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  Table of Contents    
Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 146-152
Neuropathology of COVID-19

1 Iowa Neuroscience Institute; Departments of Neuroscience and Pharmacology, Iowa City, IA, United States
2 Human Physiology, Iowa City, IA, United States
3 Iowa Neuroscience Institute; Pathology, Iowa City, IA, United States

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Date of Submission14-Sep-2021
Date of Decision23-Jan-2022
Date of Acceptance28-Jan-2022
Date of Web Publication11-May-2022


The COVID-19 pandemic has placed global health care systems under unprecedented strain but has, at the same time, provided a unique opportunity for pathologists to turn autopsy findings into directly actionable insights into patient care. The current data on the neuropathology of COVID-19 remains preliminary and is limited by the lack of suitable controls, but certain tentative conclusions can be drawn. SARS-CoV-2 can infect multiple cell types in the central nervous system and does so in a subset of patients, although the clinical significance of direct infections remains in the central nervous system (CNS) and the peripheral nervous system (PNS) infections remains unclear. The best-described neuropathological manifestations of COVID-19 in the brain are variable patterns of neuroinflammation and vascular injury, although again, it remains unclear to what degree these findings are specifically due to COVID-19. There is also intriguing preliminary data to suggest a complex relationship between COVID-19 and neurodegeneration, with certain alleles that increase AD risk also increasing the risk of severe COVID-19, and conversely, the possibility that COVID-19 may increase the risk of neurodegenerative disease. The neuropathology of so-called “long-COVID” and the potential effects of COVID-19, or critical illness in general, on neurodegenerative disease remains unclear. There is thus an urgent need for long-term cohort studies of COVID-19 survivors, including brain donation, particularly in elderly patients, with careful recruitment of controls with similar non-COVID inflammatory illnesses.

Keywords: Autopsy, Covid 19, neurologic manifestation

How to cite this article:
Lin LC, Hollis B, Hefti MM. Neuropathology of COVID-19. Indian J Pathol Microbiol 2022;65, Suppl S1:146-52

How to cite this URL:
Lin LC, Hollis B, Hefti MM. Neuropathology of COVID-19. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65, Suppl S1:146-52. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/146/345043

   Introduction Top

Coronavirus disease-19 (COVID-19) is caused by a newly discovered coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV-2). The resulting COVID-19 pandemic has challenged worldwide health care systems on a scale not seen since the 1919 influenza pandemic. It has led to massive influxes of critically ill patients in need of high levels of care, often well beyond the capabilities of existing facilities. Pathologists have been faced with the unique challenges of rapidly setting up and validating clinical tests for SARS-CoV-2 and accommodating demands for postmortem examination of patients dying of COVID-19 for medicolegal and diagnostic purposes. At the same time, this pandemic raises interesting questions and leads to an extraordinary opportunity for pathologists, and particularly neuropathologists, to provide immediate and clinically relevant feedback to clinicians, which can be rapidly translated to changes in patient care. We suggest that further studies characterizing the vulnerable populations of COVID-19 may identify novel targets with implications to prevent neurological manifestations in COVID-19 survivors.

Autopsies in COVID-19

Autopsies performed on deceased individuals with COVID-19 can help clarify symptoms and confirm details that cannot be detected in living patients. One of the most immediate questions raised about COVID-19 in the pathology community was regarding the safety of conducting autopsies in these patients. The reader is referred to published guidelines from the United States Centers for Disease Control (CDC) and equivalent agencies in the UK, European Union, and South Asia for detailed recommendations.[1]

As of this writing, there are only very rare individual reported cases of mortuary or forensic personnel contracting COVID-19 from deceased individuals, and in those cases, the exposure route has not been confirmed.[2] Since the main source of COVID-19 spread is aerosolized from the respiratory tract, the overall risk of contagion from deceased patients is limited in the absence of procedures producing such aerosols. Personal protective equipment for individuals conducting autopsies includes appropriate scrub suit attire under an impermeable gown or apron, double surgical gloves with a cut-proof synthetic mesh glove, and a minimum of an N95 or equivalent face mask. In cases where production of aerosols is anticipated, such as when sawing through the skull, the use of a powered air-purifying respirator with either N95 or HEPA filter is recommended. Eye protection covering the front and side of the face and surgical caps are likewise recommended. The use of full protective suits with self-contained air supplies such as those used in BSL-4 facilities is not required for conducting COVID-19 autopsies. Full recommendations are available from the Centers for Disease Control in the United States and from equivalent agencies in other countries. As of this writing, the Iowa NeuroBank Core has banked more than 25 cases of COVID-19 without issues and has made this fresh-frozen or formalin-fixed tissue available to multiple investigators at our institution. There have been no reported cases of COVID-19 transmission to our brain bank or mortuary staff throughout the course of the pandemic.

