Frontal Lobe Syndrome in a Patient
With Bilateral Globus Pallidus Lesions
Richard L. Strub, MD

\s=b\ This article describes a patient who
experienced the rapid onset of an irreversible behavioral change while vacationing
in La Paz, Bolivia (altitude, 4070 m). The
only lesions demonstrated on a magnetic
resonance imaging scan were bilateral
hemorrhages in the globus pallidus. The
behavior change was characterized by apathy and lack of motivation, features commonly associated with bilateral frontal

lobe disease. This case is a further demonstration of how subcortical lesions can
produce behavioral syndromes that are
clinically indistinguishable from classic
cortical syndromes. It is cases such as this
that show how a strict localizationist concept of behavioral function is too restrictive and how it is necessary to consider a
wide network of neuronal interconnections when explaining the mechanism of a
dissolution of complex higher functions.
(Arch Neurol. 1989;46:1024-1027)

than 100 years ago, a man
]\/Torenamed
Phineas Gage developed

an abrupt change in character and
personality after sustaining a destruc¬
tive lesion in the prefrontal portion of

the frontal lobes of his brain. The syn¬
drome of apathy, nonmotivation, in¬
difference, irritability, and lack of so¬
cial restraint has come to be known as
the frontal lobe syndrome. With the
examination of large numbers of pa¬
tients with frontal damage it has be¬
come obvious that there is no unitary
behavioral constellation of symptoms
among these patients. Several clinical
subtypes, possibly with separate ana¬
tomic localizations, have now been
described.1 In addition to this elabora¬
tion and separation of the clinical pre¬
sentations of patients with damage
restricted to the frontal lobes, patients
Accepted for publication October 27, 1988.
From the Ochsner Clinic and Alton Ochsner
Medical Foundation, New Orleans, La.
Reprint requests to Ochsner Clinic and Alton
Ochsner Medical Foundation, 1514 Jefferson
Highway, New Orleans, LA 70121 (Dr Strub).

have been described with the clinical
features of a classic frontal lobe syn¬
drome, yet whose lesion or lesions lay
elsewhere in the brain.
This article describes a man who de¬
veloped a clinical irreversible frontal
lobe syndrome secondary to bilateral
hemorrhages in the globus pallidus.
One unusual feature of this case was
that the behavior change began
abruptly after disembarking from a
commercial airliner in La Paz, Bolivia,
at an altitude of 4070 m.
REPORT OF A CASE

A healthy 60-year-old man from Louisi¬
(altitude, sea level) arrived in La Paz,
Bolivia (altitude, 4070 m), after an unevent¬
ful flight from Santiago, Chile (altitude, 550
m). He disembarked, and as he was enter¬
ana

ing the terminal his wife noticed that he
acting as if he were drunk. He made
inappropriate remarks to traveling com¬
panions, scattered coins to children at the
airport, and began talking in an expansive
was

fashion. He claimed that the altitude made
him feel "high," and announced that "the
trip was a drag and he needed to get out and
walk." He was physically active that first
day and did not have any physical com¬

plaints.

He vomited once that night, but in the
morning did not complain of headache or
respiratory distress. On the second day, he
again felt drunk yet continued to be active.
Throughout the course of that day he began
to look somewhat dazed and show signs of
lethargy. He slept much of that evening and
the following day. On the evening of the
third day, he was taken to a lower altitude.
Over the subsequent few days he became
more alert but was quiet and withdrawn.
He had no memory of the 3 days spent in

Bolivia.
Six days after leaving Bolivia he was ex¬
amined at the Ochsner Clinic in New Or¬
leans, La. His wife stated that since the trip
the patient had undergone a complete per¬
sonality change. Prior to his arrival in Bo¬
livia the patient had been an outgoing, am¬
bitious "dynamo," who owned and operated
several small businesses. He had previously
also been outgoing socially. After the trip
he was socially withdrawn, had no motiva¬
tion for business, showed no interest in his
hobbies, and spent much of the day watch-

