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Mixed Organic Brain Syndrome as a
Manifestation of Systemic Mastocytosis
MALCOLM P. ROGERS, MD, KERRY BLOOMINGDALE, MD,
BENJAMIN J. MURAWSKI, PHD, NICHOLAS A. SOTER, MD,
PETER REICH, MD, AND K. FRANK AUSTEN, MD
Systemic mastocytosis is a disease characterized by an excessive accumulation of mast cells,
and associated with skin lesions, flushing, diarrhea, tachycardia, and psychiatric manifestations.
In order to define more clearly the psychiatric manifestations, ten patients with this disorder
underwent unstructured psychiatric interviews and a battery of psychologic testing. Both revealed
a pattern of cognitive and affective changes in the majority of these patients, best categorized
as an atypical or mixed organic brain syndrome. The cognitive changes consisted of
diminished attention and memory, and the affective changes of anger, irritability, and, to a
lesser extent, depression. These manifestations fluctuated with the level of disease activity, and
appeared in some cases to respond to histaniine antagonists and disodium cromoglycate, medications
used to control the excessive mast cell activity. It is important for psychiatrists to be
aware that mental status changes can represent psychiatric manifestations of mastocytosis, a
readily treatable medical disorder.
INTRODUCTION
Mastocytosis is a condition characterized
by the accumulation of mast cells in
various organs of the body. It may present
in either a limited cutaneous form or a
systemic form. Systemic mastocytosis is
associated with proliferations of mast cells
in bones, liver, spleen, lymph nodes, gastrointestinal
tract, skin, and even rare appearances
in the blood. Based on a group
of 113 patients (1) and a recent review (2),
the most commonly described symptoms
were pruritic skin lesions, episodic flush-
ing and diarrhea, and bouts of tachycardia
with or without hypotension. The gastrointestinal
symptoms may be precipitated
by alcohol, the general symptoms by
mast cell-releasing agents such as codeine
or radiographic dyes, and the cardiovascular
symptoms in about 10-15% of patients
by an idiosyncratic intolerance to
nonsteroidal, antiinflammatory drugs
(NSAIDs). In Demis's review (1), 12% had
vaguely defined neuropsychiatric abnormalities.
The most extensive incidence of
neuropsychiatric symptoms was described
in 1979 by Soter, Austen, and Wasserman
(3). Five of eight patients in their
study reported poor attention span, irritability,
fatigue, difficulty in concentration,
headache, inability to work effectively,
problems in dealing with other
people, and poor motivation. Their study
documented the efficacy of disodium
cromoglycate, including the suppression
of the self-reported neuropsychiatric manifestations.
Aside from these reports and
an occasional reference to a mastocytosis
patient with a psychiatric disorder [for example,
one patient is described as a "schizoidal
personality with symptoms of hysteria"
(4)] the literature contains little
information about the psychiatric manifestations
of systemic mastocytosis. The
present report describes the results of a
pilot study of the psychiatric manifestation
of this medical disorder.
METHODS
All patients being treated for systemic mastocytosis
at the Brigham and Women's Hospital who were
available for full or partial participation in the psychiatric
evaluation were included in this pilot study.
Ten patients with systemic mastocytosis documented
by clinical features and either skin biopsy
and/or elevated 24-hr urine histamine excretion and
cared for at our hospital over a period of 2 years
constituted the subjects for our study. In only one
case (Pt #9) was the skin biopsy nondiagnostic, but
the clinical history and elevated urinary histamine
levels left little doubt as to the diagnosis (see Table
2). All gave informed consent after the psychiatric
evaluation process had been explained fully. Four of
these subjects were also described in the earlier report
by Soter, Austen, and Wasserman (3) and subsequently
continued to receive disodium cromoglycate
orally at 400 mg/day. Their progress was followed
at monthly outpatient visits. The other six patients
were treated with a variety of medications, including
antihistamines, aspirin, and sodium cromoglycate,
sometimes in combination.