Neurological manifestations and clinical features of COVID-19

COVID-19 is the clinical syndrome caused by infection with SARS-CoV-2. The syndrome is a complex clinical spectrum ranging from asymptomatic infection diagnosed only by clinical testing to life-threatening critical illness. Similarly, the neurologic manifestations range from nonexistent to devastating ischemic strokes, severe autoimmune disorders, such as acute disseminated encephalomyelitis (ADEM), and other complications. As expected, reported histopathologic findings in the central nervous system (CNS) and peripheral nervous system (PNS) likewise vary widely across subjects within and between studies. Although hundreds of case reports have been published to date, the most reliable data on the neuropathology of COVID-19 comes from a few large cases series, all of which are from institutions in the United States and Western Europe. These studies are listed in [Table 1].
Table 1: Series with >10 patients reporting COVID-19 neuropathology

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The largest case series stems from the Mount Sinai Medical Center in New York City and reports 100 autopsies, of which 58 included histopathologic examination of the brain.[2] Of these cases, 33% showed acute or subacute infarcts, and 29% showed intravascular microthrombi with associated microinfarcts.[3] A parallel study conducted in Hamburg, Germany, reported 43 patients, with the most common findings being acute infarcts (14%) and leptomeningeal T-lymphocyte infiltrates (79%), with some patients showing parenchymal lymphocytic infiltrates.[4] A smaller German study found frequent microglial nodules and showed a high rate of both microscopic and territorial ischemic lesions.[5] Microglial activation is observed in COVID-19 positive medulla and olfactory bulb with the Ionized calcium-binding adaptor molecule 1 (IBA1) immunoreactivity [[Figure 1]; Hefti et al., unpublished]. Other cases series from the United States and Western Europe reported similar findings.[6],[7],[8],[9] A study conducted in Brazil found encephalopathy, stroke, previous neurological diseases, seizures, neuromuscular disorders, and other acute brain lesions.[10] Several studies also reported peripheral nervous system manifestations, including nerve pain,[11] myalgias,[12],[13] myositis,[14],[15] cranial polyneuropathy,[16],[17] neuromuscular junction disorders,[18],[19],[20] neuroophthalmological disorder,[21],[22] and hearing loss.[23],[24],[25],[26]
Figure 1: Microglial activation in COVID-19 positive medulla (left) and olfactory bulb (right). Slides stained with the Ionized calcium-binding adaptor molecule 1 (Iba1,) a microglia/macrophage-specific calcium-binding protein, and counterstained with hematoxylin (scale bar: 100 μm)

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While the published studies showed high rates of neuroinflammation and suggest a role for vascular injury and/or thrombosis in COVID-19, all these studies have significant caveats. First, none of them include a true control group of patients dying of a similar severity of inflammatory, or ideally infectious, illness such as influenza. It is, therefore, difficult to know to what degree COVID-19 increases the severity of these findings above that normally associated with critical illness and life-threatening infection. It should also be noted that these published series, identified by a systematic search through PubMed by the authors, are all published by authors in the United States and Western Europe. Countries in East and South Asia, Africa, and elsewhere in the world, many of whom were severely impacted by the COVID pandemic, are woefully under-represented. This raises questions about the generalizability of these findings to the global population.

Proposed pathogenesis of COVID-19: Neurotropic virus

One of the earliest questions about the neuropathology and neurobiology of COVID19 involves whether the virus itself can infect the CNS. Angiotensin-converting enzyme 2 (ACE2), the entry receptor of SARS-CoV-2, is highly expressed in the human substantia nigra and cingulate cortex.[27] Early research on COVID-19 benefited from pre-existing human ACE2 transgenic models developed for research on earlier coronavirus strains (e.g., SARS-CoV-1). K18-hACE2 transgenic mice develop anosmia, pneumonia, and direct CNS infection when exposed to SARS-CoV2.[27],[28] Other investigators have reported similar findings in non-transgenic hamster models[29] and non-human primate models.[30],[31],[32] SARS-CoV-2 can infect stem-cell-derived human brain organoids,[33],[34],[35] but it appears that such infection may preferentially affect choroid plexus or glial cells rather than neurons, and it remains unclear if viral replication occurs.[36],[37],[38] A combination of in vivo and in vitro experimental data, therefore, suggests that SARS-CoV-2 can, at least in theory, infect the human CNS.