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mg television. He had no specific physical or

neurologic complaints other than the be¬
havior change and the period of amnesia for

the time spent in Bolivia.
On brief mental status evaluation he was
quiet, laconic, and offered no spontaneous
conversation. He was oriented, accurate
about his recall of recent news events, and
could name the last four presidents in
proper order, albeit rather slowly. He was,
however, able to store and retrieve only one
of four specific verbal items after 5 minutes.
Neurologically, he showed some mild cog¬
wheel rigidity in the left arm and a ten¬
dency to fall to the left on tandem walking.
He had a slightly increased muscle stretch
reflex in the left ankle, and there was a pos¬
itive Hoffmann's sign on that side.
His medical history was unremarkable;
he was normotensive, nondiabetic, with no
history of cardiac or cerebral ischemia. He
had been a heavy drinker in the past but
had not had any alcohol in 2lk years. His
wife believed that he had developed some
mild recent memory problems in the pre¬
ceding year, but this did not interfere with
his work. He had intermittent hip pain for
which he took carisoprodol; that was his
only medication. He had taken one of these
pills the day of his flight into La Paz.
Eight weeks after the onset of his frontal
lobe syndrome he was only marginally im¬
proved. He tended to talk little and watch
television for hours at a time. The family
did not notice any significant memory prob¬
lem other than his amnesia for the time
spent in Bolivia. He was totally unable to
run his business, not because of an inability
to understand the details of the business,
but because he was completely unmotivated
and procrastinated on every detail. Before,
he had spent many hours on the phone
making business calls; now he sat long
hours in the office and rarely made a single
call. He napped after lunch and slept 8 to 9
hours every night, an unusual pattern for
him. At that time an electroencephalogram
and magnetic resonance imaging scan of
the brain were performed. The electroen¬
cephalogram was normal, but the magnetic
resonance imaging scan demonstrated bi¬
lateral hemorrhages involving the inner
surface of the globus pallidus and the white
matter tracts of the posterior limb of the
internal capsule (Figs 1 and 2).
On that visit a full mental status exam¬
ination was performed.2 The patient was
alert and attentive, but quiet and laconic.

Fig 1. Sagittal magnetic resonance imaging (T,) demonstrating hem¬
orrhage in the right globus pallidus (arrow). Six weeks after hemorrhage.
—

Language functions were normal. He was
fully oriented and had good recall of recent
presidents. Again he could retain only one

of four unrelated words after 5 minutes and
two of four at 10 minutes. Only 11 of 26 bits
of information were recalled from a ver¬
bally presented short story and he could
find (after 5 minutes) only three of five ob¬
jects that he had seen the examiner hide in
the room. Drawing ability was slightly im¬
paired. Proverb interpretation was only

fair; however, similarity testing was good.
Alternating motor sequencing and repeti¬
tive drawings designed to elicit persevera¬
tion and poor set shifting were normal. On
this examination the patient demonstrated

behavioral features of the frontal lobe syn¬
drome plus impairment of new learning
ability (recent memory) and a mildly de¬
creased verbal abstracting ability.
Five months after onset of frontal lobe

syndrome a complete neuropsychologic test
battery was administered. Full-scale (re¬
vised Wechsler Adult Intelligence Scale) IQ
was 103 with a verbal IQ of 105 and a per¬
formance IQ of 101. The only significantly
impaired intellectual functions were visual
sequencing (digit symbol) and visual orga¬
nization (object assembly). Memory testing
showed marked impairment in the ability
to hold verbally presented material over
time. The Trailmaking Test (Parts A and B)

normal. The tests that showed the
maximum impairment were the Wisconsin
Card Sorting Test and the Stroop Color
Word Test. These tests evaluate the ability
to shift sets rapidly and are characteristi¬
cally abnormal in patients with frontal lobe
disease.3
Since the second month after onset of his
behavioral syndrome the patient has re¬
mained clinically stable. He has shown no
response to either methylphenidate (30 mg
was

