Autoimmune Encephalitis pathophysiology in children
Autoimmune encephalitis (AE) in children is a complex neurological disorder characterized by the immune system erroneously attacking the brain, leading to a range of neuropsychiatric symptoms. Unlike infectious encephalitis caused by pathogens, AE results from the immune system’s misguided response, which can be triggered by infections, tumors, or sometimes occurs idiopathically. Understanding its pathophysiology in children involves exploring how immune dysregulation targets the central nervous system (CNS), resulting in inflammation and neuronal dysfunction.
The core mechanism of autoimmune encephalitis involves the production of autoantibodies that target specific neuronal surface or intracellular antigens. These autoantibodies interfere with normal neuronal function, leading to the diverse symptoms observed in affected children, such as seizures, behavioral changes, cognitive decline, movement disorders, and altered consciousness. The most well-characterized forms involve autoantibodies against synaptic or cell surface proteins such as NMDA (N-methyl-D-aspartate), LGI1, CASPR2, or GABA receptors. These antibodies can cross the blood-brain barrier (BBB), which normally protects the CNS from immune components, but in AE, this barrier is often compromised, allowing immune mediators to access the brain tissue.
In children, the pathophysiology of AE frequently involves a combination of humoral (antibody-mediated) and cellular immune responses. The production of pathogenic autoantibodies typically begins with immune activation in peripheral lymphoid tissues, which may be initiated by infections or tumors that express neuronal antigens—most notably, ovarian teratomas in girls with anti-NMDAR encephalitis. These antigens can mimic neural proteins, leading to a phenomenon called molecular mimicry, where the immune system inadvertently targets the brain. Once produced, these autoantibodies travel through the bloodstream and breach the BBB, binding to their neuronal targets.
The binding of autoantibodies to surface antigens on neurons disrupts normal receptor function. For instance, anti-NMDAR antibodies cause internalization and decreased surface expression of NMDA receptors, impairing glutamatergic signaling critical for synaptic transmission and plasticity. Similarly, GABA receptor antibodies impair inhibitory neurotransmission, leading to neuronal hyperexcitability and seizures. The disruption of receptor function also triggers downstream inflammatory responses, recruiting immune cells like T lymphocytes and macrophages, which further exacerbate neuronal damage through cytokine release and complement activation.
Additionally, non-specific inflammation plays a significant role in the disease process. Once immune cells infiltrate the CNS—often facilitated by a compromised BBB—they release cytokines and chemokines that promote neuroinflammation, neuronal injury, and edema. This inflammatory cascade amplifies the initial immune attack, resulting in widespread dysfunction, which manifests clinically as encephalopathy, psychiatric symptoms, and neurological deficits.
In pediatric cases, the immune response may differ slightly from adults, often with less prominent tumor associations and a broader spectrum of presenting symptoms. Early recognition of these immune-mediated processes is crucial, as prompt immunotherapy, including steroids, intravenous immunoglobulin, or plasmapheresis, can significantly improve outcomes.
In summary, autoimmune encephalitis in children involves a maladaptive immune response where autoantibodies target neuronal surface proteins, disrupt neurotransmission, and trigger neuroinflammation. This multifaceted pathophysiology underscores the importance of early diagnosis and targeted immune therapies to mitigate neuronal injury and improve prognosis.