Nine subjects underwent a 1-2-hr, unstructured
psychiatric interview, and eight received psychologic
testing on one or more occasions These tests
administered by a psychologist included the Wechsler
Memory Scale, the Digit Span, and the Continuous
Performance Test (CPT), a measure of vigilancesustained
attention (5). In addition, at their monthly
ambulatory visits, patients were questioned about their
symptoms including neuropsychiatnc manifestations
and five patients were asked to maintain diaries
with daily observations about skin, gastrointestinal,
and psychiatric symptoms, including irritability,
memory loss, and concentration difficulty.
In addition, seven patients were given two selfadministered
rating scales, the Profile of Mood Scales
(POMS), which contains six separate subscales—
depression, tension, confusion, anger, fatigue, and
vigor (6)—and a separate, self-report irritability scale
derived from the work of Buss (7). Nine additional
test items were included that also served to divert
attention away from the irritability items. These scales
were repeated at each clinic visit for approximately
18 months.
RESULTS
Psychiatric Interviews
Nine patients with systemic mastocytosis
were available for psychiatric interviews.
The following two case histories
are illustrative.
Patient No. 1. At the time of the interview,
he was a 54-year-old married engineer
and father of two teenage girls. The
urticaria pigmentosa began when he was
only 21, and his episodes of abdominal
pain began when he was 36. Both he and
his wife had noticed the correlation between
his attacks of abdominal pain, which
occurred approximately twice per year, and
his irritability and temper tantrums. For
1—2 weeks before these abdominal attacks,
the patient would become increasingly irritable.
According to this wife, "The slightest
thing in the house would set him off."
Frequently he would not remember much
about his behavior during an attack, which
usually ended with an episode of abdominal
pain. Describing it in more detail, his
wife stated, "It's as if there is some kind
of chemical build-up going on inside him.
He gets so impatient; he starts roaring
around the room and roaring around the
house. He can't sit still. His face gets
flushed, and there are times when he starts
banging walls." Sometimes there were no
apparent triggers for his temper outbursts;
but at other times, certain events such as
the behavior of his two teenage daughters
acted as precipitant. Occasional alcohol was
also noted to be a trigger. Both the patient
and his wife mentioned that since the disodium
cromoglycate therapy was started
3s years before, he had not had a major
attack. He had had no episodes of intestinal
spasms during this time but had had
periods of irritability at about the same
frequency but of significantly lesser intensity.
For over 20 years, the patient had had
frequent but sporadic contact with psychiatrists,
mostly on an outpatient basis to
help him deal with the episodes of rage.
Other symptoms reported included forgetfulness,
"confusion," glazed eyes, mental
fogginess or wooziness, and clumsiness.
At the time of the interview, the entire
family was involved in psychotherapy to
help reduce the level of tension in the
household. Subsequent to the interview,
the patient underwent two psychiatric admissions.
On both occasions he continued
to complain of spells or irritability and
fuzzy thinking, by which he meant slow
thinking, halting speech, and difficulty
finding the right word. Neither routine EEG
nor sleep deprivation EEG nor one done
with evoked potentials revealed any abnormalities.
A head CAT scan was also
normal. Neuropsychologic testing done
during one of these hospitalizations at another
hospital showed "superior performance
level I.Q." and some "nonspecific
and mild abnormalities localized to the
right frontal lobe."
Patient No. 9. She was a 37-year-old
nurse with symptoms of mastocytosis dating
back to at least age 24 when she noticed
paroxysmal ventricular contractions
(PVCs], tachycardia, diarrhea, and abdominal
cramping. She had also experienced
depression with her menstrual periods
since the age of 21, and depression at other
times by age 25. She entered into psychotherapy
for 2 years beginning at age 26,
which she found helpful in resolving several
conflicts and painful emotions associated
with the early loss of her mother
and later divorce of her foster parents.
However, her physical symptoms were not
alleviated and gradually worsened, escaping
accurate diagnosis for another 10 years.
Sinus problems, "allergies," skin lesions,
and episodic mental states during which
she felt she was "going to explode" developed.
She began to notice increasingly
severe episodes of depression and anxiety
which occurred typically in the spring of
the year: "I would get so I was totally frustrated
and jittery and excited that I couldn't
stand it, you know . . . I just felt like I was
gonna explode."
