Challenge Case Report: PostCOVID-19 Encephalitis

Case Resolution

In light of known SARS-CoV-2 infection, negative test results including a negative brain biopsy, consistency with reported SARS-CoV-2 biopsies, and resolution of symptoms with time, OG was diagnosed with COVID-19–related encephalitis. This diagnosis is further supported by lesion resolution on MRI over time. Although OG had a positive urine drug screen, neither substance use nor toxins were considered possible causes of the seizure-like episode because they had not ingested alcohol and had no history of withdrawal seizures or signs of withdrawal during hospitalization. OG recovered over 3 months and is now symptom-free, although still treated with an antiseizure medication post brain biopsy. Their most recent brain MRI revealed near complete recovery (Figure 2).

Discussion

COVID-19

SARS-CoV-2 emerged in the Wuhan Province of China in December 2019. The virus quickly spread, resulting in a global pandemic with millions of deaths worldwide. Clinical presentation can range from asymptomatic infection to life-threatening pneumonia.^1,2 We follow a case of postviral encephalitis related to SARS-CoV-2 infection in a person, age 26, who presented to the emergency department with a generalized tonic-clonic seizure a week after a mild COVID-19 disease course. MRI studies at the time showed a single 3x5-cm enhancing lesion with surrounding edema suspicious for a brain tumor. The lesion was biopsied and determined to be consistent with post COVID-19 related encephalitis. Over time, they fully recovered. Repeat MRI showed resolution of the enhancing lesion. Post COVID-19 encephalitis rarely presents as a mass-like lesion rather than disseminated encephalitis.

Despite SARS-CoV-2 being a respiratory virus, it affects not only the respiratory system and has many documented neurologic effects.^3-5 Encephalopathy is common in hospitalized individuals. Although immune-mediated encephalitis has been documented, encephalitis related to direct viral invasion is rare. Stroke, seizures, myelitis, and peripheral neuropathies have also been reported. Anosmia is also common. People with severe infections are more likely to develop neurologic symptoms, but mild cases have also been associated with neurologic complications. Some patients may present with neurologic symptoms before a COVID-19 diagnosis has been made.⁵

COVID-19 has been associated with neurologic findings in 36% of cases.^3-5 The most common of these findings are dizziness and headache. Meningitis and encephalitis can occur, although CSF testing is often negative for SARS-CoV-2 during an active infection. Thus, the virus may rarely invade the central nervous system (CNS). Hemorrhage, vascular thrombosis, and flair signal abnormalities are also reported as common neurologic imaging findings during infection.⁶

The SARS-CoV-2 CNS mechanism of infection is not fully understood. Because the virus enters cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is found in glial cells of the brain and spinal cord, it is plausible that this receptor could be an access point. Direct invasion, however, seems to be rare. Damage to the neurologic system during infection could be caused by immune-related damage, hypoxia, molecular mimicry, or an inflammatory state from the virus.^7-9

Encephalitis

Encephalitis is a neurologic emergency defined by encephalopathy and evidence of CNS inflammation. It is most commonly caused by viruses, but many other infectious agents as well as autoimmune etiologies have been identified. CNS inflammation is defined by 2 of the following: fever, seizures, CSF pleocytosis, EEG findings, and neuroimaging findings. Typically, CSF findings are normal to moderately raised glucose, normal protein, and usually pleocytosis of more than 5x10⁹ white cells/L. EEG is useful to identify seizure activity but is not specific for encephalitis. Immunoglobulins and oligoclonal bands can be elevated in encephalitis as well. Brain biopsy for diagnosis has declined owing to availability of PCR testing. However, in patients with a questionable diagnosis with focal abnormalities, it may be indicated. Except in cases caused by herpes simplex virus (HSV), treatment is mostly supportive for viral encephalitis and meningitis.^10,11

Encephalitis is a rare but documented complication of COVID-19, with an estimated incidence of 0.215%. The onset of encephalitis from COVID-19 diagnosis can be immediate or several weeks after infection. Severely ill patients have a higher risk of developing this complication. Commonly associated MRI findings include diffuse white matter hyperintensities and hemorrhagic lesions. Cerebral edema, venous thrombosis, and seizures have also been reported. Some encephalitis subtypes, (eg, acute disseminated encephalomyelitis [ADEM]), are severe. The pathophysiology of encephalitis related to COVID-19 is still debated. Based on limited case reports, the most common cause of encephalitis seems to be autoimmune.^7,8 OG did not present with typical encephalitis on imaging, but rather with a mass-like lesion. This is scarcely reported as a complication of COVID-19 in the literature.¹²

A postmortem study in Germany investigated the neuropathology of people with COVID-19. The study revealed that SARS-CoV-2 gains access to the brain and that most cases of neurologic damage are immune mediated. Immunohistochemical staining for glial fibrillary acidic protein (GFAP) revealed astrogliosis, reactive microglia activation, occasional microglial nodules, and CD8 infiltration.⁹ Another study reported similar neuropathology findings but also discovered that around half (53.5%) of brain biopsies were positive for SARS-CoV-2 by reverse transcriptase (RT) PCR, indicating direct invasion by the virus.¹³ OG’s biopsy showed astrocytosis, necrosis, and lymphocytic infiltration consistent with COVID-19 encephalitis as described. Importantly, their biopsy was negative for atypia, anaplasia, and increased mitotic activity, making glioblastoma or other malignancy unlikely.

Treatment

Treatment of COVID-19 encephalitis is supportive. High-dose intravenous (IV) steroids, IV immunoglobulin, and immunomodulators have been tried, but data on outcomes are extremely limited.¹⁴ OG recovered to baseline following their clinical course.

Conclusion

SARS-CoV-2 is a novel virus with rare but significant neurologic manifestations. The virus could directly invade the CNS or cause damage through inflammation or molecular mimicry. COVID-19 encephalitis may present as a mass-like lesion rather than disseminated encephalitis. This presentation is not associated with any particular findings on EEG, head CT, brain MRI, or CSF analysis, so it is important to keep COVID-19–related neurologic symptoms including encephalitis on the differential.