Wirginia Maixner

Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer.

We conducted a phase 1 study of 9 pediatric patients with recurrent brain tumors using monocyte-derived dendritic cells pulsed with tumor RNA to produce antitumor vaccine (DCRNA) preparations. The objectives of this study included (1) establishing safety and feasibility and (2) measuring changes in general, antigen-specific, and tumor-specific immune responses after DCRNA. Dendritic cells were derived from freshly isolated monocytes after 7 days of culture with IL-4 and granulocyte-macrophage colony-stimulating factor, pulsed with autologous tumor RNA, and then cryopreserved. Patients received at least 3 vaccines, each consisting of an intravenous and an intradermal administration at biweekly intervals. The study showed that this method for producing and administering DCRNA from a single leukapheresis product was both feasible and safe in this pediatric brain tumor population. Immune function at the time of enrollment into the study was impaired in all patients tested. While humoral responses to recall antigens (diphtheria and tetanus) were intact in all patients, cellular responses to mitogen and recall antigens were below normal. Following DCRNA vaccine, 2 of 7 patients showed stable clinical disease and 1 of 7 showed a partial response. Two of 7 patients who were tested showed a tumor-specific immune response to DCRNA. This study showed that DCRNA vaccines are both safe and feasible in children with tumors of the central nervous system with a single leukapheresis.

Hypothalamic hamartomas—clinical, neuropathological and surgical aspects

IntroductionHypothalamic hamartomas are rare congenital lesions of the tuber cinereum presenting with the classic triad of gelastic epilepsy, central precocious puberty and developmental delay. The clinical course in the majority is one of progression, commencing with gelastic seizures in infancy, deteriorating into more complex seizure disorders and resulting in a catastrophic epilepsy associated with a concomitant cognitive and behavioural decline.ObservationElectrophysiological, radiological and pathophysiological studies have confirmed the intrinsic epileptogenicity of the hypothalamic hamartoma. Secondary generalised epilepsy seen in this condition is theorised to be through propagation via the mamillothalamic pathways with attachment to the mamillary bodies identified on MRI. Indications as to timing for surgery remain ill-defined although there is a theoretical argument to intervene before the development of secondary generalised epilepsy.Surgical approachCurrently, the most effective surgical route appears to be the transcallosal anterior interforniceal approach although newer approaches of endoscopic disconnection and radiosurgery are being assessed.

Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3

We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole‐exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator‐like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated individuals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging–negative focal epilepsy. ANN NEUROL 2016;79:132–137

Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5

Whole‐exome sequencing of two brothers with drug‐resistant, early‐onset, focal epilepsy secondary to extensive type IIA focal cortical dysplasia identified a paternally inherited, nonsense variant of DEPDC5 (c.C1663T, p.Arg555*). This variant has previously been reported to cause familial focal epilepsy with variable foci in patients with normal brain imaging. Immunostaining of resected brain tissue from both brothers demonstrated mammalian target of rapamycin (mTOR) activation. This report shows the histopathological features of cortical dysplasia associated with a DEPDC5 mutation, confirms mTOR dysregulation in the malformed tissue and expands the spectrum of neurological manifestations of DEPDC5 mutations to include severe phenotypes with large areas of cortical malformation.

Familial cortical dysplasia caused by mutation in the mTOR regulator NPRL3

We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole‐exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator‐like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated individuals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging–negative focal epilepsy. ANN NEUROL 2016;79:132–137

Multiple Factors Contribute to Neuropsychological Outcome in Children With Posterior Fossa Tumors

Cognitive deficits are frequently reported in children treated for posterior fossa (PF) tumors. A range of tumor, treatment, medical and treatment complications have been implicated in causing a variety of cognitive deficits. The aim of this study is to identify factors that influence intelligence, attention and information processing in these children. Thirty-five children (aged 4–16) with PF tumors attending the Royal Childrens Hospital Melbourne, Australia, were enrolled into a prospective, repeated measures design. Neuropsychological assessments were conducted at diagnosis and at 12 month intervals for three years. The results find that the PF tumor, hydrocephalus, white matter injury and radiation therapy have various impacts on intelligence, attention and information processing skills, and contribute to the long term outcome in children treated for PF tumor. The neurological structures that subserve the efficient function of attention and information processing are particularly vulnerable to those factors.

Acute Childhood Arterial Ischemic and Hemorrhagic Stroke in the Emergency Department

STUDY OBJECTIVE Little is known about the presenting features of acute ischemic and hemorrhagic stroke in children presenting to the emergency department (ED). Yet, initial clinical assessment is a key step in the management pathway of stroke. We describe the presentation in the ED of children with confirmed acute ischemic and hemorrhagic stroke subtypes. METHODS We conducted a retrospective descriptive case series of consecutive patients aged 1 month to younger than 18 years and presenting to a single-center tertiary ED with radiologically confirmed acute ischemic stroke or hemorrhagic stroke during a 5-year period. Patients were identified by medical record search with International Classification of Diseases, 10th Revision codes for hemorrhagic stroke and through the hospital stroke registry for acute ischemic stroke. Signs, symptoms, and initial management were described. RESULTS Fifty patients with acute ischemic stroke and 31 with hemorrhagic stroke were identified. Mean age was 8.7 years (SD 5.2), and 51% were male. Fifty-six percent were previously healthy. Median time from onset of symptoms to ED presentation was 21 hours (interquartile range 6 to 48 hours) for acute ischemic stroke and 12 hours (interquartile range 4 to 72 hours) for hemorrhagic stroke. Acute ischemic stroke presented with symptoms of focal limb weakness (64%; 95% confidence interval [CI] 49% to 77%), facial weakness (60%; 95% CI 45% to 73%), and speech disturbance (46%; 95% CI 31% to 60%). Few patients with acute ischemic stroke presented with vomiting and altered mental status. Most patients with acute ischemic stroke had a Glasgow Coma Scale (GCS) score of 14 or greater (86%; 95% CI 73% to 94%) and presented with at least 1 focal neurologic sign (88%; 95% CI 73% to 98%). Hemorrhagic stroke presented with headache (73%; 95% CI 54% to 87%), vomiting (58%; 95% CI 40% to 75%), and altered mental status (48%; 95% CI 30% to 67%). GCS score in hemorrhagic stroke was less than 14 in 38% and less than 8 in 19% (95% CI 7% to 37%). Less than one third of patients had focal limb weakness, facial weakness, or slurred speech. Nineteen percent of patients with hemorrhagic stroke were intubated in the ED and admitted to the ICU. None of the acute ischemic stroke patients were intubated in the ED, and 4% were admitted to the ICU. CONCLUSION Diagnosis of stroke in children with acute ischemic stroke and hemorrhagic stroke was delayed. Acute ischemic stroke presented mainly with focal findings; hemorrhagic stroke, with headache, vomiting, and mental status change.

Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring

ABSTRACT Objective: We sought to identify intracranial EEG patterns characteristic of epileptogenic tubers and to understand the contribution of perituberal cortex. Methods: Twenty-three intracranial EEG monitoring studies were reviewed from 17 children aged 1.3–7.7 years with tuberous sclerosis complex and intractable multifocal epilepsy, 14 with a history of epileptic spasms. Interictal epileptiform discharges and ictal rhythms for 60 electroclinically distinct seizures (EDS) were analyzed in relation to 162 sampled tubers. Results: Localized, tuber-related, ictal rhythms were seen in 49/60 EDS, most commonly as low-voltage fast activity recruiting to rhythmic spiking, then diffuse slowing or bursts of ripple range activity. Ictal onset in localized EDS involved only tubers in 57% and tubers with perituberal cortex in 31%. Ictal fast ripples (FR) noted at seizure onset in 15/38 localized EDS were confined to tubers in 73% and involved tuber with perituberal cortex in 27%. Intraictal activation occurred during seizure propagation in 19 localized EDS, being to tubers in 63% and to tubers with perituberal cortex in 37%; 63% of activated tubers generated independent EDS. Trains of periodic sharp waves on an attenuated background were seen interictally at 36/162 tubers, with 67% of those tubers generating EDS (p = 0.0001). Interictal FR, when present, involved tubers more commonly than perituberal cortex but were not associated with EDS. Conclusion: The study demonstrates interictal and ictal intracranial EEG findings characteristic of epileptogenic tubers, suggests that tubers play a greater role in seizure genesis than perituberal cortex, and suggests tuberectomy may be a sufficient surgical approach in a number of patients.

The surgically remediable syndrome of epilepsy associated with bottom-of-sulcus dysplasia

Objective: To determine clinical and EEG features that might help identify patients with epilepsy harboring small, intrinsically epileptogenic, surgically treatable, bottom-of-sulcus dysplasias (BOSDs). Methods: Retrospective review of clinical records, EEG, MRI, and histopathology in 32 patients with drug-resistant epilepsy and MRI-positive (72% 3.0 tesla), pathologically proven (type 2B cortical dysplasia) BOSDs operated at our centers during 2005–2013. Results: Localization of BOSDs was frontal in 19, insula in 5, parietal in 5, and temporal in 3, on the convexity or interhemispheric surfaces. BOSDs were missed on initial MRI at our centers in 22% of patients. Patients presented with focal seizures during infancy in 9, preschool years in 15, and school years in 8 (median age 5 years). Seizures were stereotyped, predominantly nocturnal, and typically nonconvulsive, with semiology referable to the fronto-central or perisylvian regions. Seizures occurred at high frequency during active periods, but often went into prolonged remission with carbamazepine or phenytoin. Intellect was normal or borderline, except in patients with seizure onset during infancy. Scalp EEG frequently revealed localized interictal epileptiform discharges and ictal rhythms. Patients underwent lesionectomy (median age 14 years) guided by electrocorticography and MRI, with prior intracranial EEG monitoring in only one patient. Twenty-eight patients (88%) became seizure-free, and 20 discontinued antiepileptic medication (median follow-up 4.1 years). Conclusions: In patients with cryptogenic focal epilepsy, this clinical presentation and course should prompt review of or repeat MRI, looking for a BOSD in the frontal, parietal, or insula cortex. If a BOSD is identified, the patient might be considered for single-stage lesionectomy.

Intelligence and adaptive function in children diagnosed with brain tumour during infancy

BackgroundLate effects of treatment in children diagnosed and treated for brain tumours in infancy is a major concern. Assessment of infants presenting with brain tumours is difficult and there is little information available regarding the development of infants prior to treatment and hence the impact of the tumour itself on developmental outcomes.AimTo describe the development of children diagnosed with brain tumours in infancy and to document their cognitive and adaptive function at school entry.MethodInfants were psychologically evaluated at the time of diagnosis of a brain tumour and during their fifth or sixth year in preparation for school entry.ResultsChildren diagnosed with brain tumours in infancy display developmental delays in a number of areas of adaptive function. By the time these children are school age they display further compromise in cognitive and academic skills and adaptive behaviour. Higher levels of deficit at follow-up were associated with tumour location in the supratentorium, younger age at diagnosis and longer time since diagnosis. The effect of radiotherapy could not be determined because of differing degrees of developmental compromise in the treatment groups at baseline.ConclusionBrain tumours in infancy confer a risk of poor developmental progress at the time of diagnosis. These children display additional compromise of development by the time they reach school age. Research protocols evaluating the impact of treatment in infants diagnosed with brain tumours need to take account of the developmental status of the child at diagnosis.