Autoimmune Vestibulocerebellar Syndromes.

Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.

Acute Disseminated Encephalomyelitis (ADEM) and Increased Intracranial Pressure Associated With Anti-Myelin Oligodendrocyte Glycoprotein Antibodies.

BACKGROUND: Antibodies to the myelin oligodendrocyte glycoprotein (MOG) have been identified in about 40% of children with acute disseminated encephalomyelitis (ADEM). The objective of this report is to describe three individuals with fulminant ADEM complicated by increased intracranial pressure associated with the presence of the anti-MOG antibodies. METHODS: This is a retrospective case series. Informed consent was obtained from the concerned patients or caregivers. RESULTS: High intracranial pressure associated with ADEM in the presence of MOG antibodies can result in cerebral edema, herniation, prolonged hospital stay (average intensive care unit stay: 22 days, average hospital stay: 50.6 days), and long-term disability. CONCLUSION: Increased intracranial pressure complicating MOG antibody-related ADEM is a unique finding in our cases. This can complicate the clinical picture of ADEM and confers high morbidity. Long-term immunosuppression is warranted in selected cases with persistent seropositivity.

Atypical Anti-MOG syndrome with aseptic meningoencephalitis and pseudotumor cerebri-like presentations.

OBJECTIVE: To describe 2 atypical cases with Anti-MOG antibody related demyelinating syndrome. METHODOLOGY: Case series. RESULTS: We present two cases. Case 1 is an 18-year-old woman who presented with headache, blurred vision, and papilledema and was initially diagnosed with pseudotumor cerebri syndrome. CSF showed mildly elevated opening pressure and lymphocytic pleocytosis and a diagnosis of aseptic meningitis was considered. MRI brain and spinal cord revealed longitudinally extensive bilateral simultaneous optic neuritis and multiple spinal cord lesions. Case 2 is a 28-year old man who presented initially with unilateral optic neuritis followed by aseptic meningitis three weeks later and subsequently acute disseminated encephalomyelitis (ADEM). Serology was positive for Anti-MOG antibody on a cell-based assay in both these cases. DISCUSSION: Although bilateral optic neuritis has been well described in MOG related disorders, aseptic meningitis and pseudotumor cerebri-like syndromes are notable alternate presentations. The presence of eosinophils in the CSF (in the first patient) is a unique finding in our case series. CONCLUSION: In a patient with an aseptic meningitis like presentation, the presence of optic neuritis, brain and/or spinal cord lesions should raise suspicion for an MOG-Ab related syndrome.

Unique characteristics of optical coherence tomography (OCT) results and visual acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients.

BACKGROUND: Optic nerve involvement in anti-myelin oligodendrocyte glycoprotein antibody associated syndrome (MOG ab syndrome) tends to have unique features. Few studies have reported optical coherence tomography (OCT) measures like retinal nerve fiber layer thickness findings in the setting of pediatric MOG ab syndrome. OBJECTIVES: The aim of this study is to compare visual acuity between MOG ab positive and MOG ab negative pediatric cohorts and examine correlations with OCT findings. METHODS: We included outpatients less than 18 years of age who had optic neuritis (ON) of at least one eye and who completed visual testing and OCT in the study. ON was defined based on clinical or OCT findings. Antibody testing was obtained using cell-based assay. The primary analyses of interest investigated differences in low-contrast visual acuity stratified by the defined RNFL ranges and by antibody positivity. RESULTS: We analyzed 28 eyes from 14 anti-MOG ab patients (MOG-ON cohort), 18 eyes from 9 anti-AQP4 ab (AQP4-ON cohort) patients and 26 eyes from 13 patients who tested negative for both the antibodies (seronegative ON cohort). MOG-ON eyes with zero reported clinical events had lower RNFL thickness, than the minimum RNFL thickness of either the seronegative-ON or AQP4-ON eyes with zero clinical attacks in most retinal segments. Within the lowest range of the RNFL (RNFL <50 um) in most retinal segments, the MOG-ON cohort had a statistically significant greater visual acuity relative to the AQP4 cohort. CONCLUSIONS: Patients with anti-MOG antibody mediated CNS disorders can suffer from subclinical ON events with significant reductions in RNFL. Despite equally significant damage to the optic nerve, MOG-Ab positive patients have relatively preserved visual acuity.

The Role of EGFR-Met Interactions in the Pathogenesis of Glioblastoma and Resistance to Treatment.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is a devastating and intractable disease with a poor outcome. Aberrant receptor tyrosine kinase signaling is a key driver in gliomagenesis and resistance to treatment. EGFR gene amplification and mutations are an important genetic alteration in GBM resulting in increased expression of EGFR wild type (EGFRwt) as well as mutant oncogenic forms of the EGFR. EGFRvIII is the most common oncogenic mutant in GBM and is usually co-expressed with EGFRwt. EGFRvIII does not bind ligand and is constitutively active. Recent studies have also highlighted a key role for Met in gliomagenesis and the EGFR and Met may act in concert to promote the malignant phenotype. Met is transactivated by EGFRvIII and plays a key role in EGFRvIII-mediated resistance to targeted treatment. HGF, a Met ligand, is highly expressed in GBM. HGF and Met create an important autocrine signaling loop that promotes GBM invasion. In addition, HGF/Met is able to induce EGFR activation, leading to enhanced activation of oncogenic signaling in GBM. In this review, we discuss the evidence for EGFR and Met interaction in GBM and discuss the mechanisms and biological consequences of transactivation between the two kinases. Additionally, we discuss the therapeutic potential of targeting both EGFR and Met signaling for the treatment of GBM.