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Am J Psychiatry 164:6, June 2007 877

Clinical Case Conference

ajp.psychiatryonline.org

This article is the subject of a CME course.

Treatment of Psychiatric Symptoms Associated With aFrontal Lobe Tumor Through Surgical Resection

Zachary S. Hoffer, Ph.D.

Shannon L. Allen, B.S.

Maju Mathews, M.D., M.R.C.Psych.

The frontal lobes of the brain underlie judgment, fore-sight, motivation, and personality and allow us to behave

as socially appropriate human beings (1, 2). Our under-

standing of frontal lobe function comes from animal ex-

periments (e.g., the chimpanzee experiments of Jacobsen

and Fulton that were the impetus for Moniz’s human lo-

botomies) and human neuropsychological studies, as wellas case reports involving traumatic brain injuries. These

case reports have shown that frontal lobe damage often re-

sults in antisocial behavior, apathy, disinhibition, and

emotional lability. Discrete prefrontal cortex lesions are

sometimes associated with unique behavioral profiles. Al-

though numerous exceptions exist, frontal lobe dysfunc-

tion exhibits laterality: left hemisphere lesions are more

typically associated with depression, whereas right hemi-

sphere lesions are associated with impulsivity and manic-

like symptoms (3, 4).

Brain tumors are a well-known

cause of frontal lobe dysfunction. One

type is the rare dysembryoplastic neu-roepithelial tumor, a benign supraten-

torial neoplasm seen primarily in

children and young adults (5, 6). Ap-

proximately one-third of dysembryo-

plastic neuroepithelial tumors occur

in the frontal lobes, and some become

large enough to compress regions of

the cortex and white matter to the

point of disrupting behavior (7–9). In

addition to mass effects, dysembryo-

plastic neuroepithelial tumors are a

source of epileptogenic activity, which

may lead to neuropsychiatric se-

quelae when there is frontal lobe in-

volvement (10, 11). Surgical resection, which characteris-

tically yields an excellent prognosis, is the recommended

treatment for these tumors (12, 13). Even with partial tu-

mor removal, there is little evidence of recurrence, and

most patients make a complete but slow neuropsychiatric

recovery. This case study is one of a few to report the virtu-

ally instantaneous neurosurgical cure of a psychiatric ill-

ness in a patient with a frontal lobe dysembryoplastic neu-

roepithelial tumor. We also provide a summary and review

of the literature on psychiatric disturbances associated with various frontal lobe lesions.

Case Presentation

“Jimmy,” a 16-year-old right-handed African American

boy with a 9-year history of progressively worsening

conduct was referred to our inpatient medical psychiat-

ric unit after the surgical removal of a brain tumor. At

age 7, the patient had begun exhibiting mood swings,

behavioral problems, and decreased academic perfor-

mance. According to his mother, his initial symptoms

consisted of totally unpredictable and inconsolable “cry-

ing jags” that lasted more than an hour. Over the next 5

years, his behavior had deteriorated further, and he be-came violent with suicidal ideation. During this time, he

was given multiple diagnoses: attention deficit hyperac-

tivity disorder, bipolar disorder, and conduct disorder.

Eventually his mother placed him in a residential treat-

ment facility because she could no longer manage him

at home. At age 12, a magnetic resonance imaging (MRI)

study revealed a nearly spherical 0.8-cm-in-diameter

mass located medially within the white matter of the

left frontal lobe superior to the anterior horn of the lat-

eral ventricle (Figure 1, top). Based on the indistinct ra-

diographic signature of the mass, a clinical decision was

made to treat the patient with mood

stabilizers and antipsychotic drugs.

