Kyle Williams

Microglial Dysregulation in Psychiatric Disease

Microglia, the brains resident immune cells, are phagocytes of the macrophage lineage that have a key role in responding to inflammation and immune challenge in the brain. More recently, they have been shown to have a number of important roles beyond immune surveillance and response, including synaptic pruning during development and the support of adult neurogenesis. Microglial abnormalities have been found in several neuropsychiatric conditions, though in most cases it remains unclear whether these are causative or are a reaction to some other underlying pathophysiology. Here we summarize postmortem, animal, neuroimaging, and other evidence for microglial pathology in major depression, schizophrenia, autism, obsessive-compulsive disorder, and Tourette syndrome. We identify gaps in the existing literature and important areas for future research. If microglial pathology proves to be an important causative factor in these or other neuropsychiatric diseases, modulators of microglial function may represent a novel therapeutic strategy.

Clinical Evaluation of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference

On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute-onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS.

Post-infectious autoimmune disorders: Sydenham’s chorea, PANDAS and beyond

Infections, and the resulting immune response to these infections, have recently received increased recognition as pathogenic mechanisms for neuropsychiatric disorders. Sydenhams chorea (SC), a widely recognized post-streptococcal autoimmune disorder, represents a model for this proposed pathogenesis. In SC, a dysregulated immune response to a streptococcal infection is hypothesized to result in inflammation of neuronal networks, particularly the basal ganglia nuclei. The resulting dysfunction in the basal ganglia nuclei are hypothesized to lead to a constellation of adventitious movements and psychiatric symptoms, which investigations have shown are amenable to immunomodulatory therapies. PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections) has been proposed as a variant of SC, and is hypothesized to share a pathogenic mechanism, despite a unique symptom profile of predominantly psychiatric symptoms. In this review, we present the clinical aspects of both disorders, the data for potential shared etiopathogenesis between them, and the evidence for the therapeutic use of immunomodulatory therapies for the symptoms of SC and PANDAS. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

Rapid Eye Movement Sleep Abnormalities in Children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS).

STUDY OBJECTIVES Polysomnographic investigation of sleep architecture in children presenting with pediatric acute-onset neuropsychiatric syndrome (PANS). METHODS Fifteen consecutive subjects meeting criteria for PANS (mean age = 7.2 y; range 3-10 y) underwent single-night full polysomnography (PSG) read by a pediatric neurologist. RESULTS Thirteen of 15 subjects (87%) had abnormalities detected with PSG. Twelve of 15 had evidence of rapid eye movement (REM) sleep motor disinhibition, as characterized by excessive movement, laughing, hand stereotypies, moaning, or the continuation of periodic limb movements during sleep (PLMS) into REM sleep. CONCLUSIONS This study shows various forms of REM sleep motor disinhibition present in a population of children with PANS.

Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition.