Case of the Week

Background: 

• ANE1 is a specific type of acute necrotizing encephalopathy (ANE) with autosomal dominant inheritance that often presents as recurrent or familial encephalopathy following viral infection in infancy or early childhood.
• Caused by a missense mutation in the gene responsible for RAN binding protein 2 (RANBP2), a cytoplasmic nucleoporin speculated to have function in regulating response to viral infections and safeguarding against a hyperinflammatory response
• Mortality rate: ~ 30%; among survivors, many will suffer from permanent neurologic deficits

Clinical Presentation: 

• Prodrome of febrile viral illness, with upper respiratory (cough, congestion) and gastrointestinal (diarrhea, vomiting, nausea) symptoms
• Focal neurologic deficits, ataxia, seizures, and, eventually, altered consciousness and coma
• High rates of symptom recurrence among survivors

Key Diagnostic Features: 

• T2WI-hyperintense and T1WI-hypointense bilateral thalamic and brainstem (often pontine) lesions; hippocampi, mesial temporal lobes, and amygdalae may also be involved.
• Lesions can develop a ring pattern of core varied ADC (implying necrosis or hemorrhage), surrounding low ADC (compatible with cytotoxic edema), and high ADC further peripherally (suggesting vasogenic edema). SWI may reveal areas of hemorrhages, which are associated with a poorer prognosis.
• Mutations in RANBP2 gene through genetic testing; familial history of encephalopathy or personal history of recurrent encephalopathy

Differential Diagnoses: 

• Sporadic ANE: acute encephalopathy typically following viral infection that is not related to mutations in RANBP2 or strongly associated with familial inheritance. It similarly displays T2-hyperintense bilateral thalamic lesions and ADC features suggestive of hemorrhage, edema, and necrosis. Diffuse, periventricular white matter and cerebellar lesions are more common in sporadic ANE than ANE1. 
• Japanese encephalitis: a cause of central nervous system inflammation related to a flavivirus transmitted to humans through mosquito bite. It has a similar clinical presentation with a prodrome of fever followed by neurologic deficits including dystonia, tremor, altered consciousness, and coma. MRI reveals bilateral thalamic hyperintensities on T2WI with possible hemorrhagic foci and diffusion restriction. Predominantly found in Asian countries.
• Leigh disease (subacute necrotizing encephalomyelopathy): a mitochondrial disease affecting ATP production, presenting in infancy or early childhood through psychomotor regression, ataxia, respiratory dysfunction, and other neurologic deficits. On T2WI, symmetric hyperintensity may be seen within the basal ganglia (most consistently the putamen), cerebral peduncles, and periaqueductal structures.

Treatment: 

• Early initiation of corticosteroids to diminish the degree of hyperinflammatory response. Additional interventions include tocilizumab (IL-6 receptor blockade), therapeutic hypothermia, and serine protease inhibitors. Our patient was initially ventilator-dependent on admission and was weaned off the ventilator after steroid and IVIG therapy. She was discharged 3 weeks later with mild neurologic sequelae.