or in patients with mast cell activation.
Similarly, the tumor necrosis factor antagonist infliximab has been recently shown to
improve depressive symptoms in patients with high baseline inflammatory bio-
and could target fatigue
in other conditions. Finally, ketamine or other
N-methyl-D-aspartate (NMDA) receptors antagonists, such as memantine, might be
useful to treat depression
and fatigue through blockade of NMDA stimulation by
quinolinic acid after IDO activity increase.
Tyrosine Kinase Inhibitor Therapy
KIT (CD117) is the receptor for the stem cell factor that is the main cytokine involved in
mastocytopoiesis. Adult patients with systemic mastocytosis usually have mutations
in c-Kit (D816V), which allows abnormal survival, proliferation, and activation of these
The only kinase inhibitor that has been investigated for the effect of mast cell
inhibition on neuropsychiatric symptoms is masitinib. Masitinib is an oral inhibitor
selectively blocking c-Kit wild-type, platelet-derived growth factor receptor, and Lyn
kinase activities. When tested in vivo in symptomatic patients with systemic mastocy-
tosis, masitinib was able to decrease clinical symptoms linked to the release of mast
cell mediators.
Among these symptoms, psychiatric symptoms, including depres-
sion, cognitive impairment, and anxiety, were significantly improved. The authors
Neuropsychological Features of Adult Mastocytosis 415
showed, in a sample of 35 patients, that masitinib treatment was associated (50%–
67% of cases) with a significant improvement in depression (independently), with
25% to 75% remission, depending on the criteria chosen for depression. Treatment
with masitinib was associated with a significant reduction of the scores of the dimen-
sion involving the mental depression symptoms, such as depressive mood anxiety
and guilt. This result suggests that the improvement of depression may be influenced
by the inhibitory effect of masitinib on the activation of mast cells and is consistent with
the probable systemic nature of depression in this disease. Although these results do
not definitively demonstrate the role of mast cells in the depression in mastocytosis, it
highlights their probable contribution.
Neuropsychological symptoms in matocytosis are not rare. Neurologic features are
dominated by headache but various neurologic symptoms car occur. Urticaria pig-
mentosa and unexplained recurrent episodes of flushing, palpitations, abdominal
pain, and loss of consciousness with spontaneous recovery may alert a neurologist
to a possible systemic mastocytosis diagnosis. Depression and cognitive impairment
(attention and memory) are 2 common symptoms in mastocytosis that are not linked
causally. Patients with mastocytosis have increased sensitivity to stress that has been
associated with peripheral leukocyte shorter telomeres
and may participate in dis-
eases associated with mastocytosis. Further work is warranted to assess whether
or not cardiovascular diseases, cancer, and aging are more frequent in mastocytosis
than in other systemic diseases. Alternatively, mast cells could be the link between
reactive stress and anxiety and shortening telomere.
This hypersensitivity to stress
could suggest a hyperactivation of the response to stress through the mast cells in this
pathology. This hyperactivation could be linked to the high prevalence of depression
among these patients. Finally, if the entanglement of biologic and psychological fac-
tors in this disease seems important, the role of emotional regulation mechanisms,
including difficulties in identifying emotions in the holding of depressive symptom-
atology, is not excluded, and this aspect of the emotional functioning of these patients
can be an attractive therapeutic target for those with more severe depressive symp-
tomatology. In addition, drugs that specifically inhibit release of mast cells and/or
that reduce their number may be attractive to improve these symptoms and in exten-
sion could be useful in some psychiatric and neurologic disorders, as recently sug-
gested with kinase inhibitors in multiple sclerosis
and Alzheimer disease.
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... Patients may display constitutional symptoms, hepatosplenomegaly, lymphadenopathies, severe anemia and/or thrombocytopenia, leukocytosis, and very high serum tryptase levels. Due to the massive release of mediators by MCs, clinical manifestations may be present in different organs and systems, including the (GI) tract with abdominal pain, diarrhea, nausea vomiting, peptic ulcer, and GI bleeding [32][33][34]. Depression, musculoskeletal pain, and osteopenia with or without osteoporosis may also occur [34,35]. In a series of 342 SM patients, the OS of ASM was 41 months [5]. ...
