Acute Hemorrhagic Encephalitis Responding to Combined Decompressive Craniectomy, Intravenous Immunoglobulin, and Corticosteroid Therapies: Association with Novel RANBP2 Variant

Abstract

Background: Acute hemorrhagic encephalomyelitis (AHEM) is considered as a rare form of acute disseminated encephalomyelitis characterized by fulminant encephalopathy with hemorrhagic necrosis and most often fatal outcome.

Objective: To report the association with Ran Binding Protein (RANBP2) gene variant and the response to decompressive craniectomy and high-dose intravenous methylprednisolone (IVMP) in life-threatening AHEM.

Design: Single case study.

Case report: A 6-year-old girl known to have sickle cell disease (SCD) presented an acquired demyelinating syndrome (ADS) with diplopia due to sudden unilateral fourth nerve palsy. She received five pulses of IVMP (30 mg/kg/day). Two weeks after steroid weaning, she developed right hemiplegia and coma. Brain magnetic resonance imaging showed a left frontal necrotico-hemorrhagic lesion and new multifocal areas of demyelination. She underwent decompressive craniotomy and evacuation of an ongoing left frontoparietal hemorrhage. Comprehensive investigations ruled out vascular and infectious process. The neurological deterioration stopped concomitantly with combined neurosurgical drainage of the hematoma, decompressive craniotomy, IVMP, and intravenous immunoglobulins (IVIG). She developed during the following months Crohn disease and sclerosing cholangitis. After 2-year follow-up, there was no new neurological manifestation. The patient still suffered right hemiplegia and aphasia, but was able to walk. Cognitive/behavioral abilities significantly recovered. A heterozygous novel rare missense variant (c.4993A>G, p.Lys1665Glu) was identified in RANBP2, a gene associated with acute necrotizing encephalopathy. RANBP2 is a protein playing an important role in the energy homeostasis of neuronal cells.

Conclusion: In any ADS occurring in the context of SCD and/or autoimmune condition, we recommend to slowly wean steroids and to closely monitor the patient after weaning to quickly treat any recurrence of neurological symptom with IVMP. This case report, in addition to others, stresses the likely efficacy of combined craniotomy, IVIG, and IVMP treatments in AHEM. RANBP2 mutations may sensitize the brain to inflammation and predispose to AHEM.

Keywords: Acute demyelinating encephalomyelitis; Acute necrotizing encephalopathy; Crohn disease; RANBP2; encephalitis; sclerosing cholangitis; sickle cell disease.

Figure 1

Brain magnetic resonance imaging on first presentation (day 5) showing multiple areas of abnormal signals (white arrowheads): left midbrain high signal on FLAIR sequence (A), left midbrain hypersignal on T2 weighed (T2W) sequence (B), central gadolinium enhancement of left midbrain lesion on T1 sequence (C), and scattered supratentorial white matter foci of high FLAIR signal (D).

Figure 2

Brain magnetic resonance imaging (MRI) (day 30) at the time of the relapse of the neurological manifestations showing left frontoparietal cortical and subcortical areas of isointense T1, high T2 (A), FLAIR (B), and restricted diffusion (C) signals (arrowhead) increasing in size along the MRI examination, due to an active hyperacute bleed [arrow (A) pointing at spot sign indicating active bleed]. Area of high T2 and FLAIR signal changes (arrowheads) in the head of the caudate nucleus (D) and of abnormal diffusion weighed images (DWI) in the subcortical right cerebellar white matter (arrowheads) (E). Previous left midbrain lesion has resolved with only a tiny residual of high FLAIR signal corresponding to minimal residual gliosis (arrowhead) (F). Follow-up brain MRI at D33 showing a necrotico-hemorrhagic lesion in the left hemisphere (G,I), interval evolution of cortical/subcortical lesions, with new lesions in the bilateral thalami (G), cerebellar hemispheres (H), and right cerebral hemisphere (I) (arrowheads indicate abnormal signals).

Figure 3

FLAIR sequences of brain magnetic resonance imaging (MRI) at day 39 showing interval evolution and improvement of thalamic (A), cerebellar (B), and right cerebral hemispheric lesions (C) with no additional lesions as compared to the previous MRI (arrowheads indicate hypersignal abnormalities).