This review provides an overview on different antibody test methods that can be applied in cases of suspected paraneoplastic neurological syndromes (PNS) and anti-neuronal autoimmune encephalitis (AIE) in order to explain their diagnostic value, describe potential pitfalls and limitations, and discuss novel approaches aimed at discovering further autoantibodies. Onconeuronal antibodies are well-established biomarkers for PNS and may serve as specific tumor markers. The recommended procedure to detect onconeuronal antibodies is a combination of indirect immunohistochemistry on fixed rodent cerebellum and confirmation of the specificity by line assays. Simplification of this approach by only using line assays with recombinant proteins bears the risk to miss antibody-positive samples. Anti-neuronal surface antibodies are sensitive and specific biomarkers for AIE. Their identification requires the use of test methods that allow the recognition of conformation dependent epitopes. These commonly include cell-based assays and tissue based assays with unfixed rodent brain tissue. Tissue based assays can detect most of the currently known neuronal surface antibodies and thus enable broad screening of biological samples. A complementary testing on live neuronal cell cultures may confirm that the antibody recognizes a surface epitope. In patients with peripheral neuropathy, the screening may be expanded to teased nerve fibers to identify antibodies against the node of Ranvier. This method helps to identify a novel subgroup of peripheral autoimmune neuropathies, resulting in improved immunotherapy of these patients. Tissue based assays are useful to discover additional autoantibody targets that play a role in diverse autoimmune neurological syndromes. Antibody screening assays represent promising avenues of research to improve the diagnostic yield of current assays for antibody-associated autoimmune encephalitis.

Human cytomegalovirus (CMV) is an ubiquitous pathogen, with a high worldwide seroprevalence. When acquired in the prenatal period, congenital CMV (cCMV) is a major cause of neurodevelopmental sequelae and hearing loss. cCMV remains an underdiagnosed condition, with no systematic screening implemented in pregnancy or in the postnatal period. Therefore, imaging takes a prominent role in prenatal diagnosis of cCMV. With the prospect of new viable therapies, accurate and timely diagnosis becomes paramount, as well as identification of fetuses at risk for neurodevelopmental sequelae. Fetal magnetic resonance imaging (MRI) provides a complementary method to ultrasound (US) in fetal brain and body imaging. Anterior temporal lobe lesions are the most specific finding, and MRI is superior to US in their detection. Other findings such as ventriculomegaly, cortical malformations and calcifications, as well as hepatosplenomegaly, liver signal changes and abnormal effusions are unspecific. However, when seen in combination these should raise the suspicion of fetal infection, highlighting the need for a full fetal assessment. Still, some fetuses deemed normal on prenatal imaging are symptomatic at birth or develop delayed cCMV-associated symptoms, leaving room for improvement of diagnostic tools. Advanced MR sequences may help in this field and in determining prognosis, but further studies are needed.

Objective: To describe the neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis in an archival autopsy cohort. Methods: We examined four autopsies from patients with NMDAR-encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post-transplant lymphoproliferative disease (PTLD), and overlapping demyelination. Results: The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3 + /CD8 À T cells and CD79a + B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR-immunoreactivity that correlated with disease severity. The patient with NMDAR-encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR-encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro-inflammatory activation markers HLA-DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR-encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination. Interpretation: The topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR-immunoreactivity correlates with disease severity. Co-occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome.

Genetic, molecular, and physical forces together impact brain morphogenesis. The early impact of deficient midline crossing in agenesis of the Corpus Callosum (ACC) on prenatal human brain development and architecture is widely unknown. Here we analyze the changes of brain structure in 46 fetuses with ACC in vivo to identify their deviations from normal development. Cases of complete ACC show an increase in the thickness of the cerebral wall in the frontomedial regions and a reduction in the temporal, insular, medial occipital and lateral parietal regions, already present at midgestation. ACC is associated with a more symmetric configuration of the temporal lobes and increased frequency of atypical asymmetry patterns, indicating an early morphomechanic effect of callosal growth on human brain development affecting the thickness of the pallium along a ventro–dorsal gradient. Altered prenatal brain architecture in ACC emphasizes the importance of conformational forces introduced by emerging interhemispheric connectivity on the establishment of polygenically determined brain asymmetries.

B cell depletion with the anti-CD20-antibody rituximab is widely considered treatment of choice for long-term immunotherapy in aquaporin-4 (AQP4)-antibody positive neuromyelitis optica spectrum disorder (NMOSD). However, up to 30% of patients suffer from relapses despite complete B cell depletion. In these cases, the IL6 (interleukin-6)-receptor blocking antibody tocilizumab has been suggested as an alternative. We report two female adolescents with AQP4-antibody positive NMOSD who relapsed under rituximab treatment and clinically stabilized after switching to monthly administrations of tocilizumab. Our data suggest that early escalation of therapy with tocilizumab may lead to stabilization of disease activity in pediatric NMOSD patients who relapse under B cell depletion.