B.W. is a 14 year-old right-handed Caucasian boy. He lives in a small Midwest town with his biological parents and 5 full biological siblings of which he was the second born. His parents are both college-educated; his father is an engineer and his mother a homemaker and former teacher. Through several interactions with the parents they have been regarded as pleasant, caring, and intelligent. The family history is notable for the absence of anyone with seizures or behavioral problems. The only psychiatric history in the family is mild generalized anxiety symptoms in the father and B.W.'s older sister that have not required treatment. B.W.' s mother had routine prenatal care and he was delivered at term without complications. B.W. developed normally and met all major developmental milestones on time. He had an unremarkable medical history until four years of age, at which time he began to have discrete fifteen second episodes of unresponsiveness characterized by facial flushing, hand-wringing, increased heart rate, and incoherent fearful speech followed by laughing. These episodes occurred every 30 to 40 minutes for a few days, prompting evaluation by a pediatric neurologist. A diagnostic workup included routine laboratory tests, a head computed tomography (CT), a brain magnetic resonance imaging (MRI) scan, and an electroencephalogram (EEG). The EEG showed a seizure tendency and one seizure was captured with a focal origin (focal site not reported). Other study results were reportedly within normal limits. He was started on divalproate (Depakote) with complete resolution of seizures. A subsequent review of the locally obtained brain MRI seven years later would reveal a vmPFC malformation (described below).

At age six B.W.'s parents reported the onset of defiance at home and at school, including: stealing, lying, aggression, rage, rude language, and disobedience. His parents referred to this as his 'contraband' period because he would consistently bring prohibited items to school (e.g. a pocketknife). He also stole cookies and would sell them to peers. The parents were very concerned about this behavior because it did not seem characteristic of B.W.'s previous temperament. Moreover, neither parent nor any sibling of B.W. had similar behavioral problems. He was seen by a child psychologist and diagnosed with oppositional defiant disorder and started counseling, which was discontinued after a few visits.

During ages seven to nine B.W.'s parents describe a 'cause and effect problem' in which he would behave badly and be punished and the following day would engage in the same behavior that led to the punishment. Along with his lack of response toward punishment, B.W. was impulsive and showed a lack of respect toward authority, including teachers and parents. In an effort to provide greater structure and discipline than the school could provide the parents decided to begin home-schooling B.W. and his siblings when he was nine years old (fourth grade). At the onset of home-schooling the mother noted a stark contrast between B.W. relative to his well-behaved siblings. Despite behavioral problems and lack of self-motivation he was noted to be intelligent and academically capable. The following year a child psychiatrist diagnosed B.W. with attention deficit hyperactivity disorder and bipolar disorder, for which he was prescribed carbemazepine, topiramate, and dexmethylphenidate. Counseling was again attempted briefly without effect.

At age 11 B.W. presented to the emergency room of a large tertiary care center with his mother for suicidal ideation. While at a nearby shopping mall he expressed feelings of hopelessness, unworthiness, and wanting "to kill myself... I would cut or burn myself." The talk of suicide had been ongoing for two months and had been accompanied by suicidal gestures such as jumping from a second story deck onto a trampoline and a superficial laceration to the left hand because "I wanted to kill myself." Along with the suicidal gestures the parents were alarmed about escalating aggression, destructive behavior, wandering off, and hypersexual behavior that included masturbation, accessing porn sites on the web, and asking younger peers to disrobe in a domineering manner (despite being pre-pubescent at the time). During the admission interview he reported that he had been hearing voices at night from God and the devil motivating him to do good and bad things, respectively.

B.W. was hospitalized for one week on the child psychiatry service (at which point he become known to the author, A.D.B.). He underwent extensive neuropsychological and psychiatric evaluation. His verbal and nonverbal intellectual abilities were measured using the Wechsler Abbreviated Scale of Intelligence and found to be within the average and high average range, respectively (verbal IQ 94, performance IQ 116)[29]. He endorsed extremely high levels of depression and anxiety symptoms on the Beck Depression and Anxiety Inventories for Youth (T score values of 81 for anxiety and 84 for depression), but these symptoms appeared incongruent with his mood and affect [30]. While observed on the inpatient unit B.W. displayed neutral affect though rarely had outbursts that were induced by frustration. His outward manifestations of depression were transient and thought to be manipulative in nature toward the staff and parents. On projective testing using Rotter's Incomplete Sentences [31] B.W. expressed his anger at being told no when people prevented him from carrying out his desires, which often focused on acquiring objects. My biggest problem is..."I can't get a cell phone". The worst thing that ever happened to me was..."my mom and dad saying no to it", and my mother should... "let me do some stuff that I want". The pediatric neuropsychologist conducting the tests reported that B.W. attempted to manipulate and control the interview and was angered when requests for items belonging to the examiner were denied.

