Multifactorial White Matter Damage in the Acute Phase and Pre-Existing Conditions May Drive Cognitive Dysfunction after SARS-CoV-2 Infection: Neuropathology-Based Evidence

Abstract

Background: There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms. Methods: We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria. Results: All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic–ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%). Conclusions: Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

“…Neuro-invasion of SARS-CoV-2 occurs via transcribrial (nose) route with damage to olfactory mucosa, and olfactory nerves, ultimately manifesting into anosmia (loss of smell) 197 , 198 . COVID-19 patients also display diffused white matter damage, microglial activation, and neuroinflammation at different CNS regions with olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%) 199 . Reactive gliosis, astrocytosis, and microglial activation, along with neuroinflammation gradually advances from COVID-19 to PASC 200 .…”

Reported neurological symptoms after severe acute respiratory syndrome coronavirus type 2 infection: A systematic diagnostic approach

“…These results are in line with a recently published prospective cohort study by Fleischer et al [7], and are covered by scientific progress. Currently, it is believed that SARS‐CoV‐2 is not a neurotropic virus and does not cause damage to olfactory sensory neurons, which have been considered a migration gateway to the central nervous system [10, 11]. Based on postmortem findings in 85 corona‐afflicted patients, they suggest that actually the sustentacular (supporting) cells of the epithelium are transiently damaged, which causes transient anosmia and ageusia [50].…”

“…Also of utmost importance is the causal plausibility and, thus, diagnostic certainty of whether the reported neurological complaints are due to a previous SARS‐CoV‐2 infection or to another medical (e.g., concomitant or new disease) or nonmedical (e.g., psychosocial factors related to the pandemic crisis) cause. Currently, there is no evidence of SARS‐CoV‐2 being a neurotropic virus [10, 11]. Several publications suggested psychological mechanisms behind the symptoms [12, 13].…”

S1 guidelines for the management of postviral conditions using the example of post-COVID-19

“…Auf der anderen Seite weisen sie in den Limitationen jedoch auch darauf hin, dass sich bei Hinzuziehen von weiteren Messmethoden auch andere Ergebnisse zeigen könnten [ 104 ]. Dem heutigen Stand entsprechend, ist SARS-CoV‑2 kein neurotropes Virus [ 105 ], entsprechende Auffälligkeiten im Gehirn dürften auf eine indirekte Entzündungsreaktion zurückzuführen sein [ 106 ].…”

“…Somit ist von einer persistierenden Infektion des ZNS NICHT auszugehen. Eine rezente Studie zeigt, dass inflammatorische Komponenten im Gehirn indirekte Ursache einer SARS-CoV-2-Infektion sind [ 106 ] und es sich nicht um ein neurotropes Virus handelt [ 105 ].…”