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COGNITIVE AND Case Report
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NEUROLOGY
Volume 16, Number 4
December 2003

Exacerbation of Mania Secondary to
Right Temporal Lobe Astrocytoma in a
Bipolar Patient Previously Stabilized
on Valproate
*†Kenneth N. Sokolski, MD, and *Thomas F. Denson, MA
Abstract
Objectives:
To investigate breakthrough mania secondary to a
right temporal lobe neoplasm in a bipolar patient
previously stabilized on sodium divalproex.
Background:
Right hemispheric brain tumors involving the orbitofrontal or basotemporal cortex are a rare cause
of secondary mania. In such cases, early neurologic signs may be difficult to distinguish from bipolar symptoms. Breakthrough mania secondary
to brain neoplasm in a bipolar patient stabilized on
medication is an extremely rare phenomena
which has not been previously reported.
Method:
The clinical course of a bipolar subject stabilized
on valproate who developed mania secondary to a
right temporal lobe astrocytoma is described. Serial brain magnetic resonance imaging (MRI), baseline electroencephalogram (EEG), and neuropsychiatric evaluations were used to examine the relationship between the patient’s brain mass and
behavioral disturbances.
*VA Long Beach Healthcare
System, Mental Health Care
Group, Long Beach, California;
†University of California, Irvine,
School of Medicine, Department
of Psychiatry, Irvine, California,
USA.
Received July 23, 2002;
revised January 11, 2003,
March 20, 2003;
accepted March 31, 2003.
Address correspondence and
reprint requests to Dr. Kenneth
N. Sokolski, VA Long Beach
Healthcare System, 5901 East 7th
Street (06/116a), Long Beach,
CA 90822; E-mail:
kenneth.sokolski@med.va.gov
Copyright © 2003 by
Lippincott Williams & Wilkins

Results:
Symptoms were those that accompanied prior episodes of mania. In addition, signs of temporal lobe
dysfunction were evident including periods of detachment, déjà vu experiences, and olfactory hallucinations. In the context of mania, depersonalization was initially attributed to bipolar symptoms. Only several months later, when olfactory
hallucinations and alterations in consciousness became evident, was a temporal lobe lesion suspected. Neuropsychiatric abnormalities responded
to a combination of surgical intervention, radiation therapy, and topiramate, however the tumor
was advanced and invasive at diagnosis resulting in
a poor prognosis.
Conclusions:
This case suggests that clinicians examining unexplained cases of breakthrough mania should be
vigilant for early signs of temporal lobe dysfunction, which could aid in detecting treatable lesions.

Key Words: mania, astrocytoma, temporal lobe,
seizures, Valproate, Topiramate

(Cog Behav Neurol 2003;16:234–238)

S

econdary mania is a rare complication of
brain neoplasms originating in the right
frontal and basotemporal cortex.1–3 Few
studies have documented the evolution of
neuropsychiatric symptoms related to the expansion of brain masses.4 Breakthrough mania associated with cerebral tumors in bipolar
patients stabilized on medication has not
been reported. The following case describes
an exacerbation of mania associated with an
invasive right temporal lobe grade IV astrocytoma in a patient with a primary diagnosis of
bipolar I disorder whose condition had been
previously well controlled on valproate. The
emergence of early and late temporal lobe
signs of increasing intensity and frequency is
presented and contrasted with bipolar symptoms. The difficulty in detecting early signs of
temporal lobe dysfunction in the context of
mania is discussed.

CASE REPORT
The patient, a 51-year-old Caucasian female, had experienced at least nine episodes
of mania since age 21. Manic symptoms were
severe enough to require hospitalization at
ages 21, 33, 39, and 50. She was referred by
her treating psychiatrist for a double-blind,
placebo-controlled study of topiramate in bipolar disorder due to breakthrough mania following 8 months of euthymia on 1500 mg of
valproate (serum levels = 90–110 µg/mL).

