Dramatic clinical and radiographic response to BRAF inhibition in a patient with progressive disseminated optic pathway glioma refractory to MEK inhibition.

While clinical and radiographic responses to agents targeting the mitogen-activated protein kinases (MAPK) pathway have been repor-ted in pediatric low-grade gliomas (LGG), early phase trials indicate refractoriness to these medications in some of these patients. We report a patient with disseminated LGG with the BRAFV600E mutation, which was refractory to selumetinib, a MEK inhibitor, but subsequently showed immediate clinical and radiographic response to dabrafenib, a BRAF inhibitor, with sustained effect for 9 months prior to clinical progression. In LGGs, treatment resistance to one agent targeting the MAPK pathway might not imply refractoriness to other agents targeting this pathway.

Identification and prevention of antiepileptic drug noncompliance: the collaborative use of state-supplied pharmaceutical data.

Background. Antiepileptic drugs (AEDs) noncompliance is associated with increased risk of seizures and morbidity in seizure disorder patients. Objective. To identify risk factors that correlated to higher levels of morbidity, measured by emergency room (ER) utilization by seizure disorder members taking AED. Methods. Patients with primary or secondary diagnosis of seizures, convulsions, and/or epilepsy and prescribed AEDs during an 11-month period were included in the study. Variables were analyzed using multivariate statistical analysis including logistic regression. Results. The study identified 201 members. No statistical significance (NS) between age, gender, number of tablets, type of drug, or other risk factors was associated with increased mortality. Statistical significance resulted with medication compliance review of 0-14 days, 15-60 days, and 61+ days between refills. 68% of patients with ER visit had noncompliance refill between 0 and 14 days compared to 52% of patients in non-ER group (P = 0.04). Contrastingly, 15% of ER group had refills within 15-60 days compared with 33% of non-ER group (P = 0.01). There was NS difference between two groups when noncompliance was greater than 60 days (P = 0.66). Conclusions. The study suggests that careful monitoring of pharmaceutical refill information could be used to identify AED noncompliance in epileptic patients.

Phenotypic manifestations of copy number variation in chromosome 16p13.11.

The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.

Dual pathology in Rasmussen's encephalitis: a study of seven cases and review of the literature.

Dual pathology has previously been reported in less than 10% of cases of Rasmussen's encephalitis (RE). Given the rarity of RE, it appears unlikely that dual pathology in RE is merely a coincidence. We therefore reviewed all cases of RE experienced in our institution to assess for an additional/associated pathology. A total of seven patients with RE were identified in our archives. Seven children (4 boys and 3 girls, age range: 3-16 years, mean: 9.5 years) with medically refractory epilepsy underwent surgical resection for intractable seizures. The surgical specimens were examined with routine neurohistological techniques, and immunohistochemistry was performed with an extensive panel of antibodies for viruses, lymphocytes, microglia/macrophages, human leukocyte antigen (HLA)-DR, astrocytes, and neurons. Relevant literature was reviewed. Microscopically, all seven cases demonstrated the inflammatory pathology of RE in the cortex and white matter with leptomeningeal and perivascular lymphocytic infiltration, microglial nodules with/without neuronophagia, neuronal loss and gliosis. The HLA-DR antibody was extremely helpful in highlighting the extent of microglial cell proliferation/activation that was not appreciable with standard histology. An unexpected finding in all seven cases was the presence of cortical dysplasia. In our series of seven cases, there was co-occurrence of the inflammatory/destructive pathology of RE with malformative/dysplastic features in cortical architecture in 100% of cases, raising questions about the possible relationships between the two entities. Awareness of the possibility of dual pathology in RE is important for clinical and pathological diagnosis, and may affect the management and outcome of these patients. Immunohistochemistry is very helpful to make a definitive diagnosis of both pathologies.

Spinocerebellar ataxia type 2 presenting with cognitive regression in childhood.

Spinocerebellar ataxia type 2 typically presents in adulthood with progressive ataxia, dysarthria, tremor, and slow saccadic eye movements. Childhood-onset spinocerebellar ataxia type 2 is rare, and only the infantile-onset form has been well characterized clinically. This article describes a girl who met all developmental milestones until age 3(1/2) years, when she experienced cognitive regression that preceded motor regression by 6 months. A diagnosis of spinocerebellar ataxia type 2 was delayed until she presented to the emergency department at age 7 years. This report documents the results of her neuropsychologic evaluation at both time points. This case broadens the spectrum of spinocerebellar ataxia type 2 presentation in childhood, highlights the importance of considering a spinocerebellar ataxia in a child who presents with cognitive regression only, and extends currently available clinical information to help clinicians discuss the prognosis in childhood spinocerebellar ataxia type 2.

Use of the newer antiepileptic drugs in pediatric epilepsies.

Children with epilepsy, particularly infants, differ from adults not only in the clinical manifestations of their seizures but also in the presence of unique electroencephalographic patterns, etiologies, and response to antiepileptic drugs (AEDs). There is a growing list of newer AEDs and nonpharmacologic therapies available to manage childhood epilepsy. These newer AEDs may not be overall more efficacious than the older drugs, but they do appear to be safer, better tolerated, and to have fewer drug-drug interactions. Selection of the AED for initial therapy must be based upon clinical judgment and patient-specific circumstances, such as the specific epilepsy syndrome being treated, anticipated duration of treatment, presence of comorbidities, ability to use certain formulations, and overall cost effectiveness. In some cases, seizures may be aggravated by the use of certain AEDs. Overall, oxcarbazepine is the first-line treatment for localization-related epilepsy with partial-onset seizures. For generalized epilepsies, the AED choice is highly dependent upon which specific syndrome is being treated. For generalized epilepsies with primarily absence seizures, lamotrigine is the AED of first choice. For mixed generalized epilepsies such as Lennox-Gastaut syndrome or juvenile myoclonic epilepsy, zonisamide or topiramate are the first-line agents. For infants with West syndrome, treatment is based upon the underlying etiology: vigabatrin for tuberous sclerosis; adrenocorticotropic hormone for children with no specific etiology uncovered (cryptogenic); and zonisamide for those with a severe symptomatic etiology other than tuberous sclerosis. Single drug therapy (monotherapy) is the goal of epilepsy treatment because this is associated with better compliance, fewer adverse effects, and lower cost. If the seizures prove intractable or adverse effects are encountered with the first AED, then a second monotherapy trial is undertaken. Once three appropriate medications at therapeutic doses have failed, other modalities should be considered, including epilepsy surgery, vagus nerve stimulation, and the ketogenic diet.