Our understanding of SARS CoV-2 infections and COVID-19 is rapidly evolving; significant gaps in our knowledge remain. The neuropathology in the case presented raises questions about the pathophysiology of the infection in the central nervous system (CNS) and provides insights into the neurological complications of these patients. Parainfectious conditions are well known to develop after viral infections, including SARS. In this case, the pathological lesions are distinct and the interpretation is not confounded by underlying severe global hypoxic–ischemic brain injury with concomitant regional infarcts. The striking features of the pathology presented include the range of subcortical white matter pathology, the absence of deep grey nuclei or brainstem pathology, and the lack of typical features of viral and post-viral encephalitides.
We describe several types of pathological lesions that may contribute to neurological manifestations of COVID-19 patients. The widespread hemorrhagic white matter lesions identified have some of the characteristic features of AHLE. Similar hemorrhagic lesions have previously been described with SARS-CoV, but are reported within a background of extensive neuronal necrosis , which we did not observe. AHLE often presents fulminantly and results in rapid death. The relative paucity of significant reactive changes in the case presented suggests that, indeed, these occurred in close chronological proximity to the patient’s death. Clearly necrotic blood vessels and perivascular inflammation, however, were not identified in association with the larger hemorrhagic lesions. The prominent acute axonal injury and loss, coupled with preserved remnants of myelin within these hemorrhagic lesions, is also not typical of classic AHLE. Another distinct pathology identified was characterized by small (< 5 mm) white matter lesions with clusters of macrophages and a range of associated axonal injury. Some lesions appeared to be more perivenular in nature, tracking along vessels, resembling an acute disseminated encephalomyelitis (ADEM)-like histological appearance. However, the variable perivenular association, coupled with the absence of intracortical and cortical subpial demyelination, absence of cortical microglial activation, paucity of lymphocytic inflammation, and prominent acute axonal injury are not characteristic of classic ADEM . Although not all lesions were clearly necrotic, it is also possible these white matter lesions are vascular in origin. Other lesions had marked central axonal injury, associated extravasated blood, and surrounding myelin loss, reminiscent of subtle “ball-and-ring” microhemorrhages. Whether these white matter lesions reflect distinct pathological processes or a continuum of a single disease is unclear. The neocortical microscopic infarcts identified raise the possibility of microthromboembolic events, possibly related to COVID-19 and associated complications, or in this patient, could be related to his other underlying medical conditions and treatments.
The fundamental question is whether the observed neuropathological lesions are a result of primary vascular disease with secondary white matter injury (e.g. acute axonal injury, secondary demyelinating pathology) or is due to a parainfectious primary demyelinating type of disease or a combination. Parainfectious conditions, such as post-viral autoimmune disorders, have been described in association with a variety of viruses, including coronaviruses (e.g., SARS-CoV), and variety of potential routes of CNS infection have been proposed . The potential explanations of the neurological symptoms include direct infection (e.g. viral encephalitis), metabolic etiologies of encephalopathy, and secondary cerebrovascular insults . Imaging case studies of COVID-19 patients have suggested pathological lesions characteristic of ADEM, and acute hemorrhagic AHLE . Recent descriptions of large vessel cerebral infarcts in patients that would not be expected based upon their age and co-morbidities suggest an underlying vasculopathy or coagulopathy . Research into the pathophysiology of SARS-CoV proposes a role for the viral ACE2 receptor as a potential mechanism of injury . The lack of microglial nodules, the paucity of perivascular and leptomeningeal inflammation, absence of neuronophagia, and preservation of deep gray structures/brainstem/spinal cord distinguish it from other viral encephalitides and would suggest a vascular origin with secondary myelin loss.
Parainfectious neuropathological processes typically present after a latent period following an infectious illness. The prolonged course of this patient suggests that during his hospitalization, he developed a secondary disease initiated by SARS CoV-2, which raises the clinical question of when, or if, to consider evolving neurological processes during a prolonged period of intubation. Further complicating the clinical management of these patients is the microscopic white matter lesions, and cortical infarcts would not be readily apparent with routine imaging studies. Furthermore, these patients may not be stable, or appropriate, for transporting for more complex imaging studies. Our understanding of the parainfectious neuropathology of SARS CoV-2 continues to evolve, but remains a cause of either devastating outcome or morbid sequelae in many patients that do survive.