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Hypothalamic Astrocytoma Syndrome of Hyperphagia, Obesity, and Disturbances of Behavior and Endocrine and Autonomic
Hypothalamic Astrocytoma
Syndrome of Hyperphagia, Obesity, and Disturbances of Behavior
and Endocrine and Autonomic Function
Robert M. Haugh, MD, William R. Markesbery, MD
\s=b\A 26-year-old woman had hyperpha-
gia, obesity, aggressive behavior, visual
hallucinations, reversal of wake-sleep
patterns, hypothermia, hypothyroidism,
and others.4-5 It is also believed that
period
amenorrhea
developed,
and
her
hypo¬
weight
increased from 68 to
135
kg.
Three
tumors and other lesions of the
weeks
prior
to admission
progressive
leth¬
thalamus can cause
changes
in
the
and
weakness and decline in
mental
median eminence and/or tuber cinere-
argy
function occurred.
The patient
had no his¬
and amenorrhea. She died of pancreatitis,
which are
thought
to
lead to
um,
tory
of
occupational
environmental
or
probably secondary to hypothermia.
Autopsy revealed a low-grade astrocyto-
diminution
of
releasing
factors,
exposure
to
toxins,
and she
did not
use
resulting
in decreased
pituitary
and
drugs
alcohol.
or
ma in the third ventricle and medial ante-
endocrine function.
Physical
examination showed a somno¬
rior and mid hypothalamus, primarily on
Our
is to describe a
patient
purpose
lent
woman weighing
135 kg,
with a rectal
the right. Although she exhibited thyroid
with a
hypothalamic
neoplasm
that
temperature
of
34.4
°C,
pulse of 40 beats
and ovarian hypofunction, the patient had
resulted in
behavioral
changes,
minute,
BP of 110/60
rever¬
per
mm Hg,
and
Remarkable
eminence
sal of
day-night rhythms,
hyperpha-
Cheyne-Stokes
respiration.
intact
median
and
pituitary
and
findings
physical
examination included
function,
suggesting end-organ failure,
gia, obesity,
hypogonadism,
hypo-
on
marked
obesity, pendulous
breasts without
possibly of an autoimmune nature.
thyroidism.
However,
this
patient
galactorrhea,
diffuse abdominal tender¬
(Arch Neurol 1983;40:560-563)
also
had
documented maintenance
of
and decreased bowel sounds. Neuro¬
ness,
adequate
median eminence-pituitary
logic
examination revealed the
patient
to
axis
function.
be
difficult to arouse.
Funduscopic
exami¬
"Uypothalamic
tumors are
of special
nation showed bilateral
optic atrophy. No
REPORT OF A CASE
interest since
they
offer
confir¬
other cranial nerve
abnormalities
were
found.
Sensory,
motor, and cerebellar func¬
mation
in
humans
of
the
various
A 26-year-old
woman was admitted to
Medical Cen¬
tions and muscle stretch reflex were nor¬
hypothalamic
functions described ex¬
the
University
of
Kentucky
mal. The
patient
could not
cooperate for
in others
a ter,
Lexington,
because
of
species. Only
increasing
perimentally
som¬
mental status or visual field
testing.
nolence
and
lethargy.
She had
been
in
few
reports
of the clinical
correlates
excellent health until
two years
prior
to
of discrete
hypothalamic
lesions in
Laboratory Data
admission,
when she had been
admitted to
humans have been
published
(re¬
another
hospital
because of an intracere¬
Laboratory findings were as follows: leu¬
view15).
It is well known
that
a variety
bral
hemorrhage.