... Due to the massive release of mediators by MCs, clinical manifestations may be present in different organs and systems, including the (GI) tract with abdominal pain, diarrhea, nausea vomiting, peptic ulcer, and GI bleeding [32][33][34]. Depression, musculoskeletal pain, and osteopenia with or without osteoporosis may also occur [34,35]. In a series of 342 SM patients, the OS of ASM was 41 months [5]. ...
Full-text available
Mastocytosis is a rare hematological neoplasm characterized by the proliferation of abnormal clonal mast cells (MCs) in different cutaneous and extracutaneous organs. Its diagnosis is based on well-defined major and minor criteria, including the pathognomonic dense infiltrate of MCs detected in bone marrow (BM), elevated serum tryptase level, abnormal MCs CD25 expression, and the identification of KIT D816V mutation. The World Health Organization (WHO) classification subdivides mastocytosis into a cutaneous form (CM) and five systemic variants (SM), namely indolent/smoldering (ISM/SSM) and advanced SM (AdvSM) including aggressive SM (ASM), SM associated to hematological neoplasms (SM-AHN), and mast cell leukemia (MCL). More than 80% of patients with SM carry a somatic point mutation of KIT at codon 816, which may be targeted by kinase inhibitors. The presence of additional somatic mutations detected by next generation sequencing analysis may impact prognosis and drive treatment strategy, which ranges from symptomatic drugs in indolent forms to kinase-inhibitors active on KIT. Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice.
... 78 Furthermore, SM patients may suffer from neuropsychiatric symptoms including anxiety and depression; therefore, selective serotonin reuptake inhibitors (SSRIs) can be an option to improve such symptoms. 79 In nonresponder patients, the subsequent measures should be introduced. Systemic glucocorticoids can be additionally considered, particularly if there is a proof that the symptoms are attributable to MC activation. ...
Mastocytosis is characterized by expansion and activation of clonally aberrant mast cells (MCs) in one or more organ systems. Inappropriate MC activation is a key finding in both allergy and mastocytosis; therefore, symptoms in both conditions show some degree of overlap. When mediator release is excessive and involves multiple systems, anaphylaxis may occur. In mastocytosis, the prevalence of atopy is similar to those of the general population, whereas the incidence of anaphylaxis is significantly higher. The purpose of this review is to discuss features of allergy and anaphylaxis as well as the principles of managing MC mediator release symptoms in mastocytosis.
... The neurological symptoms associated with infiltration of the brain structures include headache, described by patients as "dull" (primarily in the frontal region), vascular pains resembling migraine, and histaminergic pain, associated with lacrimation, pruritus and nasal discharge, as well as allergic disorders (presenting mainly as rash) [2,10]. Previous scientific publications report the following psychological symptoms observed in patients: permanent fatigue (76% of cases), confusion and cognitive disorders (67%), sleep disorders (60%), depression (49%) [7], reduced motivation, irritability, nervousness, negative emotions, and reduced resistance to stress [11]. Mood disorders are also characteristic of the disease: a significant reduction (95%), decreased sexual performance, temporary fits of anger, anxiety, reduced quality of life and satisfaction with life, and apathy. ...
Full-text available
Introduction: Appropriate and targeted psychological care, as well as psychoeducation covering the disease causes, symptoms, and their management are crucial elements of the therapeutic process in patients with mastocytosis. This care is based on the identification of problematic areas that are of the greatest importance for patients. The quality of life questionnaires available in Poland are designed for the general population; therefore, they do not encompass the specificity of difficulties experienced by people suffering from mastocytosis. Aim: To develop a questionnaire measuring the quality of life in patients with mastocytosis, and including the issues and symptoms typical for this group. Material and methods: The study involved 85 patients (57 women and 28 men) suffering from mastocytosis. Results: The analyses revealed that the Quality of Life in Mastocytosis Scale (QLMS) is a reliable and valid tool for measuring the quality of life, and it takes into account the specific difficulties experienced by patients with mastocytosis. Apart from the measurement of the global quality of life, QLMS offers a deeper assessment of the quality of patient's lives, including the difficulties in professional life, everyday life, leisure time, or those associated with protective behaviours. Conclusions: The presented questionnaire completes a gap in quality-of-life studies by allowing to plan psychoeducation and offering a tool for a precise diagnosis of the quality of life in patients with mastocytosis.