By age 35, she began to experience more
severe periods of tachycardia, flushing,
hypotension, impaired attention and
memory at work, especially after a hysterectomy
was performed. "I lost all my coping.
The flushing (at this point) is getting
worse. The tachycardias are coming
more . . . I think, 'What is happening to me?'
So in January 82 (then it's getting
worse.) . . . I talked to a gynecologist and
told him about the flushing. He said, "All
I can do is take your ovaries out.". . . I dismissed
that. Went back to the cardiologist
for a check-up. He said, "I don't know
what's wrong with you." So that's when I
decided it has to be psychosomatic. So I
went out and signed up for tennis classes."
She went on to say that she became
physically more ill after attempts at vigorous
exercise. Clearly there was major
emotional distress not only from the
symptoms of mastocytosis but from the
misinterpretation of these symptoms as
being psychogenic. She even began to feel
suicidal, and attributes her ability to pull
through this period to the continuous support
of her husband and two teenage
daughters.
Finally an allergist made the diagnosis
of systemic mastocytosis and started her
on cimetidine, which she described as: "just
miraculous . . . within about 2 days the
emotional cloud was just gone."
During the hospitalization when the interview
with this patient occurred, she was
temporarily off cimetidine. She made the
following observations of her mental
changes:
Pt: "They (psychological symptoms) were the first
things I noticed off the medication . . . but really the
nausea and headache came pretty quick too."
Dr: "What were the first psychological symptoms that
you noticed?"
Pt: "Crying. To just start crying . . . for no reason
. . . and I hadn't done that . . . and I noticed I get
irritated . . . I take things . . . I get kind of paranoid
. . . that's true. I take offense at what people say.
I'm a little more critical. And I'm telling you . . . that's
changed (become worse) since I've been off that medicine
(cimetidine)."
Later in the interview the patient described
a period (2 years earlier) of cognitive
change:
Dr: "Now you (said before) you had this funny feeling
you were going senile . . . and that must have been
really upsetting."
Pt: "Definitely."
Dr: "And when did that begin and what was that
like?"
Pt: I can remember most that happening from about
September 1981 (1^ years before diagnosis). I noticed
it more at work . . . maybe because I'm under a little
more stress and 1 was getting the flushing
more . . . ah . . . I would catch myself making silly
mistakes. You forget to sign this chart or you didn't
do that . . . and the head nurse would say . . . that
wasn't like me . . . and then I'd double check things
and I'd find mistakes and I'd think 'you couldn't have
done this . . that's not like you.
"From January 1982 on, it would get worse . . . the
flushing would last for hours . . . and if that would
happen, I'd get an attack. I couldn't think of anything.
I mean it's like I had a short circuit in my head . . . It
was like I was getting a shot of .adrenalin . . . this
flight feeling . . . and I couldn't think. I was petrified
somebody might ask me something. I don't know. I
couldn't remember procedures. Say, for instance, that
they came in and showed us a new' piece of equipment
to use. I'd listen to it and I'd think, 'I can't
remember what he said' . . . I'd read something . . . I
didn't know what I read and that's w h e n . . . I
thought—well maybe I am getting senile
. . . (With the cimetidine) "it's much better . .;. I have
a little trouble yet reading and remembering . . ."
Later she described her irritability and
periods of rage:
"I'd lose complete control. I'd throw things . . . things
were rushing through me at such a rate that if I didn't
release it, I didn't know what was gonna happen
. . . just like I was going to explode and if I didn't
hit something or throw something or scream . . . I don't
know what would happen'. . . And then it would just
go away on its own . . . those were episodes. The
depression—there was always a certain level of it."
Looking at ten histories as a whole, a
clear constellation of psychologic symptoms
appears (Table 1): Of the ten patients,
seven had diminished attention span; seven
had memory impairment; and nine had irritability.
Depressions severe enough to
elicit antidepressant drug treatment had
occurred in three of the patients (nos. 2,8,9].
Patient no. 2 underwent psychiatric hospitalization
following an attempted suicide
by carbon monoxide poisoning. Patient
no. 1 underwent two psychiatric
hospitalizations for evaluation of altered
mental state and behavior. He was not felt
to have a major depression, but exhibited
depressive symptoms including suicidal
ideation seemingly reactive to the more
pronounced cognitive changes and irritability.