A computed tomograph¬
kocyte
count,
normal;
hematocrit
reading,
of clinical
syndromes
with
can occur
ic
(CT)
scan
of the
head
was
reported
to
33%;
platelet
count,
78,000/cu mm;
blood
lesions of the
hypothalamus,
such as
show blood in the thalamic area and third
chemistry study using
an automated mul¬
diabetes insipidus;
alterations of tem¬
ventricle. Four-vessel cerebral
angiogra¬
tiple
analysis
system,
normal; calcium lev¬
perature
regulation,
food
intake,
phy
demonstrated no aneurysm or tumor.
el,
2.8 mEq/L;
amylase level,
328 IU/L;
and
and
After she recovered from the
hemorrhage,
level,
2.2
disturbances of
lipase
Sigma-Tietz
units/mL. Liv¬
sleep,
behavior;
the
patient
had
episodes
of
combative,
and renal function
test results were
er
autonomie
nervous
system function;
aggressive
behavior
and visual hallucina¬
unremarkable. Tests of arterial blood
gas¬
tions. She
had reversal of her
day-night
es showed a
pH
of 7.40; Pco2, 26 mm
Hg;
Accepted
for
publication
Dec 16,
1982.
rhythms, sleeping during the
day
and
stay¬
Po2,
79 mm
Hg;
and
02
saturation,
96%.
From
the
Departments
of
Pathology (Drs
ing
awake
through
the
night.
With the
Thyroxine
level
was 3.6
Mg/dL (normal,
5 to
Haugh
and
Markesbery)
and
Neurology (Dr
arrival of
spring,
her behavior and dis¬
12 Mg/dL).
Triiodothyronine
resin
uptake
Markesbery)
and the Sanders-Brown Research
turbed
sleep cycle improved
and remained
was
24%
(normal,
24%
to
34%). Thyroid-
Center
on
Aging (Dr
Markesbery),
University of
stable until winter
weather returned, at
stimulating
hormone
(TSH)
level
on
Kentucky
Medical
Center, Lexington.
which time the hallucinations, combative
admission
was 43.4
µ /mL (normal,
2 to 8
Reprint
requests
to
Department
of
Pathology,
University
of
Kentucky
Medical
Center,
behavior,
and
reversal
of
day-night
µ /mL). Thyroid
antibodies
positive
Lexing-
were
ton,
KY
40536-0230.
rhythms
returned. During this
two-year
at a
titer of
1:1,600. A protirelin (thyrotro-
Downloaded from www.archneurol.com at Washington State University, on November 14, 2011
Fig 1.—Coronal section of brain showing tumor (arrows) in third Fig 2. Moderately cellular astrocytoma
Fig
1.—Coronal
section
of brain showing tumor (arrows) in third
Fig 2.
Moderately cellular astrocytoma composed
of cells with round
ventricle ¡ust above optic chiasm, with thinning of anterior commis¬
to oval nuclei and abundant fibrillary processes
(hematoxylin-eosin,
sure.
original magnification X395).
pin-releasing
hormone)
stimulation
test
necrosis
and
saponification
of
the
sur¬
ular, and anterior
hypothalamic nuclei,
as
revealed the
following:
rounding retroperitoneal
fat. A
fibrinopu-
well as a
great
portion
of the medial
hypo¬
rulent exúdate
covered
most
intraperitone-
thalamic nucleus
(Figs
3 and 4). The tumor
TSH,
Prolactin,
al surfaces. The ovaries were
markedly
breached the lamina
terminalis, and its
µ /mL
ng/mL
atrophie,
and each
weighed
3.5 g
(normal
most
superior
extension bisected the ante¬
Baseline
53
45
premenopausal weight,
8
to
12
g).
Micro¬
rior commissure. In its anterior and mid¬
30
min
85
86
scopic
examination revealed rare
ovarian
dle
portions
the tumor exerted a
compres¬
60
min
105
84
follicles, a few corpora albicantia, and no
sive effect on the
optic
chiasm
(Fig 4).
It
90
min
68
77
evidence
of
corpus luteum formation.
essentially
replaced
the entire
right
ven¬
Luteinizing
hormone
(LH)
level was 120
Parenchymal
fibrosis was
present.
