Faculty Bibliography

We report a patient with a seronegative autoimmune panencephalitis, adding a subtype to the emerging spectrum of seronegative autoimmune encephalitis, and we review the sparse literature on isolated psychiatric presentations of autoimmune encephalitis. (A PubMed search for "seronegative autoimmune encephalitis," "nonvasculitic autoimmune inflammatory meningoencephalitis," and related terms revealed <25 cases.) A 15-year-old girl developed an acute-onset isolated psychosis with prominent negative symptoms and intermittent encephalopathy. Despite clinical worsening, her brain magnetic resonance imaging (MRI) scans remained normal for 7 years. Serology was negative for voltage-gated potassium channel (VGKC)-complex, N-methyl-D-aspartate receptor (NMDAR), and glutamic acid decarboxylase (GAD) autoantibodies. We excluded genetic, metabolic, paraneoplastic, degenerative, and infectious etiologies. The patient's symptoms remitted fully with immune therapy, but recurred in association with widespread bihemispheric brain lesions. Brain biopsy revealed mild nonvasculitic inflammation and prominent vascular hyalinization. Immune therapy with plasma exchanges cleared the MRI abnormalities but, 10 years after onset, the patient still suffers neuropsychiatric sequelae. We conclude that autoimmune panencephalitis seronegative for VGKC-complex, NMDAR, and GAD autoantibodies is a subtype of autoimmune encephalitis that can present with pure neuropsychiatric features and a normal brain MRI. Immunologic mechanisms may account for psychiatric symptoms in a subset of patients now diagnosed with classical psychotic disorders. Delay in starting immune therapy can lead to permanent neuropsychiatric sequelae. We propose a standardized classification system for the autoimmune encephalitides, integrating earlier pathology-oriented terms with more recently defined serologic and clinical phenotypes.

Pilocytic astrocytoma (PA) is a World Health Organization grade I glioma that occurs most commonly in children and young adults. Specific genetic alterations have been described in PA, but the pathogenesis remains poorly understood. We studied microRNA (miRNA) alterations in a large cohort of patients with PA. A total of 43 PA, including 35 sporadic grade I PA, 4 neurofibromatosis-1 (NF1)-associated PA, and 4 PA with pilomyxoid features, as well as 5 nonneoplastic brain controls were examined. BRAF fusion status was assessed in most cases. RNA was examined using the Agilent Human miRNA Microarray V3 platform. Expression of miRNA subsets was validated using quantitative real-time PCR (qRT-PCR) with Taqman probes. Validation of predicted protein targets was performed on tissue microarrays with the use of immunohistochemistry. We identified a subset of miRNAs that were differentially expressed in pediatric PAs versus normal brain tissue: 13 miRNAs were underexpressed, and 20 miRNAs were overexpressed in tumors. Differences were validated by qRT-PCR in a subset, with mean fold change in tumor versus brain of -17 (miR-124), -15 (miR-129), and 19.8 (miR-21). Searching for predicted protein targets in Targetscan, we identified a number of known and putative oncogenes that were predicted targets of miRNA sets relatively underexpressed in PA. Predicted targets with increased expression at the mRNA and/or protein level in PA included PBX3, METAP2, and NFIB. A unique miRNA profile exists in PA, compared with brain tissue. These miRNAs and their targets may play a role in the pathogenesis of PA.

Background: CNS tumors are the second most common cancer in children and the leading cause of mortality due to disease. New therapies are desperately needed. Specific Aims: The primary aim of this phase I study was to determine the safety and feasibility of administering HLA-A2 restricted, tumor associated antigenic peptides with Montanide ISA-51 VG to children with refractory CNS tumors. Secondary aims were to evaluate immune response to the vaccine and tumor response. Methods: Each vaccine consisted of HLA-A2 restricted peptides targeting epitopes on the tumor associated antigens Her2, Trp2, EphA2 and gp100 mixed with Montanide ISA-51 VG as the immune adjuvant. The neoantigen KLH was given with the first vaccine as a control. Patients received the vaccines divided into 2 subcutaneous injections on weeks 1, 4 and 7. Immune responses induced by the vaccine were evaluated by tetramer and intracellular cytokine staining. Results: 15 patients, females=8, median age 12 years (range 7- 20 y) were treated between August 2009 and May 2012. Diagnoses included pilocytic astrocytoma=1, low grade glioneuronal tumor=1, pilocytic/pilomyxoid tumor=2, anaplastic astrocytoma= 3, DIPG=2, radiation-induced glioblastoma=1, and ependymoma=3. Two patients had unbiopsied presumed low grade astrocytomas. One patient with an ependymoma was removed after only 2 immunizations because of progressive disease. 14 pts received all 3 vaccines. Several patients had grade 1 local skin reactions at the injection sites. No patients had grade 2 or higher adverse reactions related to the vaccine. Analysis of immune response shows induction of T cell responses to the tumor associated antigens. Impressively, most patients evaluated so far had detectable T cell responses to gp100 and Her-2 post vaccination. Furthermore, both antibody and T cell responses to the control antigen KLH were detected in most patients. Five of 6 patients with low grade astrocytomas have had stable disease for a median of 24 months (range 6-36 mo). Three patients with anaplastic astrocytomas have stable disease for 16, 24, and 24 months. Conclusions: Vaccine therapy using tumor associated antigenic peptides with Montanide ISA-51 VG was well tolerated. Despite being heavily pre-treated, these children were able to mount both humoral and adaptive immune response. Stable disease was seen in children with refractory low grade and high grade gliomas