The chronologic relationship of the
psychiatric symptoms to the medical manifestations
is shown in Table 2.
Cognitive Psychologic Testing
A total of eight patients underwent cognitive
psychological testing (Table 3). Patient
no. 1 was tested on two occasions in
our institution and on at least two other
occasions elsewhere. The tests consisted
of a memory test, the Wechsler Memory
Quotient, which should equal the predicted
Wechsler I.Q. based on vocabulary,
and two tests of sustained attention, the
continuous performance test (CPT) (normal
range 72% ± 6%, mean ± 2 SD] and
the Digit Span (normal range 6 or 7 forward
and 5 or 6 backwards given normal
I.Q.). Comparison was made to age-corrected
normal values except for the CPT
in which no such figures had been developed
for those over 70 years of age. Seven
patients were significantly abnormal (Table
3), either in the area of sustained at
attention
(6/8) (in either digit span or CPT
or both) or in memory function (7/8), or
both (6/8].
Only one patient (no. 8) was receiving
an HT and the receptor blocking agent at
the time of the testing. Her digit span was
normal, and a CPT could not be obtained
due to technical malfunction. None of the
patients was in the midst of a major attack
during the testing but the majority were
experiencing some mild central nervous
system changes. Four were receiving disodium
cromoglygate at the time of the
psychologic testing.
Other Psychologic Evaluations
Seven of the patients (nos. 1-6 and 10)
completed the Profile of Mood States
(POMS) on a monthly basis and also completed
an Irritability Scale. Six of the seven
patients had wide fluctuations in mood,
denned as a T-Score of 60 or higher, which
is one standard deviation above normal.
Anger and Fatigue (five of the six patients)
were the most frequent affects which varied
widely. Tension (four of the six patients)
was the next most frequent affect
which varied over time. Although we have
no comparable data on other patient pop-
ulations, the disease appears to affect emotional
equilibrium in the vast majority.
On the Irritability Scale all the patients
endorsed 7 or more of the 11 items on that
scale at least on one occasion. Six had high
levels on all or most occasions. This is
consistent with the ratings based on the
psychiatric interviews.
Patients nos. 8 and 9 each completed
these scales on one occasion at the time of
their cognitive testing and were in the normal
range on the POMs but showed evidence
of increased irritability.
Patients also maintained daily logs,
which included skin, gastrointestinal, and
CNS symptoms, the last of which were divided
into concentration and memory deficits
and irritability. Each of the three CNS
subscales was given a numerical score from
zero to five by the patients. In the five
patients who kept these diaries over the course
of 6 months to 1 year, there was no correlation
between reported symptoms and
the presence or absence of disodium cromoglycate
treatment.
COMMENT
The investigation of the psychiatric
symptoms of only ten patients with systemic
mastocytosis limits the basis for generalization.
Yet for the group as a whole,
a certain consistency of symptoms in most,
but not all, of the patients begins to emerge.
Eight of the ten patients (all except nos. 6
and 7) had definite subjective changes in
mood and mentation. In most cases these
were confirmed by psychologic testing.
Most of the patients clearly described new
problems in cognitive functioning and
changes in mood, especially associated with
anger and irritability. With regard to the
cognitive changes, terms like "forgetfulness,
amnesia, whooziness, fuzzy thinking,
vagueness, inability to concentrate, altered
states of consciousness, and difficulty
in word finding" abound in these patients.
Histories, then, clearly point to a fluctuating
and metabolically induced organic brain
syndrome with both cognitive and affective
elements. The cognitive changes in
acute "attacks" were often associated with
altered levels of consciousness, inattention,
and rapid fluctuations, therefore presenting
as delirium. However, several patients
complained of more chronic, and
sustained changes in memory and word
finding, giving more the clinical appearance
of dementia. In fact, two patients
thought they were "going senile." The affective
changes include irritability most
prominently, but also depression. In DSMIII
terms, the category of atypical or mixed
organic brain syndrome is most applicable.
