Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium.

BACKGROUND: Medical toxicologists are frequently consulted when young patients present with delirium attributed to suspected poisoning. Medical toxicologists should be aware of non-toxicological mimics of delirium. We describe two patients ultimately diagnosed with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis for which a toxicological consultation was requested to evaluate for neuroleptic malignant syndrome (NMS). CASE 1: A 21 year old male was sent from a psychiatric facility for new, worsening psychotic symptoms. He had autonomic instability, confusion, and hyper-reflexia. He was treated for NMS without improvement, and after an extensive workup was unrevealing, he was discharged home with significant cognitive dysfunction. Stored CSF later tested positive for anti-NMDAR antibodies. CASE 2: A 27 year old female was sent from a psychiatric facility for a seizure and new psychiatric symptoms. She was agitated and had violent, alternating extremity flexion and extension along with autonomic instability. She was treated for NMS, rhabdomyolysis, and rabies before analysis of CSF demonstrated anti-NMDAR antibodies. Treatment included surgical resection of a suspicious ovarian cyst, steroids and IVIG, with moderate improvement. DISCUSSION: Autoimmune syndromes of the central nervous system result from receptor dysfunction after an antibody response to extracellular or intracellular antigens, such as subunits of the NMDA receptor. The NMDA subunits NR2b and NR2a, in addition to the N-terminal region of the glycine binding NR1 subunit, have been implicated. Typical features such as memory loss, movement disorders, and hallucinations reflect the density and distribution of neuronal NDMA receptors. As young people, particularly young women, are predominantly affected, initial symptoms may be attributed to encephalopathy from drug abuse or schizophrenia. Toxicologists may be consulted as many features mimic NMS. Serum and cerebrospinal fluid can be checked for anti-NMDAR antibodies as part of a paraneoplastic or meningioencephalitis panel. Effective treatments have been described and include surgical resection and immunosuppressive medications.

Characterization of pro-apoptotic and matrix-degradative gene expression following induction of osteoarthritis in mature and aged rabbits.

OBJECTIVE: The genetic and molecular changes leading to the distinctive alterations of aged cartilage and its propensity for developing osteoarthritis (OA) are unknown. We hypothesized that pro-apoptotic and matrix-degradative gene expression in a rabbit model of induced OA using mature and aged animals might elucidate this relationship. METHODS: Groups of six mature and aged rabbits underwent anterior cruciate ligament transection (ACLT) and were sacrificed 4 weeks after surgery to create an Outerbridge grade II OA. RNA was extracted from the articular cartilage and menisci of the affected knee and was examined with regard to expression of the following genes: Caspase 8, Fas, Fas ligand (Fas-L), p53, aggrecanase, matrix metalloproteinase (MMP)-1, and MMP-3-MMP-13. A second cohort of mature and aged animals was sacrificed with no intervention to the joint and gene expression was assessed in a similar manner. RESULTS: Fas and Caspase 8 showed significantly increased expression in the cartilage of mature animals with induced OA when compared to unoperated controls while induction of OA in aged rabbits did not significantly increase expression of any of the apoptosis genes. Among unoperated animals, the aged cohort showed significantly increased expression of MMP-1 and aggrecanase in cartilage when compared to mature animals. MMP-13 expression was upregulated in aged cartilage following induction of OA. Although ACLT animals showed gross thinning and irregularities within the meniscus, only the expression of Caspase 8 in the aged rabbits was significantly increased after induction of OA. CONCLUSIONS: Aging of articular cartilage shares some qualities with the development of OA, as seen in the parallel increases in gene expression of Caspase 8 and Fas. Although this may imply a common mechanism of cartilage degeneration in aging and OA or even a spectrum of disease, both are complex processes requiring further study.