Fig 2. Sagittal magnetic resonance imaging (T,) demonstrating hem¬
orrhage in the left globus pallidus (arrow). Six weeks after hemorrhage.
—

daily) or bromocriptine (80 mg daily). A
follow-up magnetic resonance imaging was

obtained 12 weeks after onset of frontal
lobe syndrome (Figs 3 and 4); this second
scan again demonstrated the globus palli¬
dus lesions. These lesions gave the signal
characteristics of resolving hemorrhage. In
the fifth month a single-photon emission

computed tomographic scan was obtained,
which showed a slight decrease in blood
flow in the anterosuperior portion of the
right frontal lobe and an equivocal decrease
in blood flow in the posterior frontal lobe on
the left side.

COMMENT

The patient's outstanding clinical
signs and symptoms are those that
typify the frontal lobe syndrome. He is
apathetic, socially withdrawn, and
nonmotivated. He has given up his
hobbies and fails to make timely deci¬

sions in his work. He knows what
actions are required in his business,
yet he procrastinates and leaves de¬
tails unattended. Depression is not
present. He does not display or admit
to any dysphoric mood; he is not sad
and has not changed his eating habits;
however, he tends to sleep more than
he did in the past. Neuropsychologic
testing demonstrated a significant im¬
pairment on the sensitive set shifting
tasks (Stroop Color Word Test and the
Wisconsin Card Sorting Test) that are
usually associated with frontal lobe

dysfunction.3

The frontal lobe syndrome is usually
in patients with significant dis¬
ease of the frontal cortex. In cases of
seen

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the apathetic variety of frontal syn¬
drome, such as this patient displays, it
has been proposed that it is the lateral
portion of the frontal lobes that is
usually involved (Brodmann's areas 9,
10, 11, 46, and 47).1 This dorsolateral
localization is by no means universal;
bilateral anterior cerebral artery le¬
sions that are sometimes seen after
anterior communicating artery aneu¬
rysm rupture will produce an apa¬
thetic frontal lobe syndrome with me¬
sial and orbital frontal infarction.
In this case there was no evidence on
the magnetic resonance imaging scan
of any damage to the frontal cortex,
although the single-photon emission
computed tomographic scan did show a
minimal decrease in blood flow in the
superior frontal lobe on the right side.
It is proposed, therefore, that the subcortical lesions in the globus pallidus
alone are responsible for this patient's
clinical findings.
The behavior changes of the frontal
lobe syndrome can occur, however,
from noncortical as well as nonfrontal
lesions. Deep white matter lesions in
the frontal lobe that interrupt the re¬
ciprocal connections between the fron¬
tal cortex and limbic structures else¬
where in the brain can certainly pro¬
duce the syndrome. The frontal
leukotomies performed in the 1940s by
Freeman and Watts4 purposely in¬
volved producing such lesions by the
rather nonselect cutting of these fiber
tracts in the inferior frontal lobe. Such

procedures were performed to produce

Fig 3.—Coronal magnetic resonance imaging (T,) 10 weeks after onset
of frontal lobe syndrome demonstrating area of residual damage in the
right globus pallidus (arrow).

a state of relative apathy in psychotic
patients.4 More recently, selective cingulotomies have been performed to
help seriously obsessive-compulsive

individuals to be less obsessive. In
these cases, fiber tracts connecting the
frontal lobe with the cingulate gyrus
are

interrupted.56

Involvement or disconnection of the

deep frontal white matter is also one of
the possible mechanisms for the fron¬
tal lobe syndrome that is sometimes
demonstrated in patients after rup¬
ture of anterior communicating artery
aneurysms.7·8
It is not difficult to imagine how
damage to the major afferent and ef¬

ferent systems of an extensive area of
association cortex such as the frontal
lobes could produce a clinical picture
similar to that produced by damage to
the cortex itself. But how more remote
lesions, such as those seen in this
patient, can explain the frontal lobe
symptoms is more problematic. One
explanation could be that the frontal
lobe syndrome is not exclusively a
frontal lobe phenomenon but rather is
a general behavioral syndrome that
can be seen in patients with destruc¬
tive lesions in various areas of the
brain. Many of the features of the syn¬
drome, eg, apathy and nonmotivation,
are common general behavioral symp¬
toms that are seen in a wide variety of
organic and functional behavioral syn¬
dromes (eg, akinetic mute states, de¬
mentia, confusional states, right pari¬
etal lesions, depression). A second ex-