... such as headache or fatigue. 3,4 These might be accompanied by cognitive impairment and brain fog declared by 86% of US patients, though its relation with mastocytosis and its progression hasn't been established to date. 5 Some of these symptoms might result from abnormal MCs in central nervous system. 6 In murine model, Esposito et al. showed that stress through corticotropin stimulates brain MCs to disrupt permeability of brain-blood barrier. ...
... W wielu przypadkach chorzy wymagają leczenia objawowego, na przykład leków przeciwdepresyjnych. Pozostaje niejasne, czy te objawy są wywoływane przez mediatory pochodzące z komórek tucznych [55,56]. ...
Systemic mastocytosis (SM) is a rare hematological malignancy characterized by an abnormal expansion and accumulation of pathological mast cells in bone marrow and other organs including skin, liver, spleen and lymph nodes. The clinical manifestation can be extremely heterogeneous, from limited skin changes to multi-organ involvement or mast cell tumors. The median survival of patients diagnosed with indolent form is comparable to healthy population, while prognosis for patients with advanced disease is poor, with an estimated survival ranging from several months to several years. In most patients (> 90%), a somatic mutation in codon 816 of the c-KIT gene encoding tyrosine kinase receptor is detected. Additional molecular abnormalities and even coexistence of other hematological cancers, e.g. acute leukemia, are also observed. Regardless of the form of disease or serum tryptase concentration, patients are exposed to symptoms resulting from the release of mast cell mediators - most often itching, paroxysmal redness and blisters, and general mediator-induced symptoms - such as nausea, vomiting, diarrhea, abdominal pain, hypotensive episodes, fatigue, headache, fever, shortness of breath, osteopenia, osteoporosis and severe anaphy-lactic reactions. This paper presents current outlook on the diagnostic and treatment process of SM, taking into account the interdisciplinary aspects of the disease.
Full-text available
Mast cells are important components of the immune system, and they perform pro-inflammatory as well as anti-inflammatory roles in the complex process of immune regulation in health and disease. Because of their strategic perivascular localization, sensitivity and adaptability to the microenvironment, and ability to release a variety of preformed and newly synthesized effector molecules, mast cells perform unique functions in almost all organs. Additionally, Mast cells express a wide range of surface and cytoplasmic receptors which enable them to respond to a variety of cytokines, chemicals, and pathogens. The mast cell’s role as a cellular interface between external and internal environments as well as between vasculature and tissues is critical for protection and repair. Mast cell interactions with different immune and nonimmune cells through secreted inflammatory mediators may also turn in favor of disease promoting agents. First and forefront, mast cells are well recognized for their multifaceted functions in allergic diseases. Reciprocal communication between mast cells and endothelial cells in the presence of bacterial toxins in chronic/sub-clinical infections induce persistent vascular inflammation. We have shown that mast cell proteases and histamine induce endothelial inflammatory responses that are synergistically amplified by bacterial toxins. Mast cells have been shown to exacerbate vascular changes in normal states as well as in chronic or subclinical infections, particularly among cigarette smokers. Furthermore, a potential role of mast cells in SARS-CoV-2-induced dysfunction of the capillary-alveolar interface adds to the growing understanding of mast cells in viral infections. The interaction between mast cells and microglial cells in the brain further highlights their significance in neuroinflammation. This review highlights the significant role of mast cells as the interface that acts as sensor and early responder through interactions with cells in systemic organs and the nervous system.
