In a series of animal experiments, the scientists could demonstrate that the prerequisite for a triggering of symptoms by these autoantibodies, and thus for pathogenesis, is a dysfunction of the blood-brain barrier. In healthy organisms, this physiological barrier isolates the central nervous system like a filter from the general bloodstream, thus protecting it from circulating pathogenic agents and toxins. A disruption of its natural barrier function enables the NMDAR autoantibodies circulating in the blood to enter the brain. This is how they reach the NMDA receptors located in the brain and can cause impairments, resulting in psychosis-like symptoms, epileptic seizures or cognitive dysfunctions.
"In other words, more than 10 percent of all individuals carry a 'ticking time bomb', the disease relevance of which is only suppressed by an intact blood-brain barrier", remarks Prof. Ehrenreich. Damages to the blood-brain barrier can be caused by a stroke, a brain trauma or by a viral infection, among other causes. Next, the scientists performed an additional retrospective evaluation based on a large cohort of patients. They could show an increase in the severity of neurological symptoms in subjects with a temporary or persisting blood-brain barrier dysfunction who also carry NMDAR autoantibodies.
But how is the generation of NMDAR autoantibodies triggered in the first place? The scientists involved in this study found an association with past influenza A or B infections. They also identified a genetic risk factor related to NMDAR biology, by means of a genome-wide association study. Christian Hammer, lead author of the study, and his colleagues conclude that this finding yields considerable insight into a pathophysiological mechanism that is of crucial importance for neuropsychiatry, as well as for other clinical disciplines.
Hence the scientists recommend that "patients with acute or chronic impairment of the blood-brain barrier, e.g. after a brain injury, a stroke, any kind of encephalitis, epilepsy and also multiple sclerosis should be screened for the presence of NMDAR autoantibodies". This might contribute to improve the patient's prognosis by therapeutic methods and prevent long-term complications. (© Max Planck Institute for Experimental Medicine, CNMPB, AcademiaNet)