Mania Secondary to Right Temporal Lobe Astrocytoma COGNITIVE AND
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December 2003

Just prior to referral, the patient had decreased her dosage of valproate to 1000 mg
per day due to “side effects.” Her symptoms
included insomnia, hyperactivity, grandiosity, pressured speech, irritability, and hypersexuality. She also experienced episodes of
detachment lasting several minutes and occurring once or twice a week in which she
reported not being in touch with her emotions and feeling that “the world is an illusion” in which “everything is unreal.” At all
times during these episodes, she was reported to be awake, alert, and responsive.
Depersonalization episodes had begun
about 2 months prior to study referral, concurrent with increasing symptoms of mania.
Feelings of detachment, however, did not appear to be worsening in frequency or intensity. When measured against a background of
disorganized thinking, pressured speech, and
grandiose delusions, depersonalization was
initially attributed to exacerbation of bipolar
illness. This interpretation was consistent
with reports that detached states may be associated with mood disorders in up to 20% of
unselected patients, including conditions in
the bipolar spectrum.5–7
As part of the study protocol, the patient was hospitalized to washout divalproex
and randomized to topiramate 400 mg, 600
mg, or placebo. During the third day of randomization, she experienced an episode of
severe headache associated with vomiting
and dizziness, which the patient and staff attributed to migraine. There were no other
adverse events during the 2-week hospitalization, and she did not report any episodes of
detachment during this period.
Initially, improvements were noted in
sleep, mood, and agitation. On the second
weekly outpatient visit, however, 2 months
after her initial evaluation for the topiramate
study and 4 months after first reporting depersonalization episodes, the patient’s
spouse noted a return of mild to moderate
hyperactivity, talkativeness, and agitation.
The patient was also complaining of mild
nausea and unexplained episodes of dizziness. In addition, several previously unre-

ported symptoms were described including
blackouts, meaningless verbalizations for
which the patient had no memory, and déjà
vu episodes. Periods of derealization were
now occurring daily and preceded by a distinct “aura” in which she felt cold, had goosebumps on her skin, and experienced a burning acid smell lasting 2 to 3 minutes. They
were also accompanied by staring spells and
altered attention.
Due to these new symptoms, an electroencephalogram (EEG) was obtained that
revealed marked right frontotemporal slowing. Sleep-deprived and 24-hour EEGs were
also ordered to rule out epileptiform activity
but were never performed. Computed tomography completed the following day confirmed a 2.5-cm round mass in the right medial temporal lobe. This was further characterized on magnetic resonance imaging (MRI)
as a solitary lesion with an irregular border
within the right medial temporal lobe displacing the right lateral ventricle, adjacent
right temporal horn, and the right hippocampus superiorly and medially (Fig. 1). As a result of these findings, the patient was immediately taken off the research protocol and
referred for neurosurgical consultation. At
the patient’s request, treatment with 100 mg
topiramate twice per day was provided on an
open-label basis resulting in increased mood
stability. Due to the development of neurologic symptoms indicative of a temporal lobe
lesion several months prior to topiramate exposure, there was no consideration of any
association between topiramate and the development of the brain tumor.
An exhaustive search for a primary
metastatic neoplasm was negative. The patient was transferred to another medical center where she underwent a craniotomy and
resection, which removed over 90% of the
brain mass. Pathology reported a grade IV invasive right temporal lobe astrocytoma portending a poor prognosis. Radiation therapy
was initiated to improve quality of life. Unexpectedly, however, the combination of surgical resection and radiotherapy resulted in
temporary remission of the tumor 7 months

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FIGURE 1. Magnetic resonance image (axial
view) revealing a 2.5-cm round grade IV astrocytoma of the right temporal lobe in a bipolar patient previously stabilized on valproate. The tumor was associated with reemergence of mania,
accompanied by episodes of depersonalization,
olfactory hallucinations, and déjà vu experiences.

after diagnosis. Regression of the tumor was
associated with improvements in olfactory
hallucinations, déjà vu experiences, depersonalization episodes, mood lability, pressured speech, and hyperactivity. The tumor
remained in remission until 2 years after initial presentation when the neoplasm recurred with a rapidly deteriorating fatal
course unresponsive to antineoplastics or to
radiation therapy.

DISCUSSION
Breakthrough mania has been reported
in such diverse conditions as steroid exposure, amphetamine use, antineoplastic treatment, upper respiratory tract infections, hyperthyroidism, adrenal dysfunction, collagen
vascular diseases, multiple sclerosis, epilepsy, and vitamin deficiencies.8 While secondary mania has been described following
left frontotemporal vascular events,9 most
cases have involved lesions of the right limbic orbitofrontal and basotemporal cortex as
© 2003 Lippincott Williams & Wilkins

