Neurological Presentations of COVID-19

Encephalopathy

Encephalopathy is present in 7%–32% of hospitalized patients with COVID-19. The incidence of encephalopathy is dependent upon the severity of disease, with up to 84% of patients with severe COVID-19 disease displaying encephalopathy at some point during their hospitalization. Older age, a history of neurologic diagnoses, and chronic renal insufficiency are also associated with the presence of encephalopathy. In a French series of 140 intensive care unit patients with COVID-19 and acute respiratory distress syndrome, corticospinal tract signs such as clonus, Babinski sign, and generally increased deep tendon reflexes were seen in 63% of patients, in addition to delirium. These upper motor neuron signs often persisted to discharge. Hyperactive delirium, akinetic mutism, myoclonus, pyramidal and extrapyramidal signs, frontal release signs, and abulia have all been clinically observed in these patients.

It should be noted that encephalopathy in this context refers to any alteration in consciousness up to coma, and may ultimately include patients with other well-defined diagnoses such as stroke or encephalitis. Initial publications did not indicate other clinical impressions, nor results of diagnostic or imaging workup. It is this author’s opinion that the term encephalitis (and not encephalopathy) should be used if there is imaging, CSF, or biopsy evidence of brain inflammation in the setting of altered mental status, seizures, or focal neurologic deficits.

Brain MRI in patients with neurologic symptoms and COVID-19 admitted to the intensive care unit may be normal in up to half of patients. Abnormal brain imaging may lead to a more specific diagnosis than encephalopathy. Common abnormalities are:

• (1)

  Acute or subacute ischemic stroke. This is the most common brain MRI finding in COVID-19 patients.

• (2)

  A patchy or diffuse, confluent, and symmetrical leukoencephalopathy. Radiographically, there are T2 and FLAIR hyperintensities with restricted diffusion in the deep and subcortical white matter, with or without contrast enhancement. In confluent cases, there is a predilection for the precentral gyrus and posterior cerebral white matter.

• (3)

  Microhemorrhages on gradient echo (GRE) or susceptibility-weighted imaging (SWI) sequences. These are often in the juxtacortical white matter and corpus callosum and may be seen alone or accompanying a confluent leukoencephalopathy.

• (4)

  Multifocal linear cortical signal change, manifested by T2 and FLAIR hyperintensity of the cortical ribbon with hyperintensity on diffusion-weighted imaging, with or without changes on the apparent diffusion coefficient (ADC) map.

• (5)

  Contrast enhancement of the subarachnoid space or leptomeninges.

The individual patient’s clinical context must be considered when interpreting MRI findings. Imaging abnormalities may not be specific to SARS-CoV-2 infection and can be seen in critically ill patients due to systemic derangements. Restricted diffusion and FLAIR hyperintensity of the cortical ribbon, leptomeningeal enhancement, and cortical microhemorrhages by SWI or GRE sequences can be seen with hypoxia, hypoglycemia, encephalitis, or seizures. Confluent leukoencephalopathy with or without microhemorrhages has been described in comatose COVID-19 patients following several weeks of mechanical ventilation. This imaging pattern can be seen in encephalitis or delayed posthypoxic leukoencephalopathy; given the overall clinical scenario, the latter mechanism has been proposed as more likely.

In COVID-19-related encephalopathy, EEG is typically abnormal and nonspecific. However, a pattern of frontal abnormalities has emerged as potentially characteristic of COVID-19. The most common background abnormality is diffuse slowing (69% of EEGs); many fewer patients have focal slowing (which is frontal in half of cases) or the absence of the posterior dominant rhythm (10%). Other electrographic patterns seen in patients with COVID-19 encephalopathy are frontal intermittent rhythmic delta activity and triphasic waves. Many EEGs are nonreactive. Importantly, when the clinical indication for an EEG was encephalopathy or coma without a preceding history of seizure, epilepsy, or acute or chronic brain injury, seizures are rarely if ever found. This finding is different than that of the previous studies of patients with sepsis and it has important implications for EEG ordering and triage during a pandemic of an airborne infectious disease.

CSF analysis of patients with COVID-19 encephalopathy reveals a normal cell count or a mild pleocytosis, a normal to elevated protein, and is typically negative for SARS-CoV-2 PCR and other infectious etiologies. Serologic profiles for autoimmune antibodies are normal. Inflammatory cytokines such as IL-6, IL-8, and TNF-alpha may be elevated in the CSF.

Treatment of COVID-19 encephalopathy is not standardized. Supportive medical care, avoidance of iatrogenic causes of delirium, and tincture of time are pillars of treatment for all patients. Over the first few months of the SARS-CoV-2 pandemic, the dramatic role of systemic cytokines and autoimmunity in the pathogenesis of COVID-19 was increasingly appreciated. As such, treatments dedicated toward suppressing the systemic inflammatory response were tried in individuals or small groups of patients with severe encephalopathy. High-dose corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis (PLEX) have all been used, with reported quick and dramatic improvement in the patients’ clinical syndromes (including coma) over days. Whether these treatments led to improvement, or the improvement was the natural history of the disease, is an open question.

Encephalopathy in COVID-19 is associated with longer hospitalizations, longer mechanical ventilation, and worse discharge functional outcomes. After adjusting for age and severe COVID-19 disease, patients with encephalopathy have a higher risk of mortality at 30 days than those without encephalopathy (OR 2.92). Following discharge, about one-third of patients continued to have cognitive dysfunction, manifesting as poor attention and orientation and difficulty with movements to command. More on COVID-19-related encephalopathy can be found in Chapter 10 .

Neuroinflammatory Syndromes