Acute necrotizing encephalopathy secondary to COVID-19

Abstract

Coronavirus disease 2019 causes a range of presentations, including central nervous system involvement. Acute necrotizing encephalopathy (ANE), in particular, is a growing area of investigation. A high index of clinical suspicion is necessary for early diagnosis and appropriate management. Here, we describe two cases of suspected ANE secondary to the severe acute respiratory syndrome coronavirus-2 virus.

The severe acute respiratory syndrome coronavirus-2 virus (SARS-CoV2) has been reported to cause neurological symptoms in up to 73% of hospitalized patients.¹ The spectrum of neurologic manifestations ranges from nonspecific symptoms to highly specific variants such as Bickerstaff’s encephalitis and acute demyelinating encephalomyelitis.¹ Acute hemorrhagic necrotizing encephalitis (AHNE) and acute necrotizing encephalitis (ANE) appear to be subtypes associated with specific radiological features. Lack of specific diagnostic criteria and overlapping clinical features have led to underrecognition and, consequently, high mortality. Here, we discuss two distinct presentations of ANE/AHNE presumed to be secondary to the SARS-CoV2 virus.

CASE 1

A 58-year-old black woman with known type 2 diabetes mellitus, hyperlipidemia, and hypothyroidism was admitted after she was found unresponsive 4 days following a diagnosis of COVID-19. Her Glasgow coma scale score was 10 (M4V2E4) with a temperature of 106°F, and her white blood cell count was 12.7 K/µL. Computed tomography (CT) of the head showed no intracranial abnormalities. She received tocilizumab, high-dose intravenous steroids, and intravenous acyclovir. Two days later, she developed right-sided weakness, and a repeat CT scan of the head revealed thalamic hypodensities. She was intubated on day 3 and underwent a lumbar puncture, which revealed a cerebrospinal fluid (CSF) protein of 589 mg/dL without pleocytosis. CSF culture was negative. Magnetic resonance imaging (MRI) of the brain was consistent with ANE (Figure 1a, 1b). She underwent five treatments of plasma exchange. Following her second session, she was awake and followed commands. She was extubated on day 9 with deficits of slowed speech, conjugate gaze palsy, and diffuse weakness. Follow-up MRI of the brain was performed (Figure 1c, 1d). After 27 days, she was discharged to a skilled nursing facility.

Figure 1.

Case 1, MRI of the brain. Symmetric FLAIR abnormality in (a) cerebellum and (b) bilateral thalamic and periventricular regions. (c) T2 FLAIR with evolving diffusion restriction. (d) Susceptibility weighted imaging with thalamic microhemorrhages (black arrows).

CASE 2

A 43-year-old black man with known hypertension and hyperlipidemia presented with dizziness. His pupils were unequal in size; the Glasgow coma scale score was 9 (E2V3M4). He was afebrile with a white blood cell count of 13 K/µL. A polymerase chain reaction test for SARS-CoV2 was positive. CT of the head revealed a left occipital intraparenchymal hemorrhage (Figure 2a). MRI of the brain showed a left occipital hematoma, as well as bilateral white matter punctate acute infarcts. His mental status progressively worsened, and he was intubated. Lumbar puncture performed on day 7 revealed a CSF protein of 74 mg/dL with the absence of pleocytosis and negative cultures. Following onset of seizures on day 16, a repeat CT showed cerebral edema in the setting of a stable hematoma; thus, a 3% hypertonic saline infusion was initiated. MRI of the brain (Figure 2b, 2c) led to a diagnosis of AHNE. He was treated with high-dose steroids and plasma exchange. Despite therapies, the patient’s neurologic exam worsened and he died on day 25.

Figure 2.

Case 2 imaging. (a) Initial CT of the head showing intracranial hemorrhage. MRI of the brain: (b) T2 FLAIR showing left occipital hematoma and (c) diffusion-weighted imaging with multifocal diffusion restriction.

DISCUSSION

ANE has been reported to occur with influenza and other viral infections, including COVID-19.^1–6 While the mechanism remains unclear, it is suggested that central nervous system involvement is a result of cytokine storm–mediated IgG production, breakdown of the blood-brain barrier, and viral particle–induced endothelial injury.³

Our cases demonstrate the diversity in clinical and radiologic presentation of COVID-19–related ANE/AHNE, as well as the spectrum of disease severity. The patient in case 1 had a rapid improvement in neurologic function compared to the patient in case 2. The major difference appears to be the timing of the diagnosis and interventions. While we also noted a significant difference in CSF protein levels, one possible explanation is the use of high-dose steroids for an additional 4 days prior to lumbar puncture in case 2.

ANE/AHNE remains a diagnosis of exclusion. Lumbar puncture appears to be of relatively low yield, but the presence of elevated protein in the absence of pleocytosis may be suggestive.^4–6 Central nervous system radiologic findings tend to appear 1 to 2 weeks following the onset of upper respiratory symptoms with initial studies frequently being unremarkable.³ MRI is considered the imaging of choice, with common findings of bilateral cerebral and cerebellar hyperintensities on T2/fluid-attenuated inversion recovery (FLAIR) sequences associated with microhemorrhages and occasionally with restricted diffusion.^3–6 Symmetrical, multifocal thalamic damage is distinctive of ANE²; however, these findings may not be present on early imaging. While long-term outcomes remain uncertain, early immunomodulatory treatment with intravenous immunoglobulin, plasma exchange, and intravenous steroids may portend favorable outcomes.^3–6 Further research into more standardized ways of diagnosing and treating the disease is warranted.