Fig 4.—Coronal magnetic resonance imaging (T,) 10 weeks after onset
of frontal lobe syndrome demonstrating bilateral residual lesions in the
globus pallidus (arrows).

planation is that the symptoms of the
frontal syndrome are produced not
only by damage to the frontal lobes
and their major fiber pathways but
also by damage to other brain struc¬
tures that have strong interconnec¬

tions with the frontal lobes. The fron¬
tal lobes have rich interconnections
with many subcortical structures: cau¬
date nuclei, thalamus (dorsomedial
and anterior nuclei), temporal lobe lim¬
bic structures, and the periaqueductal
gray and associated mesencephalic lim¬
bic structures.9 Because of this system
of dense reciprocal interconnection it
is not surprising that patients with subcortical lesions in some of these areas
can have symptoms of frontal lobe
dysfunction. Several recent clinical re¬
ports support this notion.
Richfield et al10 described a 25-yearold patient who developed a pattern of
inappropriate, vulgar, impulsive, anti¬
social behavior after bilateral destruc¬
tion of the head of the caudate nuclei;
and Bogousslavsky et al11 described a
72-year-old patient with an infarct in
the right thalamus who demonstrated
a behavioral state that fluctuated be¬
tween manic delirium and apathy. In
addition to these cases in which the
frontal lobelike behavior change was
the principal behavioral feature of the
subcortical lesions, Katz et al12 have
described six patients with dementia
secondary to multiple subcortical
strokes in the mesencephalon and di¬
encephalon in whom features of a fron¬
tal lobe syndrome (apathy, lack of mo-

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tivation, and impulsiveness) accompa¬

nied the cognitive loss.
In the case described here, the exact
anatomic extent of the lesions is not
known; however, they appear to be
largely confined to the globus pallidus
and possibly some portion of the pos¬
terior limb of the internal capsule. It
may be possible that some of the fibers
from dorsomedial thalamus to frontal
lobe may be affected by this lesion.
Crosby et al13 also describe thalamofrontal fibers that make connections
through the putamen and globus palli¬
dus. It is not known whether these
pathways are of sufficient influence
that their damage could cause this de¬
gree of behavior change,13 but it is
possible. Further speculation without
pathologic examination is clearly un¬

justified.

The functions of personality, drive,
and character that are attributed to
the frontal lobes are enormously com¬
plex functions that undoubtedly re¬
quire vast integrated cerebral neu¬
ronal networks for their elaboration.14
The frontal cortex is an important part
of that network, but, as this and other
reported cases show, it is not the ex¬
clusive center for such functions. Dam¬
age anywhere within the entire net¬
work is likely to produce, in some
measure, symptoms akin to the classic
frontal lobe syndrome.
This same network model can be
used to explain the findings in cases of
subcortical dementia,15 subcortical
aphasia,16 subcortical neglect,17 and

any number of similar cases that do
not fit the strict localizationist model

of the 19th century.
Other than the anatomic mecha¬
nism in this case, there is a further
unexplained issue in this particular
patient; ie, the exact relationship
among this patient's symptoms, his
brain lesions, and the fact that they
both occurred at an altitude of more
than 4000 m above sea level. The pa¬
tient's initial symptoms of light-headedness, intoxication, and poor judg¬
ment occurred within minutes of en¬
tering the rarefied air of La Paz. These
symptoms are certainly consistent in
many ways with the symptoms of
acute anoxia that have been reported
by military recruits exposed to low
oxygen tension in experimental de¬
compression chambers and by pilots
who have experienced explosive de¬
compression at high altitudes (8000 to
16000 m) when the canopy of their
aircraft unexpectedly ejected.1819 In
such cases of anoxia, however, patients

