Behavioral disorders as unusual presentation of pediatric extraventricular neurocytoma: report on two cases and review of the literature

Extraventricular neurocytoma (EVN) is a parenchymal brain tumor distinct from central neurocytoma. It is most commonly located in the frontal and parietal lobes [1] and included in the 2007 World Health Organization (WHO) classification of tumors of the central nervous system [2].

Although the incidence of EVN in childhood is not known, it is certainly a rare tumor. It is composed by either glial or neuronal cell differentiation. EVNs have a potential aggressive behavior based on the MIB-1 labeling index (>3%) and on atypical histological features. They are mostly confused with oligodendrogliomas or ependymomas [3]. Clinical symptoms are usually dependent on side and size tumor. Partial seizures and headache represent the most frequent clinical presentation of EVN. Even though the EVNs are commonly located in the frontal lobe, behavioral or cognitive development disorders have never been described as presentation symptoms.

Written informed consent was obtained from the patients’ parents for publication of this Case report and any accompanying images. We report on two cases of extraventricular neurocytoma in two children referred to the Neuropsychiatry Unit of Bambino Gesù Children’s Hospital in Rome with the diagnosis of attention deficit/ hyperactivity disorder (ADHD). We further reviewed 43 pediatric cases of EVN included in the PubMed database with particular reference to onset symptoms.

Neurocytoma is a rare tumor of the central nervous system, mainly recognized within the ventricular system adjacent to the Monro’s foramina in middle-aged patients. It displays both neuronal and glial differentiation. Extraventricular neurocytoma was introduced as a separate entity from central neurocytoma in the 2007 World Health Organization (WHO) classification of CNS tumors [2], because of a parenchymal site and a more aggressive neurobiological behaviour. EVN has a marked tendency to glial differentiation [4]. Raised intracranial pressure symptoms are commonly associated to the presence of these lesions, not only due to the size of the lesion but also to the perilesional edema. It can also rarely occur in childhood. Data from the literature about EVNs in the pediatric population, derive almost exclusively from case reports. A literature review about pediatric cases of EVNs included in the PubMed database in the last 20 years identified 29 studies, overall 43 patients [5]-[8],[4],[9]-[14],[1],[15]-[31]. Tumor location and presenting symptoms are summarized in Table 1. Lesions were supratentorial in 32 out of 43 cases (74%) and infratentorial in 5 cases (11%). In the remaining six patients (13%) the lesion was located in the spinal cord. Among patients with a supratentorial tumor, EVN was located in the frontal lobe in 20 cases (62.5%), whereas in the remaining 12 patients (37.5%) the tumor location was temporal, parietal, occipital, thalamic or hypothalamic. Age at clinical onset ranged from 1 to 18 years (mean 8.5 yrs). Despite the prevalence of the EVN in the frontal lobe, the seizure activity is the most common presenting symptom, followed by headache and cranial nerve palsy. None of the reported patients had behavioral disorders or ADHD as presenting symptoms. In our patients a diagnosis of ADHD had been made several years earlier than the occurrence of classical symptoms of EVN such headache, vomiting, papilloedema and seizures.

Attention deficit/hyperactivity disorder has to be well defined among the behavioral disorders appearing at school age, in order to avoid misdiagnosis. ADHD defines significant and wide-ranging impairments and affects as many as 3 to 9% of children worldwide. It is based on strict criteria but is often over-diagnosed. The diagnosis of primary ADHD is made by DSM IV criteria when there is no evidence from the history, the physical examination or laboratory findings of any other condition producing a similar clinical picture. Other psychiatric and neurological disorders such as traumatic brain injury, epilepsy and depression can lead to disturbances in attention and/or activity level. In patients with frontal tumor masses and low proliferation index, the attention impairment and behavioral disorders probably result from direct disruption of frontal lobe functioning or disconnection from subcortical afferents.

Our patients were evaluated with cognitive and behavioral assessment at the time of admission, before and after surgery, with one-year follow-up intervals. Clinical history reported by parents showed that language and motor delay had already been present since they were 4-year-old. Therefore we hypothesized a delayed global development, overlooked and underestimated when the ADHD was diagnosed. Cognitive assessment was performed by Wechsler Intelligence Scales for Children (WISC III), documenting a normal range and no significant difference between verbal and performance skills. Behavioral symptoms were clinically investigated and standardized by Child Behavior Checklist (CBCL 6-18) DSM IV oriented, used for children and teenager [32]. Patient 1, preoperatively evaluated, showed an affective (T score = 70) and attention impairment (T score = 70) and a significant anxiety problem (T score = 73). Postoperative assessment, 14 months after surgery, showed no evidence of symptoms previously reported: affective (T score = 67) and attention impairment (T score = 59) and anxiety problem (T score = 66) (Figure 5). Patient 2 showed before surgery affective (T score = 75) and anxiety problem (T score = 73); 12 months after surgery there was a persistence of a affective problems (T score = 75) and a lowering of anxiety problem (T score = 68) (Figure 6). Both patients showed an affective and attention impairment and significant anxiety. Based on these evaluations a diagnosis of ADHD could not be confirmed. Previous formal testing for ADHD diagnosis was not available at the time of admission in the described cases.

Patient 2 had focal seizures shortly before diagnosis and they stopped after surgery, with normal EEG pre and post-operatively. Moreover, the progressive improvement after tumor resection suggests a frontal lobe disfunction as the origin of observed neuro-behavioural symptoms.

Attention deficit hyperactivity disorder is associated with multiple neuropsychological deficits. Several studies underline how difficult it is to make a diagnosis of ADHD. Our experience suggests caution in cases with significant comorbidity before excluding alternative diagnoses.

A recent study, based on electronic records of Emergency Department visits for 87 pediatric patients with brain tumors, retrospectively reviewed from 2002 to 2011, shows that behavior/school change and altered mental status appear with a low frequency, less than 17% [33]. These data are probably justified by brain plasticity during childhood allowing good compensation of neuro-cognitive impairment and resulting in intracranial hypertension as the most frequent symptom at diagnosis.

Our patients underwent gross total resection. Surgical resection remains the main management strategy for a good outcome. When a subtotal surgical resection is performed, radiotherapy could be considered to ensure better local disease control.

Neuropsychological follow-up one year after resection showed progressive behavioral improvement in both patients, suggesting that the initial diagnosis was not ADHD.

Attention deficit in childhood, not symptomatic of other injuries, do not tend to improve with age, while an age-related improvement is possible in hyperactivity disorders. We ascribe the improvement of the behavioural performance to the surgical resection, in our patients. This suggests that the attention deficit/hyperactivity disorder was linked to the presence of the EVN. Our report should stimulate clinicians to be careful to the behavioral disorders in childhood not connectable to a clear neuropsychological diagnosis, such as a poor academic achievement and problematic peer relationship, since they could have an organic etiology.