His mother reported that Jimmy’s

teenage years were characterized by

extreme irritability and that “the

sound of my voice seemed to anger

him.” Over the next 4 years, the pa-

tient was poorly controlled with vary-

ing combinations and doses of lithium,

methylphenidate, quetiapine, and ris-

peridone. Higher dosing and polyphar-

macy were at times associated with

increasingly violent behavior. EEG

studies recorded symmetric 9–10-Hz

alpha rhythms anteriorly with faster

overlying frequencies but failed to re-

veal frank seizure activity. At age 16, a

second MRI showed that the mass had

grown to 1.3×1.4×1.0 cm and was now within 0.1 cm of

the adjacent anterior cingulate cortex, but there was no

neurological evidence of a mass effect. Around this time,

the patient refused to take lithium and risperidone; de-

spite the discontinuation of pharmacological treatment,

his behavior did not worsen in the 3 weeks before sur-

gery. Postoperative imaging studies (Figure 1, bottom) re-

vealed transection of the left cingulum and total removal

of the mass, which was histologically identified as a dys-

embryoplastic neuroepithelial tumor.

“Human frontal lobelesions can result inalterations in attention,

insight, mood,planning, andinterpersonal

communication— changes that are often

permanent.”

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878 Am J Psychiatry 164:6, June 2007

CLINICAL CASE CONFERENCE


Postoperatively, the patient’s behavioral recovery, as

described by his mother, was “nearly instantaneous,” al-

though he did have mild weakness and paresthesias of

the right lower leg that lasted several weeks. During a 4-week postoperative observation period, he exhibited

none of his earlier aggressive behaviors or violent out-

bursts and was easily managed on the inpatient medical

psychiatric unit. Upon discharge, he returned to foster

care for an additional 6 months before being released to

his mother. At home, his mother reported that her son’s

behavior was dramatically improved, and a written eval-

uation by a school psychologist indicated that our patient

had no trouble concentrating and exhibited no notewor-

thy behavioral problems in the classroom. Psychological

testing (see Tables 1 and 2) failed to reveal any perma-

nent cognitive sequelae of the neurosurgical procedure.

Outside the classroom, the patient had a renewed inter-

est in sports and was forming adequate peer relation-

ships. At a 1-year follow-up visit, the patient and hismother reported that he continued to do well socially,

and although he decided to leave school for personal

reasons, he had completed his General Equivalency Di-

ploma (GED) and was planning a career in the military.

Discussion

Many studies of humans and nonhuman primates have

established that lesioning the frontal lobes can result in

abnormal behaviors (14, 15). Depending on the affected

hemisphere and the location within the hemisphere, hu-

man frontal lobe lesions can result in alterations in atten-

tion, insight, mood, planning, and interpersonal commu-

nication—changes that are often permanent (15).

In each hemisphere, the bulk of the nonmotor frontallobe is subdivided into the prefrontal anterior cingulate

and the dorsolateral, orbitofrontal, and ventromedial cor-

tices. The dorsolateral cortex receives the majority of its

distant afferent inputs by means of the superior longitudi-

nal and uncinate fasciculi, and short-range association fi-

bers (U-fibers) mediate local p refrontal connections.

Medially, the orbitofrontal cortex connects to limbic struc-

tures by means of the uncinate fasciculus and to the ven-

tromedial cortex through U-fibers. The orbitofrontal and

ventromedial cortices are reciprocally interconnected,

and it is likely that both are connected with the anterior

cingulate by means of fibers of the rostral cingulum. Com-

munication between the prefrontal cortices of the cerebralhemispheres is mediated by reciprocal callosal projec-

tions, but these are generally much sparser than ipsilateral

corticocortical connections and are usually limited to ho-

motopic areas (16–18). In addition to corticocortical con-

nections, all prefrontal areas receive robust input from the

limbic channel of the basal ganglia.

The dorsolateral prefrontal cortex plays an essential role

in weighting and integrating impulses from various sen-

sory and limbic channels for the purpose of generating

goal-directed behaviors (19). This brain region is also ac-

FIGURE 1. Preoperative Magnetic Resonance Imaging (MRI) (top) (1.5 T magnet, T1 weighted) Showing a DysembryoplasticNeuroepithelial Tumor (hypoattenuated mass, arrows) in the Paraventricular White Matter in Three Planes of Section;Postoperative MRI (bottom) (3.0 T, T1 weighted) Showing Residual Cavity (arrows) in the White Matter 5 Months After Tu-mor Removal in Approximately the Same Planes of Section

Preoperative

Postoperative

ParasagittalCoronal

Axial

Anterior Posterior R L R L

3.0 cm

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tive in working memory tasks (20–22). Thus, major fea-tures of dorsolateral lesions regularly include labile affect,

depression, and decreased executive function (19, 23–25).