There
tromedial
and
dorsomedial nuclei. There
ImU/mL,
and
follicle-stimuating
hormone
were
no
inflammatory
infiltrates in the
was minimal involvement of the
right
pos¬
(FSH)
level was 9
ImU/mL. Serum cortisol
ovaries. These
histologie findings
are con¬
terior
hypothalamic
nucleus. The
right
for-
level
was 14.3
Mg/dL.
A cortrysyn
stimula¬
sistent with features of
an
autoimmune
nix was
interrupted.
It had extended into
tion test showed normal
results. The CSF
ovarian failure. The
thyroid
was
grossly
the left anterior
hypothalamus,
with oblit¬
contained no
cells,
a protein
level of 159
normal
(weight,
17.5 g),
but
microscopical¬
eration of the
preoptic
and
mg/dL,
and a
glucose
level of
93
mg/dL.
An
ly, lymphocytic
and
plasma
cell infiltration
ic
nuclei,
a small
portion
suprachiasmat-
of the anterior
ECG revealed
nonspecific
T-wave
changes
in
the
gland,
consistent with
seen
hypothalamic nucleus,
was
and
the
inferior
and
prolonged
Q-Tc,
suggestive
of
hypothy-
chronic thyroiditis.
There were no inflam¬
portion
of
the
paraventricular
nucleus
roidism.
A
CT scan
and
ultrasonogram
of
matory
infiltrates
in
other
endocrine
(Figs
3 and 4). Tumor and
gliosis
involved
the abdomen were consistent
with
acute
organs.
only
a small
part
of the inferior left ven¬
pancreatitis.
The brain
weighed
1,340
g.
There was no
tromedial nucleus. Other
nuclei were not involved on
hypothalamic
evidence of herniation or abnormalities of
the left. The
Hospital Course
the cortical surfaces. No
abnormali¬
gross
tumor did not
involve the tuber cinereum,
The patient's temperature
remained in
ties of the
tuber cinereum, infundibulum,
pituitary gland,
or
mammillary
bodies.
the
of
range
33.9 °C
to 34.4
°C
during
the
pituitary
were noted.
Coronal sections
The
median
eminence
slightly
or
was
first
three
days of hospitalization
but on
revealed
a soft, gray-brown,
well-circum¬
involved
by
the
gliosis delimiting
the
edge
the fourth
day
rose
to
38.3
°C. Serum
scribed tumor
arising
in
the
right
anterior
of the tumor.
In
the
anterior
pituitary,
amylase
level continued to
rise,
calcium
hypothalamus
(Fig
1).
The
neoplasm
filled
acidophils
were
prominent
and had
a nor¬
level
declined, and abdominal tenderness
much of the anterior and mid
third
ventri¬
mal
pattern of
granulation.
Some baso-
worsened. Treatment
for pancreatitis
was
cle. The lateral
ventricles
were
not
phils
showed mild
degranulation.
There
started, and antibiotics
were
given
for
enlarged.
No
other
lesions
gross
were
or ische¬
presumed
sepsis. The results of the TSH
found in
hemispheres, brain
no evidence of
mia in the anterior
compression
was
the cerebral
pituitary. The posterior
and
prolactin
response
were
thought
to be
stem,
or cerebellum.
pituitary was unremarkable.
consistent with
hypothalamic
disease
a
Histologie
examination demonstrated a
process.
Intravenous
(IV) thyroxine was
moderately
cellular
neoplasm
with cells
COMMENT
administered, and serum
TSH level
even¬
containing slightly
pleomorphic
oval- to
tually
returned to normal. The initial bra¬
This
had a
spindle-shaped
nuclei
(Fig
2).
Eosinophilic
patient
low-grade
astro¬
dycardia
resolved after institution of
dopa¬
cellular
rise to a
fibrillary
cytoma
involving
the
right
anterior
processes gave
mine
hydrochloride
and
aminophylline
background,
and
Rosenthal
fibers
and mid
and a small
were
hypothalamus
therapy;
however,
the
patient
remained
abundant.
Vascular channels were
promi¬
portion
of the left
anterior hypothala¬
hypotensive.