Translating these findings into human COVID19 has, however, proved both complex and controversial. Viral nucleic acids and proteins can be detected in the human olfactory bulb and olfactory mucosa.[5],[39] There are also case reports of SARS-CoV2 meningitis, confirmed by viral detection in cerebrospinal fluid (CSF).[40],[41] One study based in Germany reported viral nucleic acids in the olfactory bulb, olfactory tubercle, and medulla oblongata, with each in less than 20% of total patients studied (6 of 33 total).[5] Other investigators have used immunohistochemistry to detect SARS- CoV-2 in formalin-fixed paraffin-embedded (FFPE) brain tissue[33] while studies using single-nu- clear RNA sequencing[42] or mass cytometry[43] have been negative. Unfortunately, successful detection of the virus appears to depend strongly on the precise method used. Droplet digital PCR (ddPCR) appears to be particularly sensitive, while qRT-PCR and IHC are less so.[4],[6],[44] Although the number of cases and the available clinical data are both limited, there does not appear to be any correlation between detection of virus in the central nervous system and either presentation or severity of disease, including microthrombotic events, neuroinflammatory and autoimmune syndromes, anosmia, and dysgeusia.[4],[45],[46],[47] The clinical significance of direct viral involvement of the CNS as opposed to secondary inflammatory effects of autoimmune disease thus remains unclear.

Proposed pathogenesis of COVID-19: Neuroinflammatory response

In contrast to the controversy surrounding direct viral infection of the CNS, neuroinflammation appears to be a relatively consistent feature of COVID-19 at autopsy. This ranges from relatively mild, manifesting as perivascular macrophage and focal lymphocytic infiltrates to devastating neuroinflammatory complications such as acute demyelinating encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE, also known as Hurst's disease). A recent large meta-analysis reported a total of forty-six patients who developed ADEM or AHLE with a median age of 49.5 and 1/3 of patients over age 50. The presentation and epidemiology of COVID-19 associated ADEM and AHLE appears to differ from that of its sporadic counterpart, with patients being, on average older, having a more severe antecedent illness and a high mortality rate.[48] Other reported neuroinflammatory complications include rhombencephalitis[49] and posterior reversible encephalopathy syndrome.[50],[51] Initial reports of increased numbers of intra-vascular megakaryocytes proved to be illusory as similar findings were seen in several non-COVID-19 autopsies.[52] Single-cell sequencing and proteomic studies have demonstrated a global immune activation with the involvement of microglia, reactive astrocytes, and macrophages.[43],[53],[54],[55] As with other questions related to the neuropathology of COVID-19, the lack of suitable controls has been a persistent problem. It is not clear to what degree any of these neuroinflammatory changes are associated specifically with infection by SARS-CoV-2 versus viral infection in general or even severe inflammatory illness.

Proposed pathogenesis of COVID-19: Secondary vascular effects on the CNS

Vascular manifestations of COVID-19 are one of the areas for which there is currently the best pathologic evidence. This is an area where data from early autopsies of COVID-19 patients provided immediately actionable data to clinicians treating these patients. One of the first large reported autopsy cohorts from Mount Sinai Medical Center in New York City saw intra-vascular thrombi in multiple organ systems, which prompted increased use of systemic anticoagulation in COVID-19.[3] Further studies by a large group of neuropathologists in the US showed increased leakiness of the blood-brain barrier with increased fibrinogen staining in the parenchyma perivascular macrophage infiltrates in patients with COVID-19, again reinforcing the critical role of vascular injury in these patients.[9] The presence of microvascular injury, including leakiness of the blood-brain barrier is well-documented in both imaging and histologic studies and may relate to direct viral infection of endothelial cells.[7],[56],[57],[58],[59],[60],[61],[62] Again, however, it is unclear to what degree the vascular injury in COVID-19 is different from other patients with systemic infectious and/or inflammatory disorders.

Neuropathology and autopsy findings: “Long-COVID” neuropathology

Although COVID-19 has been responsible for a sharp rise in overall mortality, most patients do, fortunately, recover from their disease. Many of these survivors have experienced long-term complications attributed to COVID-19, including neurocognitive impairment, which is often termed “long-COVID.[63]” The symptoms vary from individual to individual but frequently include the inability to concentrate, cognitive and memory impairment, particularly in older individuals. Although the symptoms themselves are well-documented, the underlying mechanisms remain unclear. Since the pandemic only began in late 2019, there is little neuropathological data on these cases, as most brain banks have only recently begun receiving tissue from COVID-19 survivors, and many of these donations do not have accompanying neurocognitive or neuropsychological testing data, making it difficult to correlate neuropathological findings with clinical signs and symptoms.

Another major issue is that prolonged critical illness and psychological stress are both known to cause long-term cognitive sequelae and that these are also particularly common in older individuals. Distinguishing COVID19-specific neurocognitive impairment from that caused by critical illness and/or extreme emotional stress is therefore very difficult. Doing so would require age- and clinically- matched controls who have similar degrees of physiological and psychological stress. The ideal control population would be individuals of similar age and co-morbidities who died after prolonged infectious or inflammatory disease (e.g., urosepsis, pneumonia) not caused by COVID-19, but, again, due to the relatively early stages of research in this area, such clinical data is not yet available, although a recent initiative by the National Institutes of Health in the United States promises to provide at least preliminary data on COVID19 survivors in the coming years.