Full-text available
Mast cells (MCs) are the major effector cells of allergic responses and reside throughout the body, including in the brain and meninges. Previously, we showed in a mouse model of subclinical cow’s milk allergy that brain MC numbers were elevated in sensitized mice. However, the neurophysiological consequences of intracranial MC accumulation and activation are unclear. We hypothesized that centrally recruited MCs in sensitized mice could be activated by the allergen via the IgE/FcεRI mechanism and increase the blood–brain barrier (BBB) permeability to promote neuroinflammation. Furthermore, we suspected that repeated allergen exposure could sustain MC activation. To investigate our hypothesis, we sensitized C57BL6/J mice to a bovine whey allergen, β-lactoglobulin (BLG), and subsequently placed them on a whey-containing diet for two weeks. MC activity and associated changes in the brain were examined. BLG-sensitized mice showed mobility changes and depression-like behavior with significantly increased MC numbers and histamine levels in select brain regions. IgG extravasation and perivascular astrogliosis were also evident. Importantly, myelin staining revealed cortical demyelination in the BLG-sensitized mice, suggesting a potential neural substrate for their behavioral changes. Our findings support the ability of brain MCs to release histamine and other mediators to increase BBB permeability and facilitate neuroinflammatory responses in the brain.
Mastocytosis is an orphan disease associated with many systemic symptoms, chronic handicap, and potentially marked social consequences despite improved therapies. In this study, the authors aimed to measure the effect of 2 hypnosis sessions on mastocytosis symptoms in a clinical setting. Questionnaires (pain, flushes, energy, digestive symptoms, quality of life, perceived symptom severity, and global impression of change) were completed pre- and posthypnosis intervention. Data from 20 patients were analyzed (mean age: 53.3 years, 75% female). Compared to baseline assessment, patients exhibited a significant improvement immediately after the first and second hypnosis sessions with regard to the number of days with abdominal pain, abdominal pain intensity and fatigue (p = .03 and p = .005; p = .05 and p = .02; p = .034, and p = .039, respectively). Perceived severity of symptoms was significantly improved throughout the study (p = .0075). Long-term improvement in global impression of change was observed in half the responders (8/16). Patients with mastocytosis had an improvement in disabling symptoms with the impact of hypnotic intervention persisting at 1 month. Several patients experienced long-term improvement.
Background Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy (BMB) is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a BMB is not performed the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients. Objective To develop a risk score to predict SM in adults with MIS. Methods We examined 1145 patients with MIS from the European Competence Network on Mastocytosis (ECNM) registry who underwent a BMB. 944 patients had SM and 201 patients had cutaneous mastocytosis (CM); 63.7% were female, 36.3% were male. Median age was 44±13.3 years. The median serum tryptase level amounted to 29.3±81.9 ng/ml. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver operating curves. Results In the multivariate model, the tryptase level (p<0.001), constitutional/cardiovascular symptoms (p=0.014) and bone symptoms/osteoporosis (p<0.001) were independent predictors of SM (p<0.001, sensitivity 90.7%, specificity 69.1%). A 6-point risk score was established (risk, 10.7-98.0%) and validated. Conclusions Using a large dataset of the ECNM registry we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure CM.
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Mastocytosis is a heterogeneous group of diseases characterized by excessive accumulation of mast cells in various organs or tissues (skin, bone marrow, digestive tract, bones) and which, through degranulation reactions, release histamine, being cells with an essential role in inflammation and allergic reactions anaphylaxis type. They secrete various chemical mediators, which being released by the mast cell can induce symptoms, without a direct relationship between total mast cell mass and the appearance of symptoms. The pathogenic mechanisms of mastocytosis are represented by the existence of somatic mutations, activators at the level of the c-kit molecule and by the presence of specific immunophenotypic aberrations at the level of mast cells. Serum tryptase, bone marrow biopsy and KIT D186V detection in peripheral leukocytes are the main approaches to patients with systemic mastocytosis. Therapeutic principles include symptom control, administration of antimediator therapy and tyrosine kinase inhibitors.
Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally.Design A prospective, longitudinal inception cohort.Setting General community clinic.Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively.Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
Recent research has seen low-dose ketamine emerge as a novel, rapid-acting antidepressant. Ketamine, an N-methy-d-aspartate (NMDA) receptor antagonist, leads to effects on the glutamatergic system and abnormalities in this neurotransmittor system are present in depression. This article aims to (1) review the clinical literature on low-dose ketamine as a rapid-acting antidepressant in affective disorders, (2) provide a critical overview of the limitations of ketamine and research attempts to overcome these (3) discuss the proposed mechanisms of action of ketamine and (4) point towards future research directions. The electronic database Pubmed, Web of Science and sciencedirect were searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, electroconvulsive therapy, mechanism of action. The literature demonstrates evidence supporting a rapid-acting antidepressant effect of low-dose intravenous ketamine in major depressive disorder, in bipolar depression and in depression with suicidal ideation. There are mixed results as to whether ketamine leads to a reduction in time to remission in patients undergoing electroconvulsive therapy (ECT). Efforts to unravel ketamine's therapeutic mechanism of action have implicated the mammalian target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen synthase kinase (GSK-3). Ketamine's limiting factors are the transient nature of its antidepressant effect and concerns regarding abuse, and research efforts to overcome these are reviewed. Current and future research studies are using ketamine as a promising tool to evaluate the glutamatergic neurotransmittor system to learn more about the pathophysiology of depression and develop more specific rapid-acting antidepressant treatments.
Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia, and other neuropsychiatric disorders. The term “anhedonia” was introduced by the French psychologist Ribot in 1896 to describe the counterpart to analgesia in his patients, for which “it was impossible to find the least pleasure”. Over the last decades, the clinical definition of anhedonia has remained relatively unchanged, but recently, behavioral neurosciences have significantly changed our knowledge of reward-related processes. Now, the construct of anhedonia reflects deficits in hedonic capacity, and is closely linked to the processes of reward valuation, decision-making, anticipation, and motivation. The neural circuits underlying these reward-related mechanisms include essentially the ventral striatum and prefrontal cortical regions. Here, we review the clinical concepts, neural bases and psychopharmacological data related to the deficits of hedonia in depression. Understanding anhedonia will facilitate diagnosis and treatment management.
The exact nature and pathophysiology of fatigue remain largely elusive despite its high prevalence in physically ill patients. Studies on the relationship between the immune system and the central nervous system provide a new perspective on the mechanisms of fatigue. Inflammatory mediators that are released by activated innate immune cells at the periphery and in the central nervous system alter the metabolism and activity of neurotransmitters, generate neurotoxic compounds, decrease neurotrophic factors, and profoundly disturb the neuronal environment. The resulting alterations in fronto-striatal networks together with the activation of insula by inflammatory interoceptive stimuli underlie the many dimensions of fatigue including reduced incentive motivation, decreased behavioral flexibility, uncertainty about usefulness of actions, and awareness of fatigue.
Curcumin has various biological activities including antioxidant and antiinflammatory actions, and alcohol detoxification. However, because of its poor absorption efficiency, it is difficult for orally administered curcumin to reach blood levels sufficient to realize its bioactivities. We have generated capsules and tablets containing Theracurmin, a highly absorptive curcumin. In addition, we recently created a drinkable preparation of Theracurmin. To evaluate the absorption efficiency of this type of curcumin, we performed a single-dose, double-blind, 4-way crossover study. We compared plasma curcumin levels after the administration of Theracurmin beverage and 3 other drinkable types of curcumin sold in Japan. Twenty-four healthy subjects (male/female=13/11, age: 23-32) were administered with these 4 drinkable preparations of curcumin. The area under the blood concentration-time curve at 0-8 h was found to be 1.5 to 4.0-fold higher with Theracurmin than with the other 3 kinds of curcumin beverage. Moreover, maximal plasma curcumin concentrations (0-8 h) of Theracurmin were 1.8 to 3.8 times higher than those of the other 3 curcumin beverages. These data indicate that our newly prepared Theracurmin beverage exhibits a much better absorption efficiency than other kinds of curcumin beverage sold in Japan.