well as right-sided deep gray structures including the head of the caudate and thalamus.10,11 Mania associated with brain tumors
is exceedingly rare with less than 20 cases
documented in the literature.12,13 The majority of tumor-related cases of secondary mania
have been associated with right-sided gliomas, meningiomas, astrocytomas, or neuromas as well as pituitary neoplasms and metastases.14–17 When tumors have been treatable, resection along with anticonvulsants
have improved behavioral symptoms. 18
While cortical lesions have resulted in unipolar mania, damage to subcortical structures
has produced an alternating manic-depressive course.19
This is the first case to describe breakthrough mania secondary to a brain neoplasm in a bipolar patient previously stabilized on medication. While the breakthrough
episode appeared typical of mania, it was accompanied by infrequent periods of depersonalization that were difficult to discern
from psychiatric symptoms. Reports documenting depersonalization in patients with
a variety of mood disturbances5–7 further
lowered suspicions that the patient’s initial
complaints were of neurologic origin. Only
several months later, when her condition
evolved into a more dramatic presentation,
including frequent disturbing periods of depersonalization, déjà vu episodes, vivid olfactory hallucinations, and alterations in consciousness, was the diagnosis of temporal
lobe pathology considered. The escalation of
temporal lobe dysfunction following the
withdrawal of valproate suggests that this
medication may have limited initial symptoms by controlling seizure activity.
Although the patient had a 30-year history of bipolar I disorder, the breakthrough
episode documented here involved a constellation of symptoms that were distinctly different from any she had experienced during
prior episodes of mania. While bipolar pathology was present, she also exhibited
symptoms indicative of temporal lobe compromise, including depersonalization, déjà
vu experiences, and olfactory hallucina-

Mania Secondary to Right Temporal Lobe Astrocytoma COGNITIVE AND
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NEUROLOGY
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tions.20–25 In addition, staring spells, dizziness, and vocalizations that are not specific to
temporal lobe lesions, but may occur in association with partial complex seizures of the
right temporal lobe, were also evident.26–28
The occurrence of ictal verbalizations in
this patient further suggests that seizure activity in the nondominant temporal lobe may
have been involved in her clinical presentation.29,30
The mechanisms through which a right
temporal lobe mass can produce secondary
mania are unknown. Damage to right-sided
frontotemporal limbic connections has been
found in most cases of mania associated with
cerebral lesions10 and may represent a common pathway for the development of bipolar
symptomatology. Alternatively, unilateral disruption of ascending biogenic amine pathways by frontotemporal brain masses may
create hemispheric catecholaminergic imbalances thought to underlie mood disturbances.2 The rarity of such lesions resulting
in mania suggests that prior damage or atrophy of right limbic structures accompanied
by a genetic predisposition may be a prerequisite for such an outcome.31
As already suggested, the potential involvement of seizure activity affecting temporo-limbic structures as a cause of both the
neurologic and psychiatric symptoms of this
patient must also be considered. This possibility is supported by the common association between invasive astrocytomas and epileptiform activity32 as well as reports documenting the occurrence of mania in patients
with seizure disorders.33–36 Although epileptiform tracings were not noted in the EEG of
this patient, such activity is often missed due
to the brevity of studies or difficulty in analyzing foci not easily referenced by standard
surface EEG leads. More revealing tests such
as a sleep-deprived EEG and 24-hour monitoring, which might have uncovered ictal
events, were not obtained.
This case illustrates the importance of
recognizing early signs of temporal lobe dysfunction such as dissociative states that may
indicate treatable lesions. Detection of cere-

bral pathology may be delayed in patients
with mania due to the difficulty in distinguishing signs of early temporal lobe dysfunction from manic symptoms and due to the
low index of suspicion related to the rarity of
such events in clinical practice. In the present case, diagnosis of a right temporal lobe
astrocytoma was made at a late, invasive
stage only when symptoms of more advanced
temporal lobe alterations were evident. Although the tumor was initially responsive to
surgical resection, radiotherapy, and anticonvulsant treatment, prognosis was poor at diagnosis, and the neoplasm ultimately recurred. Increased vigilance to the presence
of subtle temporal lobe signs in the context
of breakthrough mania may allow for recognition of brain lesions at an earlier stage, improving the chances for more successful
treatment.
ACKNOWLEDGMENTS
This study was completed as part of the
authors’ research-related activities at the VA
Long Beach Healthcare System. No direct
funding was obtained from the pharmaceutical industry; however, the patient was a subject in a study funded by R.W. Johnson to
investigate topiramate in mania. The contents of this report have been approved for
publication by R.W. Johnson. Special thanks
to Brenda Brown, MA, for reviewing the paper and providing helpful suggestions.
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