Flank hematomas
developed,
nent in
the
tumor; however, endothelial
The
of
hemosid-
mus.
presence
many
and
hypocalcemia
persisted
in
spite
of
proliferation
was not
present.
No tumor
erin-laden
macrophages
in
the tumor
high-dose
IV calcium
gluconate
replace¬
necrosis
was seen. Hemosiderin
pigment
and on
its
surface
indicated that the
ment.
Despite vigorous
supportive efforts,
prominent
in
macrophages
and
was
many
patient's
initial
symptoms
the patient
died
were
the
on
15th
hospital
day.
lying
by
hemorrhage
the tumor.
margin
free within the medial and inferior
of the tumor. There was a rim of
caused
into
Autopsy Findings
She
had
reactive gliosis lateral to the tumor. On the
subsequently
hyperphagia,
The
autopsy
showed an edematous
right,
the
astrocytoma
gliotic
obesity, periods
of
unprovoked
aggres¬
pan¬
and its
rim
creas discolored by hemorrhage, with fat
replaced the suprachiasmatic, paraventric-
sive
behavior,
visual
hallucinations,
Downloaded from www.archneurol.com at Washington State University, on November 14, 2011
Massa Intermedia Fig 3.—Sagittal diagrams showing location of tumor (pitted area) in hypothalamus. SCN indicates
Massa Intermedia
Fig 3.—Sagittal
diagrams showing location of tumor (pitted area) in hypothalamus. SCN
indicates
suprachiasmatic nucleus;
PO, preoptic area;
PV, paraventricular nucleus;
DM,
dorsomedial nucleus; VM, ventromedial nucleus; and P, posterior
hypothalamic nucleus.
Left
Fornix
Right
Fornix
Right
Left
Optic Tract
Optic Tract
Optic Chiasm
Fig
4.—Transverse
diagrams showing
tumor location in
hypothalamus
and third ventricle at level
of
optic chiasm (left)
and mid
hypothalamus (right). SO indicates supraoptic nucleus; A, anterior
hypothalamic nucleus; L, lateral hypothalamic nucleus; M, medial hypothalamic area; PV,
paraventricular nucleus; DM, dorsomedial nucleus; VM, ventromedial nucleus; and 3V, third
ventricle.
reversal
of
wake-sleep
pattern,
obesity,
and
attacks in human
nucleus lesions alone do not
produce
rage
marked
hypothermia,
hypothyroid-
beings.
A wealth
of data from
experi¬
obesity.7
Although
the
neoplasm
in
ism,
and amenorrhea.
mentally induced ventromedial
hypo¬
patient
primarily
involved the
our
It has been shown that bilateral
thalamic
lesions in animals showed
right
ventromedial nucleus with mini¬
lesions in the ventromedial
hypotha¬
similar clinical
findings,6
although
it
mal involvement of the left ventrome¬
lamic nuclei result in hyperphagia,
has been shown
that
ventromedial
dial nucleus, it is likely that compres-
Downloaded from www.archneurol.com at Washington State University, on November 14, 2011
sion of the latter caused functional ing endocrine end-organ hypofunc- rhythms, including sleep-wake an
sion of the latter caused functional
ing
endocrine
end-organ
hypofunc-
rhythms,
including
sleep-wake
an
impairment
that led to
hyperphagia,
tion.
More
specifically,
the
patient
cycle,
drinking, activity,
temperature,
obesity, and episodes of
unprovoked
was found to
have
hypofunction
of the
ovulation,
and
adrenocorticosterone
aggression.
thyroid
and
which has been referred
ovary,
possibly secondary
production,
In
other bilat¬
our
patient the only
to
autoimmune
disease,
and
would
to as
the
suprachiasmatic syndrome.17
eral
hypothalamic
involvement
in¬
therefore have autoimmune
polyglan-
Convincing
evidence has
accumulated
cluded
the
suprachiasmatic
and
dular
organ-failure syndrome.