It should also be noted that most studies and reports of “long-COVID” stem from the United States and Western Europe. The incidence of such symptoms in other populations remains largely unknown, and such studies will be critical to a proper understanding of the long-term sequelae of COVID19, whether specific to viral infection or a product of an unprecedented rise in critical illness in an aging population. Limited imaging studies suggest that there may be an element of metabolic dysfunction with global brain hypo-metabolism in patients with long COVID, but again, these studies are extremely difficult to interpret in the absence of rigorous neuropsychological workups and carefully selected controls.[64]

COVID-19 pathology in vulnerable populations: Elderly and young children

Although there are certainly cases reported in younger individuals and children, the highest burden of COVID-19 related mortality is among the elderly. Since the incidence of neurodegenerative disease is, of course, also higher with increasing age, this raises the inevitable and difficult to address question of a potential relationship between COVID-19 and neurodegenerative disease. Given that the first cases of COVID-19 were only reported in late 2019, long-term follow-up is, of course, not available. There is, however, an intriguing report, thus far not replicated, suggesting that SARS-CoV-2 can induce tau hyperphosphorylation in human stem-cell-derived brain organoids.[65] The relationship between COVID-19 and Alzheimer's disease is likely to be complex, with APOE4 increasing the risk of both AD and severe COVID-19, and patients with AD having higher ACE2 receptor expression and thus a potentially higher risk of CNS infection by SARS-CoV-2.[66],[67] Given the enormous number of COVID-19 survivors over the age of 65 and thus at the highest risk of developing a neurodegenerative disease, even a small potential increase in neurodegenerative disease risk has the potential for huge impacts on global public health, making this an urgent area for further study.

Children have been, in large part, spared the ravages of the COVID-19 pandemic, but a subset of patients have developed a sometimes-fatal multi-system inflammatory syndrome known as multi-system inflammatory syndrome in children (MIS-C). The Overcoming COVID-19 public health registry, based in the United States, reported a total of 1695 children hospitalized for COVID-19, of which 365 (22%) showed neurologic symptoms. Of these 365 patients, 12% had life-threatening neurologic complications, including severe encephalopathy, stroke, fulminant edema ADEM, and Guillian-Barre syndrome.[68] Existing neurologic conditions (seizures, developmental delay, etc.) were more common in children with neurologic symptoms, although most such cases were in previously healthy patients. Interestingly several conditions associated with prematurity, such as autism, developmental delay, and static encephalopathy, were more common in children with neurologic manifestations of COVID-19. This is in line with other studies suggesting that history of prematurity may itself be a predictor of more severe illness in COVID- 19.[69] Other smaller case series support the broad range of neurologic symptoms in COVID, including strokes like those seen in some adults.[70],[71],[72],[73],[74] As is the case in older adults, the long-term sequelae of COVID-19 on the pediatric nervous system remains unclear. It should also be noted that perhaps thankfully, the number of reported autopsies in children with COVID-19 is very low, which, although it limits our ability to draw conclusions about the neuropathology of pediatric COVID-19, speaks to the skill and heroic efforts of the treating health care providers.

   Conclusions Top

Our understanding of COVID-19's effects on the brain is only in the earliest stages. The data currently available, although the product of heroic efforts by pathologists, other physicians, and researchers worldwide, have only begun to scratch the surface. The available data does, however, suggest some tentative conclusions as a basis for future research. Although SARS-CoV-2 is most likely able to directly infect the human nervous system, such infection is generally at low levels, may not be productive, and does not appear, based on the available data, to correlate with severity of disease or neurologic symptoms. There does appear to be a link between COVID-19 and vascular injury in the central nervous system, as well as in other organs, which appears to increase the risk of stroke in affected individuals, although the underlying mechanisms remain an active area of investigation. COVID-19 patients also appear to have a neuroinflammatory response to infection, although the nature of the response and its clinical manifestations vary significantly between studies. It remains unclear, however, to what degree these findings are unique to COVID-19, rather than being products of severe systemic illness and/or inflammation, and resolving these questions will require continued study and comparison to rigorously selected controls. Given the enormous numbers of COVID-19 survivors worldwide, the long-term health effects of COVID-19 are a public health question of critical importance. There is a critical need for systematic, carefully controlled studies of post-COVID syndrome or “long COVID” to better characterize this debilitating but poorly described syndrome and identify the underlying mechanisms and potential treatment modalities. In older individuals, intriguing preliminary data that suggests a potential link between COVID-19 and neurodegenerative data need to be rigorously and systematically followed up with long-term cohort studies, ideally with neuro-pathological confirmation at the time of death.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Marco M Hefti
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1103_21

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