Functional imaging studies have linked the negative

symptoms of schizophrenic patients to perturbations of

dorsolateral cortical metabolism (26, 27).

Altho ugh our patient’s decreased aca dem ic perfo r-

mance might suggest a lesion of the dorsolateral prefron-

tal cortex and/or the underlying white matter, other func-

tions subserved by the dorsolateral prefrontal cortex, such

as decision making, working memory, and capacity to

plan (1, 2, 20–22), were largely spared. Thus, we surmise

that our patient’s dorsolateral cortex remained intact, a

conclusion most strongly supported by serial imaging studies that showed that the dysembryoplastic neuroepi-

thelial tumor was many centimeters away from the dorso-

lateral prefrontal cortex. We believe our patient’s de-

creased school performance was more directly related to

the tumor’s effects on other prefrontal areas and to the

side effects of the polypharmacy intended to treat his psy-

chiatric symptoms.

Intact orbitofrontal cortices are required for normal

judgment and socialization. Patients with orbitofrontal le-

sions tend to be disinhibited (24, 28). Unlike dorsolateral

lesions, orbitofrontal lesions generally spare cognitive

abilities and volition, but they can significantly contribute

to the genesis of antisocial behaviors, prompting some au-thors to rename the orbitofrontal syndrome acquired

“pseudopsychopathy” (28, 29). Indeed, the outbursts,

mood fluctuations, self-mutilation, and splitting behav-

iors seen in borderline personalities may be related to a

hypofunctioning orbitofrontal cortex (30, 31). Neuroana-

tomically, the explosive antisocial traits associated with

orbitofrontal lesions have been postulated to result from a

loss of inhibitory control over the amygdala (28, 32, 33).

Although our patient exhibited many antisocial behav-

iors strongly associated with an orbitofrontal lesion, his tu-

mor was not located within the orbitofrontal cortex. Thisincongruency might be explained by the fact that his tumor

was strategically situated in the white matter just superior

to the anterior horn of the left lateral ventricle. Tumors in

this location can compress corticofugal orbitofrontal axons

as they join the uncinate fasciculus. Thus, in our patient,

corticofugal orbitofrontal fibers may have been compro-

mised enough to partially denervate the amygdala and un-

cover behaviors that are normally suppressed.

The ventromedial prefrontal cortex is believed to regu-

late empathy, foresight, and reversal learning (14, 34). In

reversal learning tasks mediated by the ventromedial

cortex, subjects are trained to respond differentially to

two stimuli under reward and punishment conditions,and later they are trained to reverse the reward values

(35). Reversal learning deficits cause patients to persist in

simple tasks or deleterious high-risk behaviors that in

the past paid dividends, as, for example, in pathological

gambling, where high-risk behaviors persist despite re-

duced payoffs (36, 37).

Our patient exhibited significant signs of reversal learn-

ing impairment as evidenced by his repeatedly engaging

in high-stakes behaviors that had been rewarded on the

streets but resulted in harsh punishment in the residential

treatment facility. These negative behaviors are consistent

with dysfunction of the ventromedial cortex, an interpre-

tation further supported by MRI studies showing that thedysembryoplastic neuroepithelial tumor encroached on

the caudal boundary of the ventromedial cortex. Based on

this proximity, it is very likely that the dysembryoplastic

neuroepithelial tumor, by either compression or ephaptic

activation of corticofugal axons, perturbed ventromedial

efferent impulses and mimicked features of a ventrome-

dial cortical lesion.

The anterior cingulate cortex borders the genu of the

corpus callosum and merges into the posterior cingulate.