In at least three patients—nos. 1, 2,
and 4—the sudden alterations in consciousness,
strange sensations including
olfactory symptoms, and transient loss of
motor control also raised the possibility of
transient partial seizure activity, although
episodic hypotension may have accounted
for some of the episodes of loss of consciousness.
Of the three patients with apparently
major, drug-treated depressions, one (pat.
no. 2) required hospitalization following
a suicide attempt. In three of the four patients
with depressive episodes, the onset
seemed in part triggered by the loss and
helplessness engendered by other manifestations
of systemic mastocytosis. Two
patients (nos. 2 and 9) seemed particularly
distressed about the uncertainty of what
was happening to them, as well as the
perception that various care providers regarded
their symptoms as psychogenic. In
general, it appears that depression was a
reaction to mastocytosis rather than an intrinsic
part of the syndrome, although potentially
of major importance.
We were not able to obtain psychologic
testing at a time when any of these patients
was in the midst of an acute episode; yet
eight out of ten patients studied showed
specific evidence of impaired sustained attention
or impaired memory, or both. Even
when not experiencing acute attacks of the
disease such as flushing, tachycardia, or
diarrhea, many of these patients continued
to experience some irritability or intellectual
slowing.
The mechanisms accounting for these
symptoms are unknown but presumably
result in part from the pharmacologic effect
of the products of mast cells on neuronal
tissue. Histamine is a likely candidate
and is, of course, known to be elevated
in the urine of these patients.
It is conceivable that other known products
of mast cells increased in mastocytosis,
such as prostaglandin D2 (8), also
play a role in these CNS symptoms. Prostaglandins
are known to be synthesized in
the brain and to modulate the effects of
various neurotransmitters (9). Their CNS
role is probably clearest in the hypothalamic
regulation of temperature, and water
and food intake (10). Prostaglandin injection
into the cerebral ventricles of cats has
been reported to produce many different
stimulant and depressive effects (9). Further,
many of the NSAIDs, which exert their
effect by blocking the production of prostaglandins,
are known to have CNS side
effects. For example, indomethacin has
been associated with headache, mental
confusion, and severe depression (11).
Some therapeutic effects of NSAIDs,
such as analgesia and antipyrexia, result,
in part, from a direct effect on the hypothalamus.
A major question is whether there is an
excessive accumulation of mast cells within
the nervous system itself, or whether CNS
symptoms result from a flood of systemically
secreted mast cell products carried
in the bloodstream. One important problem
with the systemic hypothesis is that
histamine does not penetrate the
blood-brain barrier to any significant degree
(13). Parenteral injections of histamine
do not usually produce any evident
effects on the CNS except emesis relating
to its effect on the chemoreceptor trigger
zone (13) and vascular headache (14). Direct
administration of histamine into certain
regions of the brain and/or intraventricularly
are associated with some
observable effects such as arousal, altered
neuronal firing, and desynchronization of
the EEG (15). It is clear that there are specific
histamine receptors (both Ha and H^j
in the rat brain, and that histamine synthesis
can be altered by hypnotic and anesthetic
agents (16) and in circadian
rhythms (17). Preloading with a precursor,
L-histidine, has been shown to produce
slight motor depression (18).
In addition to their presence in various
organs, an accumulation of mast cells may
also exist in the brain, as it does in most
other mammals (19) and also in humans
(20), especially in the infundibulum, pineal
organ, area postrema, and the choroid
plexus.
SUMMARY
Whatever the mechanisms, it seems clear
that many, if not most, patients with systemic
mastocytosis experience at least
transient central nervous system effects
characterized by diminished attention and
memory and associated affective changes
ranging from irritability to frank episodes
of rage (atypical or mixed organic brain
syndrome). It would appear that some of
the cognitive changes persist between attacks.
Depression appears to be a significant
secondary problem. Many of these patients
may initially present as psychiatric
patients so that psychiatrists need to be
aware of this uncommon illness. From a
practical point of view, any patient complaining
of episodic cognitive and affective
changes associated with flushing or
cutaneous lesions, intermittent diarrhea
and abdominal pain possibly aggravated
by alcohol, or hypotension, especially precipitated
by NSAIDs, should raise the diagnostic
possibility of systemic mastocytosis.
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