The Big Tent

CTSI 2016 NIH Renewal Proposal Launchpad

Brain on Fire Network

Proposal Status: 

Problem: Rapidly progressive encephalopathies are diagnostically challenging and provide great potential for scientific and clinical advancement by harnessing the interdisciplinary resources and collaborative infrastructure of the CTSIs.We need systems to rapidly identify emerging infections and immunologically-mediated nervous system disorders and to investigate their causes and possible genetic contributors in order to provide rapid, efficient and cost-effective diagnosis, discover new diseases, and guide appropriate treatment.

A revolution has occurred in neurology and psychiatry with the identification of antibody-mediated neurological encephalopathies and psychiatric illness. A similar development has occurred in pathogen discovery with the use of high throughput techniques (many pioneered here at UCSF). As genome sequencing rapidly becomes more affordable, obtainable and powerful, it should provide new insights into the mechanisms and risk factors for these disorders spanning several medical disciplines.  

We propose to establish a “Brain on Fire” Network to actualize a vision of translational medicine by connecting the clinic to outstanding laboratory cores. The goal will be to create a pipeline for identifying whether patients with rapidly progressive encephalopathies or psychiatric disorders might have an infection or a primary immunological disorder, and if so, what are the genetic contributors. This network will link the clinic, research units, and high-throughput laboratory pipelines for pathogen discovery (requiring CTSI expertise/resources for coordinating, including engagement with research cores and appropriate public health labs, such as the CA Department of Health and the CDC), and CNS antibody discovery programs (utilizing CTSI expertise/resources to create and support national collaboration). This network will link investigators from a broad range of disciplines.

Antibodies against extracellular neuronal or other CNS cell antigens cause these syndromes. Unlike the known paraneoplastic antibody-associated syndromes, which were primarily due to intracellular antigens and were difficult to treat, these newer syndromes caused by antibodies against extracellular neuronal or other CNS cell antigens are readily treatable, even curable. They also are now at least five times more common than typical paraneoplastic antibody associated syndromes. The phenotypes often involve cognitive impairment, movement disorders, psychiatric disorders, seizures, or a combination of these symptoms. These disorders overlap multiple disciplines, including medicine (general, immunology, rheumatology, infectious disease), psychiatry, neurology and others. One common syndrome, which begins with psychiatric symptoms that progress to frank psychosis and then to violent movement disorders and pulmonary failure, is associated with antibodies to the N-methyl-D-aspartate receptor (NMDAR). For many years, these unfortunate patients were thought to have infectious encephalitis due to unidentified viruses; only with new immunological techniques and methods has the cause of these enigmatic disorders been identified. Other related disorders include voltage-gated potassium channel complex (VGKC encephalopathies), AMPAR encephalitis, GAD65 associated seizures, ataxia and/or encephalopathy. New syndromes are rapidly being discovered, making this one of the most exciting new areas of medicine.

Current approaches (nationally): Only a few centers in the world have the technical and clinical expertise to identify new syndromes and manage these patients. To our knowledge, only three laboratories in the world (Oxford, Mayo and Barcelona) are actively identifying novel antibodies and syndromes. Despite a few institutions working to identify these disorders, there is no consistent, multidisciplinary approach. As these syndromes are becoming more frequent, we need to develop a systematic network for surveillance, identification and study of these disorders.

Solution: Establish a network of centers with clinical expertise in identifying possible autoimmune mediated neurological, psychiatric, and “infectious” disorders. Asses and follow patients in a comprehensive, standardized, manner clinically, immunologically, radiologically, and genetically. Clinicians work closely with various CTSI basic science cores. Immunology cores will screen for known and novel antibodies and antigens. Genetic cores will assess various risk factors.

Potential partners: Various CTSIs, including our own, as well as Mayo and UPENN, already have some expertise in these areas. It would be important to train and incorporate other centers as well.

Projected impact: As these patients often require a long time for proper diagnosis, this system should greatly decrease the time to diagnosis and initiation of appropriate therapies and lead to significant cost savings to the medical system. Discovery of new diseases and disease mechanisms should have significant impact on public health, save millions of dollars annually and prevent unnecessary morbidity and death.

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