Functionally, the anterior cingulate can be divided into

TABLE 1. Pre- and Postoperative Scores for Jimmy on the Wechsler Intelligence Scale for Children, Third and FourthEditionsa

Measure

7 Years, 0 Months 11 Years, 11 Months

WISC-IV

16 Years, 8 Months(postoperative)

Score Percentile Score Percentile Score Percentile

Full-scale IQ 106 66 95 37 Full-scale IQ 94 34Verbal IQ 119 90 110 75 Verbal comprehension 110 75Performance IQ 91 27 87 19 Working memory 107 21

Perceptual reasoning 88 21

Processing speed 73 4a The test was administered on the second postoperative month.

TABLE 2. Pre- and Postoperative Subtest Scores for Jimmy on the Wechsler Individual Achievement Test, Second Editiona

Measure

7 Years, 0 Months 11 Years, 11 Months16 Years, 8 Months

(postoperative)

Score Percentile Score Percentile Score Percentile

Word reading 103 58 108 70 102 55Spelling 93 32 94 34 96 39Mathematics reasoning 111 77 113 81 102 55Numerical operations — 104 61 91 27a Selected components of the test were administered at each testing session; the numerical operations subtest was not administered at age 7

years, 0 months.

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two regions, a rostral affective division and a caudal cogni-

tive division, although recent functional MRI studies sug-

gest even greater functional subdivisions probably exist

(38, 39). The rostral anterior cingulate receives robust in-

put from the amygdala, whereas the caudal anterior cin-

gulate receives projections from the entorhinal cortex and

parahippocampal/hippocampal regions (40). Connecting

these areas is the cingulum, a fiber tract embedded within

the anterior cingulate gyrus and terminating in more ros-tral prefrontal cortices. Functionally, the anterior cingu-

late may underlie drive (motivated attention) and concen-

tration (attention allocation), and it may recognize affect-

mood conflicts and other processing errors requiring

heightened awareness (cognitive and limbic error detec-

tion) (38, 39, 41, 42). Anterior cingulate lesions interfere

with these functions, whereas anterior cingulate hyperac-

tivity has been described in most anxiety disorders, in-

cluding obsessive-compulsive disorder (OCD) as well as

schizophrenia and chronic pain syndromes (42).

Our patient’s clinical and MRI findings strongly suggest

the tumor had the greatest effect on the anterior cingulate.

Clinically, Jimmy was apathetic and had difficulty sustain-ing attention, and he often would respond inappropriately

to another person’s affect; both of these behavioral deficits

are associated with anterior cingulate dysfunction. Multiple

MRIs revealed that of all the prefrontal regions, the dysem-

bryoplastic neuroepithelial tumor was closest to the ante-

rior cingulate (approximately 1 mm of separation), necessi-

tating a mid-rostral cingulotomy for surgical access.

Frontal lobe lesions exhibit lateralization with respect to

psychiatric or behavioral disturbances. Left hemisphere

lesions are more likely to be associated with depression,

particularly if the lesion involves the dorsolateral portion

of prefrontal cortex. By contrast, right hemisphere lesions

are associated with impulsivity and manic behaviors (3, 4).Our patient’s dysembryoplastic neuroepithelial tumor was

located in the left frontal lobe, but his behaviors were

more consistent with right frontal lobe dysfunction, e.g.,

aggressiveness and disinhibition. This discrepancy could

be explained by several neuropsychiatric observations. In

children and young adolescents, symptoms of depression

can manifest as irritability and psychomotor agitation (43,

44). Our patient periodically exhibited these traits, but

they were consistently overshadowed by his more extreme

behaviors. Another explanation is centered on the obser-

vation that dysembryoplastic neuroepithelial tumors can

be epileptogenic foci (10, 11, 13). Although this patient’s

EEG did not show frank epileptic activity, abnormal elec-trical activity associated with seizures was detected on at

least one occasion, and at some point the tumor may have

affected the activity of neurons in the left frontal cortex

and contributed to his abnormal behaviors.

This case supports other studies demonstrating that

neurosurgical cure of a psychiatric disorder is feasible

(45). Probably the most remarkable aspect of this case is

the fact that the worst of our patient’s long-standing con-

duct disorder traits resolved within hours of neurosurgery.

