COVID-19-Associated Acute Necrotizing Encephalopathy with Neuronal Autoantibodies

A case study published earlier this summer describes COVID-19-associated acute necrotising encephalopathy with the presence of IgG reactive to cerebral fibers. Writing in J Neurol Neurosurg Psychiatry, Dalamarre et al. describe the case of a 51-year-old man without family history of neurological disease (Delamarre et al., 2020). After 10 days of fever and cough, he was hospitalized and diagnosed with COVID-19 via positive rtPCR and bilateral ground-glass opacities on chest CT. On day 12, he was admitted to the ICU for non-invasive ventilation and by this point, his neurological examination was normal.

“At day 21, while the patient had been weaned off oxygen, he became unresponsive and rapidly comatose (Glasgow Coma Scale 6: E1, V1, M4) with a disconjugated gaze. The patient was groaning and showing rhythmic movements of the right upper limb.”

Brain MRI ruled out vertebrobasilar ischemic stroke and “gradient echo T2-weighted images excluded hemorrhage and thrombus in the venous system.” There were only subtle hyperintensities in bilateral thalami on FLAIR. At this point, the patient’s consciousness was imparied, which required him to get intubated. Blood and CSF sample analysis revealed thrombopenia (low blood platelet count) and lymphopenia (low blood lymphocyte count), “mild inflammatory response (C reactive protein, ferritin and fibrinogen), CSF albumin-cytological dissociation with increased CSF IgG antibodies[…] and altered blood-brain barrier integrity[…]” On day 22, a contrast-enhanced MRI revealed progressive lesions in the thalami, cerebellum, brainstem, supratentorial gray and white matters. The authors then began looking for autoantibodies in serum and CSF. Anti-ganglioside autoantibodies in serum were negative, anti-myelin oligodendrocyte glycoprotein in CSF were negative, and anti-neuronal (NMDAR, AMPAR, GABAbR, AMPA1/2, Caspr2, Lgi, DPPx, FA 112d-1003-6) autoantibodies were negative in serum and CSF. However, indirect immunofluorescence revealed specific and atypical IgG staining on monkey cerebellum slices which was not seen on any other tissues tested. The staining was located around Purkinje cells as well as fibers in the inner portion of the molecular layer. They then tested patient IgG on rat hippocampal slices and found strong yet unusual staining in fiber tracts. Parts of the fiber network that were strongly stained were the ventral hippocampal commissure and the brachium of the colliculus and the stria medullaris.

An MRI on day 25 revealed stable lesions. The patient’s neurological status improved and he was taken off mechanical ventilation. He had complete motor recovery and was discharged from the ICU at day 29. On day 35, MRI brain revealed significant improvement in lesions although clinical examination demonstrated memory and attentional impairment. Patient was diagnosed with acute necrotizing encephalopathy without hemorrhage due to respiratory virus. The authors suspect that the neurological disease was triggered by host immune response to COVID-19, and was associated with IgG targeting an unknown neuronal antigen through molecular mimicry with the virus.

This case study is one of a few that has described a suspected autoimmune disorder associated with COVID-19, and it is one of the only studies that has traced an  autoantibody in the patient’s case. It is evident that more scientific and clinical work needs to be done to identify potential autoantigens that share structural similarities with SARS-CoV-2 antigens.