Case report: Acute necrotizing encephalopathy: a report of a favorable outcome and systematic meta-analysis of outcomes with different immunosuppressive therapies

Abstract

Acute Necrotizing Encephalopathy (ANE) is a condition characterized by symmetric, bilateral lesions affecting the thalamus and potentially other areas of the brain following an acute febrile illness. It manifests clinically as abrupt development of encephalopathy, or alteration in mental status that often includes development of seizures and progression to coma. Treatment strategies combine immunosuppressive therapies and supportive care with varying levels of recovery, however there are no universally accepted, data-driven, treatment algorithms for ANE. We first report a case of a previously healthy 10-year-old female with acute onset diplopia, visual hallucinations, lethargy, and seizures in the setting of subacute non-specific viral symptoms and found to have bilateral thalamic and brainstem lesions on MRI consistent with ANE. She was treated with a combination of immunomodulatory therapies and ultimately had a good outcome. Next, we present a meta-analysis of 10 articles with a total of 158 patients meeting clinical and radiographic criteria for ANE. Each article reported immunosuppressive treatments received, and associated morbidity or mortality outcome for each individual patient. Through our analysis, we confirm the effectiveness of high-dose, intravenous, methylprednisolone (HD-IV-MP) therapy implemented early in the disease course (initiation within 24 h of neurologic symptom onset). There was no significant difference between patients treated with and without intravenous immunoglobulin (IVIG). There was no benefit of combining IVIG with early HD-IV-MP. There is weak evidence suggesting a benefit of IL-6 inhibitor tocilizumab, especially when used in combination with early HD-IV-MP, though this analysis was limited by sample size. Finally, plasma exchange (PLEX) improved survival. We hope this meta-analysis will be useful for clinicians making treatment decisions for patients with this potentially devastating condition.

Keywords: acute necrotizing encephalopathy; autoimmune diseases of the nervous system; immunosuppressive therapy; meta-analysis; outcomes; pediatric neurology.

Figure 1

PRISMA diagram of meta-analysis: Reason 1: Not treatment-outcome focused case series or meta-analysis. Reason 2: Single case report. Reason 3: Not about ANE. Reason 4: Did not report individual patient data (treatment and associated outcome). Reason 5: only reported steroid use and did not report timing.

Figure 2

(A) Timeline of major clinical events, Imaging findings and immunosuppressive treatments. A1: CT scon at time of mental status change-bilateral thalamic hypodensities. A2–5: T2 Flair MRI at level of thalamus at indicated time points-time course of resolution of bilateral thalamic lesions. (B) Additional relevant MRI imaging findings. B1: T2 Flair MRI at time of initial MRI-bilateral pontine hyperintensity, subtle right temporal lobe edema. B2: T2 Flair MRI on day 2 - midbrain edema. B3: T1 with contrast MRI demonstrating ring enhancing thalamic lesions. B4: Diffusion weighted imaging (DWI) MRI-core of thalamic lesions restrict diffusion. B5: Susceptibility weighted imaging (SWI) MRI hemorrhage in thalamic lesions.

Figure 3

Meta-analysis of ANE outcomes in patients treated with different immunosuppressive agents. (A) Outcomes of patients treated with early, late or no IV steroids. Patients treated with early steroids had better outcomes than those treated without early steroids or with late steroids. *p < 0.01. (B) There were no differences observed in patients treated with IVIG. (C) Combination therapy with IVIG and ES did not lead to superior outcomes than ES alone. *p < 0.017. (D) There was a trend toward a significant improvement in patients treated with tocilizumab and a significant Improvement in patients treated with a combination of ES and tocilizumab. *p < 0.017. (E) There was a significantly greater % of patients who survived after treatment with PLEX compared to no PLEX. *p < 0.05.