usually experience paresthesias in var¬
ious parts of the body, which this pa¬
tient did not; and they are usually not

amnesic unless the anoxia is severe
and their behavior much more disor¬
dered and confusional than that of this
patient. Simple hypoxia is probably an
insufficient explanation for his initial
behavior change.
In commercial airplanes the pres¬
sure in the cabin is maintained at an
equivalent of between 1830 and 2440 m
above sea level. Ambient cabin pres¬
sure is supposed to be gradually de¬
creased during descent into La Paz so
as to avoid the explosive decompres¬
sion (by definition, a drop in pressure
of 1524 m in 1 minute or less) that
would occur if the cabin door was
opened in La Paz without the gradual
change. Assuming that these precau¬
tions were taken, this patient should
not have experienced a rapid change in
pressure, but rather, a gradual one.
There are other clinical syndromes
that can occur when individuals are
exposed to a change in ambient baro¬
metric pressure. One is acute moun¬
tain sickness, a syndrome seen in
mountaineers who climb at altitudes
above 3350 m.2022 This syndrome
evolves over hours to days and is char¬
acterized by both pulmonary and cere¬
bral edema. The patient presented
here did not describe the headache,
blurred vision, and respiratory prob¬
lems associated with that condition, so
it is doubtful that diffuse edema played
a part in his symptoms. Acute moun¬
tain sickness can be fatal but autopsy
reveals cerebral edema, petechial hem¬
orrhages on the pial surface of the

brain and anoxie necrosis in basal
ganglion and cortex but no parenchymal hemorrhage.2324 Another mecha¬
nism of neurologic symptoms with
rapid decompression is the release of
nitrogen bubbles into the system. This
is usually associated with decompres¬
sion from underwater dives and is
rarely, if ever, seen in high-altitude ex¬

posure.25
The relationship between the globus
pallidus hemorrhage and the altitude
exposure remains, therefore, unclear.
It is possible that the hemorrhages are
coincidental and that the high altitude
played no physiologic role in the pro¬
duction of the hemorrhage. Several
factors, however, make it difficult to
accept this supposition; basal ganglion
hemorrhage is uncommon in normotensive individuals, basal ganglion
hemorrhage is usually unilateral, and
such hemorrhages are much more
common in the striatum and thalamus

than in the globus pallidus. It is possi¬
ble that this patient had bilateral
cryptic vascular malformations in
each globus pallidus and that the com¬
bination of tissue hypoxia and com¬
pensatory vasodilatation produced the
hemorrhage, but this seems unlikely.
A final possibility is that the hypoxia,
to which the globus pallidus is rela¬
tively sensitive, coupled with vasodi¬
latation that occurs at high altitude
caused the rupture of some small nor¬
mal vessels in this area thus causing
the restricted areas of hemorrhage. If
this is what happened, this event most
likely occurred in the first hour after
disembarking. The patient's excitation
the first day would therefore have rep¬
resented the combined effects of the
acute hemorrhage and general cere¬
bral hypoxia. By the third day, the in¬
toxication of the hypoxia receded and
the apathy and lethargy caused by the
focal lesions prevailed.
From review of the literature and
the general knowledge that people fly
in and out of high-altitude airports on
a daily basis without developing the
problems encountered by this patient,
it is clear that this case is, if not
unique, decidedly rare. There was
nothing in the patient's medical his¬
tory or his evaluation after the inci¬
dent to suggest a medical condition
that would render him unusually sus¬

ceptible to the effects of high-altitude

exposure. Since this is an isolated case,
there seems little reason to suggest
that people not engage in air travel to
altitudes above 2000 m; however, this
case does bring up many interesting
issues about the rather sudden expo¬
sure to high altitude experienced dur¬

ing air travel.

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