There
for the
suprachiasmatic
nucleus as an
preoptic
nuclei and
a portion
of the
serologie
confirmation
of
thyroid
important
link between the
and
was
eye
paraventricular
nuclei.
Bilateral le¬
autoantibodies,
and
histopathologic
the
body
that controls circadian
sions of
the preoptic nuclei are associ¬
findings
compatible
with
and functions as a
were
a diag¬
rhythms
primary
ated with
faulty
temperature
control.8
nosis
of autoimmune
thyroiditis.
The
circadian
oscillator,
at least
in the
Our
patient's
marked
hypothermia
ovaries were
atrophie
and
fibrotic,
rat.18 Our
patient
had bilateral abla¬
possibly
resulted from bilateral
tumor
with only rare primordial
follicles and
tion
of the
suprachiasmatic
nucleus
involvement of
the preoptic nuclei,
luteum
formation
despite
and
no
changes
in
day-night rhythm,
corpus
hypothyroidism,
combination of
elevated
levels. Al¬
loss of normal
circadian
or
a
gonadotropin
indicating
these
Hypothermia
probably
though
serologie
evidence of ovarian
rhythms.
The normal
two.
four-day ovula-
caused
antibodies
was not
available,
our find¬
acute
pancreatitis,
tory
cycle
of the
rat
depends
on its
her severe,
with the
sequelae
of hypocalcemia
and
ings
circadian
are
certainly
consistent with an
rhythm.
secondary
bacterial
sepsis
that led to
autoimmune
ovarian failure.12
suprachiasmatic
Ablation of the
nucleus will abolish
her death. Massive
pancreatitis
is
a
It is possible
that this
patient had
the
LH
surge
and, therefore, ovula¬
major
cause of death
survivors
two
unrelated disease
tion.19
processes
Thus,
alternative
explana¬
among
rare,
an
of accidental
hypothermia.911
or diverse clinical
findings
all
related
tion
to
an
autoimmune disorder
for
The
development
of
hypothyroidism
to the
hypothalamic
tumor.
What
patient's
amenorrhea would be
our
and
hypogonadism
in our
patient
is
of
makes
the
autoimmune
endocrine
that the bilateral lesions of the
supra¬
considerable
interest. The mechanism
interesting
is
organ
hypofunction
chiasmatic nucleus resulted in loss of
documented in
of
experimen¬
evidence
of the
menstrual
reports
emerging
hypothala¬
rhythm.
Perhaps
our
tal
hypothalamic
lesions in animals
mus' role
in modulating
the immune
patient's findings
represent
a partial
and in
humans is that ablation
response.1314
Experimental
data
for
some
expression
of
the
suprachiasmatic
of the median eminence or tuber cine-
the role of the
hypothalamus,
limbic
syndrome.
reum causes cessation
of production
system,
and
pituitary
in
suppression
The
patient's
clinical
manifesta¬
of
releasing
factors.2 In
turn,
there
and enhancement
of
the
immune
tions
reaffirm
the
hypothalamus'
would be
decreased levels of
in the rat are accumulat¬
one
or
complex
functions.
We
documented
response
hor¬
ing.1416
However, there is no evidence
numerous abnormalities in this
more of
TSH, FSH,
LH,
growth
and
adrenocorticotropic
hor¬
date
that alterations in
some of which
have their
mone,
to
suggesting
patient,
may
and an
increase
in
prolactin
the
hypothalamus
basis in the destruction
can
trigger
an
of nuclei and
mone,
level,
resulting in hypofunction
of the
autoimmune reaction.
their connections in a
relatively
small
endocrine
end
The
The reversal of
day-night rhythms
area of the anterior and mid
hypo¬
organs.
median
eminence and tuber
cinereum were
in our
patient
is also of interest. Abla¬
thalamus.
spared
patient,
and
TSH, FSH,
tion of the
nucleus in
in our
suprachiasmatic
and
LH levels
elevated,
indicat-
the rat leads
to
loss
of
normal circadi-
were
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