Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis.

SEE ZEKERIDOU AND LENNON DOI101093/AWW213 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Little is known about the cerebrospinal fluid autoantibody repertoire. Antibodies against the NR1 subunit of the NMDAR are thought to be pathogenic; however, direct proof is lacking as previous experiments could not distinguish the contribution of further anti-neuronal antibodies. Using single cell cloning of full-length immunoglobulin heavy and light chain genes, we generated a panel of recombinant monoclonal NR1 antibodies from cerebrospinal fluid memory B cells and antibody secreting cells of NMDAR encephalitis patients. Cells typically carried somatically mutated immunoglobulin genes and had undergone class-switching to immunoglobulin G, clonally expanded cells carried identical somatic hypermutation patterns. A fraction of NR1 antibodies were non-mutated, thus resembling 'naturally occurring antibodies' and indicating that tolerance induction against NMDAR was incomplete and somatic hypermutation not essential for functional antibodies. However, only a small percentage of cerebrospinal fluid-derived antibodies reacted against NR1. Instead, nearly all further antibodies bound specifically to diverse brain-expressed epitopes including neuronal surfaces, suggesting that a broad repertoire of antibody-secreting cells enrich in the central nervous system during encephalitis. Our functional data using primary hippocampal neurons indicate that human cerebrospinal fluid-derived monoclonal NR1 antibodies alone are sufficient to cause neuronal surface receptor downregulation and subsequent impairment of NMDAR-mediated currents, thus providing ultimate proof of antibody pathogenicity. The observed formation of immunological memory might be relevant for clinical relapses.

High frequency of cerebrospinal fluid autoantibodies in patients with seizures or epilepsies of unknown etiology.

Introduction: The increasing identification of specific autoantibodies against brain structures allows further refinement of the group of autoimmune-associated epilepsies and affects diagnostic and therapeutic algorithms. The early etiological allocation of a first seizure is particularly challenging, and the contribution of cerebrospinal fluid (CSF) analysis is not fully understood. Methods: In this retrospective study with a mean of 7.8 years follow-up involving 39 well-characterized patients with the initial diagnosis of new-onset seizure or epilepsy of unknown etiology and 24 controls, we determined the frequency of autoantibodies to brain proteins in CSF/serum pairs using cell-based assays and unbiased immunofluorescence staining of unfixed murine brain sections. Results: Autoantibodies were detected in the CSF of 30.8% of patients. Underlying antigens involved glial fibrillary acidic protein (GFAP) and N-methyl-D-aspartate (NMDA) receptors, but also a range of yet undetermined epitopes on neurons, glial and vascular cells. While antibody-positive patients had higher frequencies of cancer, they did not differ from antibody-negative patients with respect to seizure type, electroencephalography (EEG) and cranial magnetic resonance imaging (cMRI) findings, neuropsychiatric comorbidities or pre-existing autoimmune diseases. In 5.1% of patients with seizures or epilepsy of initially presumed unknown etiology, mostly CSF findings resulted in etiological reallocation as autoimmune-associated epilepy. Discussion: These findings strengthen the potential role for routine CSF analysis. Further studies are needed to understand the autoantibody contribution to etiologically unclear epilepsies, including determining the antigenic targets of underlying autoantibodies.

Exploiting the Ring Strain of Diphosphetanes: A Synthetic and Computational Approach towards 1,2,5-Selenadiphospholanes.

Invited for this month's cover is the group of Prof. Evamarie Hey-Hawkins from Leipzig University, Germany. The cover picture, designed by Dr. Christoph Selg, shows two pots on a crowded table planted with bulky tert-butyl groups symbolizing the phosphorus atoms in the strained ring system of a carborane-substituted 1,2-diphosphetane. However, selenium can still be inserted into the P-P bond, as reported by Hey-Hawkins et al. in their present publication, which combines experimental and computational studies. Read the full text of the article at 10.1002/cplu.201800391.

Exploiting the Ring Strain of Diphosphetanes: A Synthetic and Computational Approach towards 1,2,5-Selenadiphospholanes.

A carboranyl-based meso-1,2,5-selenadiphospholane diselenide was synthesised starting from a strained carborane-substituted 1,2-diphosphetane and subsequently reduced to an unprecedented carboranyl-based meso-1,2,5-selenadiphospholane. The electronic structure and the bonding situation for both compounds were investigated by density functional theory (DFT), Natural Bond Orbital (NBO) analyses, Fractional Occupation Density (FOD) analysis, Complete Active Space Self Consistent Field (CASSCF) calculations and time-dependent DFT (TDDFT) calculations. Ring-opening reactions of meso-1,2,5-selenadiphospholane with nucleophiles and electrophiles are reported together with calculated reaction mechanisms (DFT level). Isolated compounds were characterised by NMR and IR spectroscopy, high-resolution mass spectrometry, elemental analysis and single-crystal X-ray diffraction.

"Hirnsymptome bei Carcinomatose" - Hermann Oppenheim and an Early Description of a Paraneoplastic Neurological Syndrome.

Paraneoplastic neurological syndromes belong to the most enigmatic and fascinating disorders. Their remarkable clinical spectrum ranges from sensory neuronopathy to cerebellar degeneration or limbic encephalitis. We retrace the clinical and pathological description of a forgotten case published by Hermann Oppenheim in 1888, which to our knowledge represents the first report of a paraneoplastic neurological syndrome. The young Oppenheim used thorough observation and good clinical judgment to suggest a causal link between the seemingly mere association of an underlying malignancy and a neurological syndrome, decades before Denny-Brown's identification of sensory neuronopathy in 1948 and a century before the discovery of "anti-Hu" antibodies. Oppenheim anticipated that scientific progress was required to prove this link, and he indicated his finding as "a pointer for future observers." In this way, he leaves the reader with the fascinating question of which observations during our current neurology practice could be the next "pointers" in medical research.