key: cord-0989206-h786qsjt
authors: Young, Michael J.; O'Hare, Meabh; Matiello, Marcelo; Schmahmann, Jeremy D.
title: Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration?
date: 2020-07-15
journal: Brain Behav Immun
DOI: 10.1016/j.bbi.2020.07.007
sha: 282804bc3372b81e19f3c4a8d1a5653b71f71e0d
doc_id: 989206
cord_uid: h786qsjt

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 (COVID-19). Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient’s prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 . Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient's prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.

A 65-year-old previously healthy man developed fever several days after co-habitant family members were diagnosed with COVID-19. He became confused, slowed and forgetful, and tested PCR positive for SARS-CoV-2. Over two weeks his disorientation worsened, he developed paucity of speech with paraphasic errors, and unsteady gait with intermittent right-hand clenching. On admission he was inattentive and perseverative, with non-fluent discourse, anomia, impaired comprehension, phonemic paraphasias, and intermittent myoclonic jerks of the right arm. Laboratory studies revealed abnormal inflammatory markers (summarized in Table 1 ). Cerebrospinal fluid (CSF) was acellular, with normal opening pressure, protein, glucose, bacterial culture, IgG and banding pattern, and HSV PCR. CSF and serum autoimmune encephalopathy panels were negative. Electroencephalogram (EEG) revealed abundant 1-1.5 Hz left lateralized periodic discharges and diffuse delta-theta slowing (Figure 1 ). Brain 

Neurological manifestations of COVID-19 include headache, delirium, anosmia, increased stroke risk, dizziness, and encephalitis. This first report of CJD in a patient with COVID-19 may reflect pure coincidence, given the high, likely underestimated, prevalence of clinically manifest and asymptomatic COVID-19, and the annual incidence of CJD of approximately 1 per million. However, this case raises the specter of a clinically meaningful interaction in which infection with SARS-CoV-2 precipitates or accelerates neurodegenerative diseases.

Animal and human studies of neurodegenerative disease and brain injury show that release of pro- Depending on local milieu, astrocytes may be induced to assume one of two distinct reactive forms: a neurotoxic A1 phenotype and a neuroprotective A2 phenotype. A1 astrocytes potentiate death of neighboring neurons and oligodendrogliocytes. 4 Il-1, TNF and C1q are collectively necessary and sufficient for A1 astrocyte activation. 4 In prion disease, A1 reactive astrocytes are thought to be neurotoxic by mediating neuronal damage of adjacent neuronal processes and serving as foci for PrPSc propagation. 5 Pre-clinical CJD is marked by retention of region-specific homeostatic identities of glia, including astrocytes. During the transition to clinical CJD these region-specific signatures are lost and replaced by a neuroinflammatory transcriptome signature that affects astrocyte sub-populations in a region-dependent manner. 5 The simultaneous clinical presentations of COVID-19 and CJD in this patient led us to hypothesize that the cascade of systemic inflammatory mediators that characterize COVID-19 may have accelerated the prion disease pathogenesis and neurodegeneration by facilitating loss of region-specific homeostatic identities of astrocytes and fostering a neuroinflammatory transcriptional signature. The molecular mechanism remains to be determined, but there is empirical support for our hypothesis in that there is inflammasome activation and increased secretion of Il-1 6 , TNF and complement cascade in COVID-19 7 , and the fact that Il-1, TNF and C1q are necessary and sufficient for activation of A1 astrocytes 4 which affect prion propagation.

Lateralized presentation of CJD has been reported previously. Notably, lateralized modulation of immune function 8 and inter-hemispheric asymmetry in basal levels of cytokines and distribution of microglia are documented 9 , perhaps predisposing to asymmetric prion disease propagation and neurodegeneration, and compounded by systemic inflammatory responses.

Neurological dysfunction in COVID-19 is likely caused by immune responses systemically and within the nervous system. 10 Our hypothesis that inflammatory responses to SARS-Cov-2 precipitate or exacerbate neurodegenerative disease is urgent because COVID-19 portends disproportionately worse outcomes in the elderly who are already at risk of neurodegenerative disease. 

Inflammation in the early stages of neurodegenerative pathology

Immune responses in rapidly progressive dementia: a comparative study of neuroinflammatory markers in Creutzfeldt-Jakob disease, Alzheimer's disease and multiple sclerosis

Accelerated onset of cnS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase

Neurotoxic reactive astrocytes are induced by activated microglia

Region-specific glial homeostatic signature in prion diseases is replaced by a uniform neuroinflammation signature, common for brain regions and prion strains with different cell tropism

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Cerebral lateralization and the immune system

Brain interleukin asymmetries and paw preference in mice

Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19