Although antibodies to NMDA receptor were not measured back then, a more recent case that gained widespread attention provided the clinical proof. Susannah Cahalan, a 24-year-old reporter for the New York Post, started to notice a change in her behavior. She first became anxious, then agitated and very paranoid. A seizure episode followed, then another, followed by worsening delusional and suicidal behavior and, finally, catatonia. A lumbar puncture identified a leukocytosis. Coupled with her other findings, an astute neurologist speculated that she was not schizophrenic but was suffering from an autoimmune illness, likely a cerebritis, that was being driven by the generation of autoantibodies targeting the NMDA receptor. He recalled a recent paper describing a similar syndrome affecting women with ovarian teratomas who were found to have very high circulating titers of these antibodies.11 In this case, the presence of these autoantibodies was confirmed, and Cahalan was treated and made a full recovery. She describes her ordeal in the book, Brain on Fire, which is soon to be released as a movie, too.12
Whether a similar form of this illness might be occurring in some of our lupus patients with cerebritis is not yet settled. Although these are rare conditions, gaining a better insight into the pathogenesis of these disorders will provide us with more than just a glimpse of how the mind works in health and in disease.
Tying It All Together
The beauty of rheumatology may lie in the fact that our specialty lacks boundaries. Rhumatologues sans frontières! We are not constrained by the physical location of our connective tissues nor limited by the reach of our immune system, which lacks an identifiable home. Autoimmune illnesses can pop up anywhere.
For years, it was believed that the BBB performed an effective job in keeping the brain isolated from the toxins, humors and microorganisms that occupy the rest of our body’s real estate. Two recent developments have shaken this dictum. First, was the discovery that the mammalian brain, long thought to lack a lymphatic system, actually contains canonical lymphatic vessels that bear the molecular markers of the structures that carry fluid and immune cells from the tissues to the lymph nodes elsewhere in the body.13 This observation raises the tantalizing possibility there is far more crosstalk between the brain, the body and the immune system than was previously imagined.
A second finding was recently described in a mouse model of an autism spectrum disorder. In this model, feeding rodents the human commensal Bacteroides fragilis corrected their underlying gut permeability, altered their microbial composition and, most strikingly, reversed the defects in their communicative, stereotypic and anxiety-like behaviors, suggesting that gut bacterial effects on the host metabolome can impact behavior.14 The brain and the mind, the bowel and the immune system are all linked together. To paraphrase Winston Churchill, although the mind remains a riddle wrapped in a mystery inside an enigma, perhaps the wrapping is not as impenetrable as once imagined.
