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Neuropsychological Features of
Adult Mastocytosis
Daniela S. Moura, PhD
a,b,c,d,e
,
Sophie Georgin-Lavialle, MD, PhD
a,b,c,d,e,f
,
Raphaël Gaillard, MD, PhD
g,h
, Olivier Hermine, MD, PhD
a,b,c,d,e,
*
FUTURE CONSIDERATIONS
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.
a
INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological
Disorders and Therapeutical Implications, Paris, France;
b
Paris Descartes – Sorbonne Paris Cite
´
University, Imagine Institute, Paris, France;
c
CNRS ERL 8254, Paris, France;
d
Laboratory of
Excellence GR-Ex, Paris, France;
e
Service d’He
´matologie clinique, Assistance Publique-Ho
ˆpitaux
de Paris, Ho
ˆpital Necker, Paris, France;
f
Service de me
´decine Interne, Ho
ˆpital Tenon, Assistance
Publique-Ho
ˆpitaux de Paris, Universite
´Pierre et Marie Curie, 4 rue de la chine, Paris 75020,
France;
g
Laboratoire de “Physiopathologie des maladies Psychiatriques”, Centre de Psychiatrie
et Neurosciences, U894, INSERM, Universite
´Paris Descartes, Sorbonne Paris Cite
´, Paris, France;
h
Service de Psychiatrie, Faculte
´de Me
´decine Paris Descartes, Centre Hospitalier Sainte-Anne,
Universite
´Paris Descartes, Sorbonne Paris Cite
´, Paris, France
* Corresponding author. Service d’He
´matologie Adultes et centre de re
´fe
´rence sur les mastocy-
toses, Ho
ˆpital Necker-Enfants Malades, 161 Rue des Se
`vres, Paris 75743 Cedex 15, France.
E-mail address: ohermine@gmail.com
KEYWORDS
Mastocytosis Mast cell Kit Depression Anxiety Cognitive impairment
Headache
KEY POINTS
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
http://dx.doi.org/10.1016/j.iac.2014.02.001 immunology.theclinics.com
0889-8561/14/$ – see front matter Ó2014 Elsevier Inc. All rights reserved.
INTRODUCTION
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.
EPIDEMIOLOGY
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.
1–3
In addition, several case reports discussed rare asso-
ciations between mastocytosis and various neurologic conditions, including chorea,
encephalopathy, and strokes.
4–8
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.
2,3
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
headache.
3
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.
3
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,
25
2011
Headache 35–56 Smith et al,
3
2011
Including migraine 37.5 Smith et al,
2
2011
Cognitive impairment 38.6 Moura et al,
32
2012
Syncope 5 Smith et al,
2
2011
Back pain 4 Smith et al,
2
2011
Multiple sclerosis 1.3 Smith et al,
2
2011
Moura et al
408
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.
Depression
In mastocytosis, although mood disorders are clinically observed and are one of the
main complaints of patients, specific descriptive literature reports are rare
9–12
and
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,
9
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
disease.
13
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.
9
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
12
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.
12
Complaints
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.
9
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%.
14–17
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%.
18–20
CLINICAL SYMPTOMS
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.
3
In a second
study by the same group based on a smaller number of patients (36 patients) using a
questionnaire, it was shown
2
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
21
reported syncope as early as in 1971, and this
symptom has been more extensively reported by Smith and colleagues
3
in 12 patients
of 223 with mastocytosis.
22
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
3
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).
4–8,23,24
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).
25
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.
26
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.
27–29
By studying in detail the Hamilton
Moura et al
410
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.
30,31
The
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
medications.
Cognitive impairment characteristics and assessment
Among mastocytosis patients, cognitive symptoms were mostly characterized by
attention impairment.
9,32
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).
26
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.
33,34
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.
35
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.
PATHOPHYSIOLOGY
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.
36
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.
37–43
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.
38,44–47
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.
37,42,48–57
In a previous work, the authors
showed that patients with mastocytosis displayed high levels of perceived stress
linked to lower telomere length.
31
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.
31,58–61
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-
tion,
62–64
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
TNF-a),
23,30,31
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.
65–67
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
412
mastocytosis, Roger and colleagues
9
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.
68
In
mastocytosis, Kushnir-Sukhov and colleagues
69,70
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-
sis.
56,71–76
Several studies have shown that inflammation related to mediator
release by mast cells is linked to depression.
34,73,77–84
Moreover, inflammation could
lead to activation of indoleamine 2,3-dioxygenase (IDO), which breaks down trypto-
phan into kynurenine, explaining fatigue
35,85
and cognitive impairment
86
through
accumulation of kynurenic acid and quinolinic acid and possibly the reduced levels
of serotonin in mastocytosis patients.
70
Mast Cells and Headache
In migraine, mast cells might be involved through their interactions with peptidergic
and cholinergic neurons.
87
At this level, presynaptic endings may capture mediator
release by mast cell granules.
44,88–90
In agreement with this hypothesis, some studies
have suggested a direct role of mast cell degranulation in headache
91
and found that
symptoms reflective of mast cell activity were significantly greater in individuals
reporting headaches.
2
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.
3
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.
92–95
Furthermore, several
studies have found an association between mast cell burden and susceptibility to
experimental autoimmune encephalitis.
3,96
DIAGNOSIS
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.
97
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,
9
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
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.
98
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
mastocytosis.
1
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.
68
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
414
manage (sense of manageability) and feeling they have a sense (sense of meaningful-
ness). The sense of coherence promotes better emotional adjustment to dis-
ease.
99–103
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,
104
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
consequence.
Psychotropic Drugs
According to general guidelines,
105
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
106
and even pre-
vent depression induced by high-dose interferon-alpha, another condition related to
inflammation.
107
Considering noradrenaline and dopamine involvement in motivation
and lack of energy,
108,109
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.
110
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.
111
Even
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-
markers
112
and could target fatigue
78
in other conditions. Finally, ketamine or other
N-methyl-D-aspartate (NMDA) receptors antagonists, such as memantine, might be
useful to treat depression
113
and fatigue through blockade of NMDA stimulation by
quinolinic acid after IDO activity increase.
85
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
cells.
98
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.
13
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.
SUMMARY
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
31
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.
114
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
115
and Alzheimer disease.
71
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