Table 2.

Proposed mechanisms of AM in COVID-19 and associated case reports

Etiology	Proposed mechanisms	Hypotheses	Case references
Severe respiratory illness	Systemic inflammation Hypoxic-ischemic injury Coagulopathy	AM may result from BBB and mesolimbic disruption from systemic inflammation; from DPHL or other direct hypoxic injury; or strategic infarcts from COVID-19 associated hypercoagulability; neuronal pathways from lung to CNS	Cani et al. 2021 Lang et al. 2020 Muccioli et al. 2020 Nersesjan et al. 2021 Wu et al. 202046
Meningoencephalitis	Systemic inflammation CSF-specific antigens Local CNS invasion	AM may result from local inflammation disrupting BBB in frontal subcortical circuitry (fenestrated endothelium and choroid plexus), producing inflammatory responses either to direct viral invasion or CSF-specific antigens, the latter of which may develop from parainfectious immune dysregulation.	Gaughan et al. 2021 Pilotto et al. 2020 Pilotto et al. 2021 Achar and Ghosh 202047
Neuropsychiatric vulnerability	Systemic inflammation Underlying dopaminergic deficit/dysregulation	AM may result from systemic inflammation disrupting dopamine synthesis, producing AM in patients with pre-existing dopaminergic dysfunction.	Ahmad and Rathore 2020 Beach et al. 2020 Brown et al. 2020

AM = akinetic mutism; BBB = blood-brain barrier; DPHL = posthypoxic leukoencephalopathy.