Clinical Manifestations and Pathogenesis of Acute Necrotizing Encephalopathy: The Interface Between Systemic Infection and Neurologic Injury

Abstract

Acute necrotizing encephalopathy (ANE) is a devastating neurologic condition that can arise following a variety of systemic infections, including influenza and SARS-CoV-2. Affected individuals typically present with rapid changes in consciousness, focal neurological deficits, and seizures. Neuroimaging reveals symmetric, bilateral deep gray matter lesions, often involving the thalami, with evidence of necrosis and/or hemorrhage. The clinical and radiologic picture must be distinguished from direct infection of the central nervous system by some viruses, and from metabolic and mitochondrial disorders. Outcomes following ANE are poor overall and worse in those with brainstem involvement. Specific management is often directed toward modulating immune responses given the potential role of systemic inflammation and cytokine storm in potentiating neurologic injury in ANE, though benefits of such approaches remain unclear. The finding that many patients have mutations in the nucleoporin gene RANBP2, which encodes a multifunctional protein that plays a key role in nucleocytoplasmic transport, may allow for the development of disease models that provide insights into pathogenic mechanisms and novel therapeutic approaches.

Acute Necrotizing Encephalitis as an Early Manifestation of COVID-19

“…Similarly, the mechanism(s) driving ANE remain unknown. It is hypothesized that a 'cytokine storm' during systemic illness leads to blood-brain barrier breakdown, vascular endothelial injury, and cytotoxicity [15,16]. Elevated serum levels of tumor necrosis factor (TNF) and IL-6 are a typical feature of ANE, though CSF levels are less clear [15].…”

“…It is hypothesized that a 'cytokine storm' during systemic illness leads to blood-brain barrier breakdown, vascular endothelial injury, and cytotoxicity [15,16]. Elevated serum levels of tumor necrosis factor (TNF) and IL-6 are a typical feature of ANE, though CSF levels are less clear [15]. After SARS-CoV-2 was found to use the angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry [17], which is expressed by neurons and glial cells, it was speculated that direct invasion of the CNS by SARS-CoV-2 could be pathogenic [18].…”

Roles of Nucleoporin RanBP2/Nup358 in Acute Necrotizing Encephalopathy Type 1 (ANE1) and Viral Infection

“…The diagnostic criteria of ANE and ANE1 have been well described previously [ 37 , 41 , 47 , 83 ]. Briefly, ANE patients present an acute encephalopathy within 1–3 days following the onset of a febrile illness, which frequently show deterioration of consciousness, seizures, and culminate in coma.…”

“…Aside from the genetic influence of RANBP2 mutations, additional environmental factors, such as pathogen infection, are required for ANE1 development [ 47 , 83 ]. As discussed above, most ANE1 cases were induced by various viral infections (see Table 1 and Figure 1 ).…”

Workshop on RanBP2/Nup358 and acute necrotizing encephalopathy

“…In the case of mutations in RANBP2 , they are only 40% penetrant, at least according to the initial reports, and thus these alterations are often passed down by unaffected carriers. How these mutations cause ANE remains unclear [for excellent recent reviews on this topic see 2 , and 3 ]. This gene encodes the RanBP2/Nup358 protein, which is ubiquitously expressed and is part of the cytoplasmic filaments that are present on the cytoplasmic face of the nuclear pore complex [ 4 , 5 ] ( Figure 1a ).…”