Acute Disseminated Encephalomyelitis and Acute Hemorrhagic Leukoencephalitis Following COVID-19: Systematic Review and Meta-synthesis

Abstract

Background and objectives: Since the onset of the COVID-19 pandemic, a growing number of reports have described cases of acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE) following infection with COVID-19. Given their relatively rare occurrence, the primary objective of this systematic review was to synthesize their clinical features, response to treatments, and clinical outcomes to better understand the nature of this neurologic consequence of COVID-19 infection.

Methods: Patients with a history of COVID-19 infection were included if their reports provided adequate detail to confirm a diagnosis of ADEM or AHLE by virtue of clinical features, radiographic abnormalities, and histopathologic findings. Cases purported to be secondary to vaccination against COVID-19 or occurring in the context of a preexisting relapsing CNS demyelinating disease were excluded. Case reports and series were identified via PubMed on May 17, 2021, and 4 additional cases from the authors' hospital files supplemented the systematic review of the literature. Summary statistics were used to describe variables using a complete case analysis approach.

Results: Forty-six patients (28 men, median age 49.5 years, 1/3 >50 years old) were analyzed, derived from 26 case reports or series originating from 8 countries alongside 4 patient cases from the authors' hospital files. COVID-19 infection was laboratory confirmed in 91% of cases, and infection severity necessitated intensive care in 67%. ADEM occurred in 31 cases, whereas AHLE occurred in 15, with a median presenting nadir modified Rankin Scale score of 5 (bedridden). Anti-MOG seropositivity was rare (1/15 patients tested). Noninflammatory CSF was present in 30%. Hemorrhage on brain MRI was identified in 42%. Seventy percent received immunomodulatory treatments, most commonly steroids, IV immunoglobulins, or plasmapheresis. The final mRS score was ≥4 in 64% of patients with adequate follow-up information, including 32% who died.

Discussion: In contrast to ADEM cases from the prepandemic era, reported post-COVID-19 ADEM and AHLE cases were often advanced in age at onset, experienced severe antecedent infection, displayed an unusually high rate of hemorrhage on neuroimaging, and routinely had poor neurologic outcomes, including a high mortality rate. Findings are limited by nonstandardized reporting of cases, truncated follow-up information, and presumed publication bias.

Figure 1. PRISMA Flow Diagram Demonstrating Case Selection Methodology

PRISMA flow diagram illustrating source information used, the screening process used and its effects on excluded articles, and final articles and cases selected for study inclusion.

Figure 2. Neuroimaging Examples From the MGB Case Series

Axial brain MRI sequences of patients with post-COVID ADEM from the MGB case series. (A–C) Axial brain MRI sequences from case 1 display FLAIR hyperintensities in the bilateral frontal lobes, anterior temporal lobes, and cerebellum. (D and E) Axial brain MRI sequences from case 2 show bilateral FLAIR hyperintensities with a prominent right parietal lesion that enhances, as well as nodular enhancement of the right corona radiata and occipital horn of the right lateral ventricle. (F) Sagittal postcontrast T1 sequence of the cervical spine MRI from case 2 displays a focus of intramedullary enhancement at C4-5 (red box). (G–I) Axial brain MRI sequences from case 3 show diffuse, multifocal T2 FLAIR lesions (G and I) and a predominant open-ring contrast enhancement pattern of several lesions in the T1 postcontrast sequence (H). ADEM = acute disseminated encephalomyelitis; MGB = Massachusetts General Brigham.

Figure 3. Neuropathology Examples of Post–COVID-19 ADEM

Brain pathology from case 2 of the MGB series (case details provided in the supplementary files, links.lww.com/NXI/A584). Low-power images (A–D) demonstrate markedly cellular brain parenchyma with prominent perivascular inflammation and reduced myelinated fibers (A, Luxol–H&E stain), with relative preservation of axons (B, neurofilament immunohistochemistry). The cellular population is composed largely of macrophages (C, CD68 immunohistochemistry), whereas the perivascular infiltrates are predominantly T cells (D, CD3 immunohistochemistry). Higher-power views (E–H) characterize the perivascular infiltrates as composed of small mature lymphocytes and focally prominent plasma cells (E, H&E, open arrows), whereas the surrounding tissue is composed of numerous foamy macrophages (solid arrows) and reactive astrocytes. Immunohistochemistry demonstrates scattered perivascular and parenchymal plasma cells (F, CD138), numerous parenchymal foamy macrophages (G, CD68), and marked perivascular T cells (H, CD3). ADEM = acute disseminated encephalomyelitis; MGB = Massachusetts General Brigham.