Our patient had a remarkable recovery, but several key is-

sues need to be addressed. The impetus for neurosurgery

in our patient was tumor growth, not cure of his behav-

ioral problems. Forecasting neuropsychiatric cure after

frontal lobe surgery for tumor removal is difficult at best as

differences in tumor size, subtleties in surgical technique,

and susceptibilities of different brain regions to operative

trauma have left patients like ours with a worsening clini-

cal course, such as postoperative psychosis or epilepsy

(46, 47). The prognosis is worse when bulky tumors de-stroy a larger volume of the brain parenchyma, fundamen-

tally altering the neuroanatomical substrates of behavior.

Fortunately, our patient’s tumor was relatively small, well

circumscribed, and surgically accessible, requiring only

partial removal of the overlying anterior cingulate gyrus

and cingulum. Partial cingulotomy may have even con-

tributed to our patient’s psychiatric improvement, as sev-

eral reports have indicated that cingulotomy is an effective

treatment for chronic pain, intractable depression, and

medication-resistant OCD (48, 49).

Pharmacological management of psychiatric illnesses is

the cornerstone of modern psychiatry, but this case shows

that medication failures may occur in the setting of an un-derlying brain tumor. Our patient was treated with a num-

ber of different medication combinations over the course

of 9 years. Both by the patient’s report and according to his

mother and professional staff at the residential treatment

facility, the side effects of polypharmacy made him very

uncomfortable and probably did little to control his ex-

treme behavior. In fact, 3 weeks before surgery, our patient

elected to discontinue all psychiatric medications in favor

of reduced side effects, yet his behavior did not worsen

during that time. These clinical observations suggest that

the deleterious effects of the dysembryoplastic neuroepi-

thelial tumor were far beyond the reach of the then-cur-

rent neuropsychiatric pharmacopeia.

Conclusion

This case study is one of a handful of reports of near-in-

stantaneous cure of a psychiatric disorder following the re-

moval of a frontal lobe tumor. It illustrates how a more

thorough understanding of regional frontal lobe function

as it pertains to behavior, cognition, and mood may be

helpful when we attempt to use clinical observations to de-

duce the location of a putative frontal lobe mass. Although

exceptions exist, dorsolateral frontal lobe lesions shape

mood, volition, and executive function; orbitofrontal le-

sions affect socialization; ventromedial lesions have an ef-

fect on aspects of foresight and reversal learning; and ante-rior cingulate lesions influence awareness, concentration,

error detection, and affect-mood congruence. Small le-

sions in the frontal white matter, which can affect efferent

impulses originating from widespread prefrontal areas,

may produce a wider array of aberrant behaviors than sim-

ilarly sized lesions confined to a single area of the overlying

cortex. Furthermore, this case emphasizes that frontal lobe

masses causing severe psychiatric disturbances may bene-

fit from evaluation for neurosurgery. Such an evaluation

may not be prioritized when there is no evidence of malig-

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nancy or significant mass effect, but our case suggests that

surgery may potentially lead to significant clinical im-

provement even in the context of longstanding psychiatric

symptoms. In cases in which neurosurgery might damage

critical anatomy, drug therapy is usually warranted, but we

should expect more frequent medication treatment fail-

ures in this patient population.

Received Sept. 19, 2006; revision received Jan. 30, 2007; acceptedFeb. 9, 2007. From Drexel University College of Medicine, Philadel-

phia; and the Department of Psychiatry, Hahnemann University Hos-

pital. Address correspondence and reprint requests to Dr. Mathews,

Department of Psychiatry, Hahnemann University Hospital, Broad

and Vine St., Philadelphia, PA 19102; [email protected]

(e-mail).

The authors thank Drs. Richard Roth, Myrna Miller, and Sandra Kof-

fler for criticisms of earlier versions of the article.

CME DisclosureThe authors report no competing interests.

APA policy requires disclosure by CME authors of unapproved or in-

vestigational use of products discussed in CME programs. Off-label

use of medications by individual physicians is permitted and com-

mon. Decisions about off-label use can be guided by scientific litera-

ture and clinical experience.

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