It became apparent that B.W. wanted to stay in the hospital for an extended period, ("at least a month") for reasons that were not clear. When he spoke with the staff and with his parents he persistently bargained for items that would improve his mood when he returned home. He was fixated on getting a cellular phone, an electric scooter, and his own bedroom. The parents and staff became suspicious that the mood symptoms and psychosis that prompted hospitalization may have been contrived for these secondary gains. This deception may have contributed to the discrepancy in B.W,'s high subjective reports of depression and anxiety that did not match his neutral affect. The parents confirmed a long history of being manipulative in multiple settings, often for the purpose of acquiring toys or avoiding punishment. For example, he would persuade his friends to allow him to spend the night at their house and would return home with their prized goods (e.g. toys, clothes, shoes). He had a history of persuading his friends to steal money from their parent's purse or wallet for him. While hospitalized B.W. lied on occasion in an attempt to receive rewards such as small toys and credit for playing video games that he did not earn. He also attempted to spread lies among the staff that his parents were not comfortable taking him home as his discharge approached. He was given the following psychiatric diagnoses according the diagnostic and statistical manual of mental disorders (DSM-IV): oppositional defiant disorder, attention deficit and hyperactivity disorder (ADHD) combined subtype, and mood disorder not otherwise specified [32]. None of these diagnoses captured what was believed to be the core deficit, his ability and willingness to manipulate others as he pursued his own interests, which, at this point in his life, focused on the acquisition of prized items such as a cellular phone. Months later during a follow-up psychiatry visit he reported that he never intended to harm himself and did not hear voices.

Following this hospitalization B.W. responded poorly to a behavioral incentive program and his antisocial behavior escalated. Within a couple of months he had several very serious altercations. He set fire to a piece of furniture in his home and to multiple items in the church his family attends, because he "doesn't like to go to church." He was apprehended by police during an attempted break-in-and-entry where he was alone and in possession of a hammer, a box cutter, and a lighter. He assaulted his principal and then resisted the arresting officer. He began stealing and lying constantly without remorse. He threatened his mother with a knife. Of most concern to the family was a malicious attack on his father. On the night before the attack he had to be restrained by his father for fear of hurting a sibling. To revenge the unwanted restraint he snuck up from behind his father the following day and delivered a blow to his father's head with a crescent wrench in a planned attack. His father said the most concerning aspect of the episode was that he did it "in cold blood, without any emotion."

Neurology Evaluation

From age six to eleven B.W. had sporadic clusters of complex partial seizures occurring once every several months. The seizure frequency increased in parallel with the rise in behavioral problems in the months following psychiatric hospitalization at age eleven, prompting reevaluation by pediatric neurology (where he was seen again by A.D.B. along with C.J.). An MRI at this time showed evidence of a previously undetected vmPFC malformation (described in next section). He underwent an extensive diagnostic evaluation in an attempt to detect the seizure focus, including two inpatient admissions at major university hospitals. Video EEG monitoring captured 7 seizures with evidence of left frontal anterior-temporal onset in four, right-sided onset in one, and unclear laterality in two others. An ictal SPECT study showed increased perfusion diffusely in the left hemisphere, suggestive of a left-sided seizure focus but not localized further.

Neuroimaging Results

Three of B.W.'s MRI studies of the brain were reviewed in detail and form the basis for our description. Two 1.5 Tesla (T) MRI examinations were done for clinical indications at ages four and eleven years, and a 3.0T MRI scan was done at age thirteen years for research purposes. The main finding was persistent and stable increased T2-signal intensity in the subcortical white matter of the left gyrus rectus in the vmPFC. This abnormal signal was best seen on thin section coronal T2-weighted and FLAIR sequences, and did not enhance following contrast administration (Figure 1A). Linear extension and tapering of the T2-hyperintense abnormality towards the frontal horn of the left lateral ventricle presumably reflects a radial neuronal migration line. Associated focal abnormal thickening of the cortex and blurring of the gray-white matter junction along the gyrus rectus were also evident (Figure 1B). These findings were stable between the patient's three available MRI studies. This constellation of MRI findings was thought to be compatible with Taylor type focal cortical dysplasia (FCD) with balloon cells, though confirmation of this subtype of FCD was not confirmed on histological analysis (see below) [33, 34]. No other abnormalities of the brain were identified. The region of affected cortex is displayed in Figure 1C using thickness data generated from FreeSurfer software http://surfer.nmr.mgh.harvard.edu/. The lesion appears to involve a portion of Brodmann areas 11, 12, 25, and 32. See appendix for details regarding the generation of Figure 1C.

Figure 1 MRI Images. 1A. This is an oblique coronal T2 image at the level immediately anterior to the horn of the lateral ventricles. Note the hyperintense white matter just deep to the gyrus rectus (indicated by arrow) with a linear extension tapering as it courses toward the anterior horn of the ventricle. Also note the cortical thickening of the left gyrus rectus relative to the right gyrus rectus. 1B. This coronal T1 MPRAGE image shows thickening of the left ventromedial prefrontal cortex and blurring of the gray-white interface in this same region. 1C. This is a surface rendering of B.W.'s brain viewing the medial left hemisphere surface with thickened cortex highlighted, which approximates the lesion site. See the appendix for further information on 1C. Full size image

Therapeutic Attempts\Surgical Resection

Therapeutic interventions for B.W.'s behavioral problems have included brief attempts at counseling beginning at age six and again at age nine, behavioral incentive therapy at age 11, and a panoply of medication trials. B.W. eventually underwent invasive grid mapping and subsequent resective epilepsy surgery in the summer of 2011. After extensive invasive mapping of the left ventromedial prefrontal region and also the left temporal area using grids and depth electrodes he underwent resection of the left prefrontal region as well as the mesial and lateral temporal structures. Pathology confirmed the presence of dysplastic neurons in clusters as well as scattered in the white matter of the left ventral prefrontal region and left amygdala, including surrounding mesial temporal cortex. The left amygdala region had been silent on MRI, however microscopic dysplastic neurons have been well described in other cases of malformations of cerebral cortex. B.W. remains seizure free on lamotrigine as the only drug for seizure control.

Behavioral and Neuropsychological Testing

In addition to an extensive review of B.W.' s medical records, interviews with the family, and careful review of a detailed journal the parents kept detailing B.W.'s problem behavior we also obtained further behavioral and neuropsychological data. Informed consent was obtained in accord with the policies of the Institutional Review Board of the University of Iowa Carver College of Medicine. To serve as an intra-family comparison group we also obtained behavioral results for the siblings when possible (newborn and toddler excluded). All testing was performed when B.W. was 13, prior to surgical resection of the vmPFC lesion.

Behavioral Questionnaires

B.W.'s parent(s) filled out the Child Behavior Checklist [35], the Antisocial Process Screening Device [36], and a version of the Iowa Scales of Personality Development (ISPD) [23] developed specifically for children with brain lesions [37]. The CBCL is a broad parent-completed questionnaire that examines a broad spectrum of childhood behavioral and emotional problems. The APSD is a parent-completed screening tool to evaluate for affective and interpersonal character traits of psychopathy. The ISPD is a tool developed to assess behavioral, emotional, and personality traits following childhood-onset brain damage. Items commonly associated with bilateral vmPFC damage are shown in bold. Specifically these items were rated as acquired disturbances (defined as a rating > 5) by over 70% of patients with bilateral vmPFC damage or were significantly higher in patients with vmPFC damage relative to non-prefrontal injuries (p < 0.001) [23]. The results of the CBCL, APSD, and ISPD are shown in Table 1. Superscripts in B.W.'s ISPD ratings denote statements and clarifications provided by B.W.'s mother.

Table 1 Behavioral Questionnaire Results Full size table

Based on B.W.'s propensity for acquiring material items we also evaluated whether he had pathological collecting behavior using a standardized questionnaire, which has been used previously to demonstrate pathological collecting behavior in vmPFC patients [38]. We found that B.W. did collect quarters and pocket knives, but not extensively and the parents never considered this to be out of the ordinary. The parents reported that B.W. had difficulty throwing unneeded items away and had a tendency to accumulate useless items in Tupperware containers in his room (e.g. parts of watches, pieces of broken chairs, disassembled bike parts, buttons, ect.). The mother would periodically dispose the items so they never accumulated. He did not hoard food items. No collecting behavior data was gathered for the siblings.

Neuropsychological Testing

B.W. completed additional neuropsychological testing to assess his executive functioning abilities. On testing, he showed average set-shifting skills on the Trail-Making Test [39]. On the Wisconsin Card Sorting Task [40], he did not have difficulty with nonverbal concept formation or set-shifting. Perseverative errors and responses were minimal (superior range on both indices). Verbal fluency skills were solidly average on the Controlled Oral Word Association Test (COWA; [41]) and no set- losses or perseverative tendencies were observed. However, his performance on a design fluency task was somewhat perseverative. On a measure of attention, flexibility and ability to inhibit responses (Stroop Color and Word Test; [42], B.W. showed a normal performance across subtests. He had some difficulty with thinking ahead and planning on the Tower of Hanoi [43]. Specifically, once he got the correct concept on this task, he was not able to consistently use the information to repeat the task. Learning from consequences was also a weakness for B.W. His performance on the Iowa Gambling Task [44] suggested no learning and he was not able to determine which were good versus bad decks.

Moral Judgement

B.W. completed the Kohlberg Moral Judgement Task [45] and he and his siblings completed a paper-and-pencil version of the moral\convention distinction task [46]. Responses on the Kohlberg Moral Judgment Task suggested a relatively immature, preconventional, stage of moral development, in which moral dilemmas were approached primarily from the perspective of avoiding negative consequences for one's self. In the moral\convention distinction task B.W. and all of his siblings appropriately labeled moral transgressions as worse than conventional ones, particularly those causing physical pain to others. Qualitatively B.W. cited pain as a reason for not punching someone in the face, and for a story involving pulling a girls hair he stated that 'boys should never hurt a girl.' In terms of moral transgressions that damage property B.W. cited possible detention as the reason why it would not be acceptable to break a swing on the playground. It is noteworthy that all the siblings completed the task including those younger than B.W. On his first attempt, B.W. skipped several questions and scribbled over the entire second sheet and drew a goblin. He completed the task at a later date.