- The first presumptive case of COVID-19 associated acute necrotizing hemorrhagic (ANE)—related to intracranial cytokine storms, which result in BBB breakdown.
- 3-day history of cough, fever, and altered mental status 
- Testing for the presence of SARSCoV-2 in the CSF was unable to be performed
- Evidence of ANE:
- CT images demonstrated symmetric hypoattenuation within the bilateral medial thalami with a normal CT angiogram and CT venogram (Fig 1).
- Images from brain MRI demonstrated hemorrhagic rim enhancing lesionswithin the bilateral thalami, medial temporal lobes, and subinsular regions (Fig 2).


Case Study: COVID-19–associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features

- show brain tissue edema
- partial neuronal degeneration
- presence of SARS-CoV-2 in the CSF

Brain Autopsy Reports of CoV-19 patients in Beijing Ditan Hospital

Several studies have reported case studies of patients who experienced ophthalmoparesis-like symptoms including diplopia. MRI imaging points toward forms of cranial and bilateral abducens nerve palsy as possible associated-structural deficits. One patient was diagnosed with Wernicke's encephalopathy.

Case Study: COVID-19-Associated Ophthalmoparesis and Cranial Nerve Palsy

When SARS-Cov2 activates cytokines (interleukin-1, interleukin-16, and TNF-alpha), it penetrates the blood-brain barrier (BBB), leading cytokines to cross the brain parenchyma. A powerful subsequent inflammatory response and the influx of blood material into the brain causes encephalopathy, as well as seizures.

Cause of Encephalopathy in COVID-19 Patients

In a study of 43 patients, one (55-year old female) was diagnosed with acute parainfectious encephalopathy with psychosis. The patient did not have a psychiatric history. A day after she was discharged after having COVID-19, her husband reported confusion, abnormal behaviour, and features of psychosis. Even though her disorientation improved, her psychosis did not. Though fluctuating, she trended towards improvement after treatments with haloperidol, followed by risperidone.

Case Study: Acute Parainfectious Encephalopathy with Psychosis 

In studies conducted in Wuhan, China and France, 93 patients total were found with encephalopathy. Most of these patients experienced symptoms such as dizziness, headaches, and a reduced state of consciousness.

Smith College

University of Michigan - Ann Arbor

Encephalopathy is an umbrella term for damages and diseases to the brain. They include, but are not limited, to the following:
- Ischemic Stroke
- Ophthalmoparesis

Encephalopathy 

- Encephalopathy (overall)
- Ischemic Stroke
- Multisystem Inflammatory Syndrome in Children (MIS-C)
- Induce brain and spine demyelinating lesions
- Mast cell activation
- Acute cerebrovascular disease 
- Intracranial hemorrhage
- Seizure (caused by meningitis)
- Neuroinflammatory syndromes 
- Post-infection cerebral changes

COVID-19 Reports on Patient Neurological Symptoms, Organized by Symptoms Affecting the CNS

Filatov, A., Sharma, P., Hindi, F., & Espinosa, P. S. (2020). Neurological complications of coronavirus disease (COVID-19): encephalopathy. Cureus, 12(3).

doi: 10.7759/cureus.7352

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170017/

Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy

Ellul, M. A., Benjamin, L., Singh, B., Lant, S., Michael, B. D., Easton, A., 
     Kneen, R., Defres, S., Sejvar, J., & Solomon, T. (2020). Neurological 
     associations of COVID-19. Lancet. https://doi.org/10.1016/ 
     S1474-4422(20)30221-0 
https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(20)30221-0/fulltext#seccestitle10

Neurological Associations of COVID-19

Ischemic stroke refers to a stroke caused by blockage of an artery delivering blood to the brain. Limited oxygen and blood flow leads to cell death.

Ischemic Stroke

Encephalopathy in COVID-19 Patients.

A type of encephalopathy that is associated with weakness and/or paralysis in the extraocular muscles of the eye orbit.

Ophthalmoparesis

- Encephalopathy
- Meningism
- Headaches
- Ataxia
- Dysarthria
- Dysphagia
- Splenium of the corpus callosum (SCC) lesions

Multisystem Inflammatory Syndrome in Children (MIS-C) in COVID-19 Patients: CNS Symptoms

SARS-CoV-2 is known to activate mast cells in affected patients, along with other immune cells including monocytes/macrophages, neutrophils, T cells, killer cells, and resident tissue epithelial and endothelial cells. These various groups cells have been thought to induce the "cytokine storm syndrome" that is experienced by COVID-19 patients. However, since mast cells are well-expressed throughout the body (including the CNS) and are involved in certain neuroinflammatory diseases, it is hypothesized that their activation by SARS-CoV-2 upregulates certain neuroinflammatory responses, which may result in some of the other symptoms observed in COVID-19 patients, including ischemic stroke.

Mast Cell Activation in COVID-19 Patients

In the study by Li et al., a majority of the 221 COVID-19 patients had ischemic infarcts in both small and large arterial vessels, and 13 (5.4%) had imaging-confirmed cerebrovascular disease. Another study by Oxley et al. reported 5 patients under age 50 with cerebrovascular disease and noted that even without presenting typical respiratory symptoms, young healthy patients with COVID-19 may experience large strokes. The 5 young patients were treated with either antiplatelet or anticoagulation.


Acute Cerebrovascular Disease in COVID-19 Patients

While a majority of COVID-19-related strokes have been ischemic, a few have been intercranial hemorrhage, although the causes of the latter are not yet understood. One potential explanation is that SARS-Cov2 binds to and downregulates ACE2, slowing the conversion of angiotensin II to angiotensin, and that since higher levels of angiotensin II are associated with vasoconstriction, this causes blood vessels in the brain to rupture. ACE2 polymorphism may explain the increased risk of intracranial hemorrhage among the East Asian population.


Intracranial Hemorrhage in COVID-19 Patients

As the meninges have high quantities of blood vessels and ACE2, damage to these blood vessels and meninges inflammation resulting from SARS-Cov2 can lead to symptoms of meningitis, such as acute headache, stiff neck, confusion, and seizure. 

Potential Link Between Seizure and Meningitis in COVID-19 Patients

Neuroinflammation is an innate immune response to percieved threats in the nervous system, which can lead to neurological complications. In a study of 43 patients, 12 developed neuroinflammatory syndromes, including:

- Encephalitis 
- Acute disseminated encephalomyelitis (including acute haemorrhagic leucoencephalitis and ADEM-like illnesses)
- Myelitis

Neuroinflammatory Syndromes in COVID-19 Patients 

Several studies have suggested that COVID-19 patients have long-term structural changes within certain structures in their brains. As an example, an MRI- and DTI-based 3-month follow up study from Lu et al. (2020) found that patients have significantly higher gray matter volumes in their olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus, and right cingulate gyrus. General diffusivity had declined. Left hemisphere changes correlated with memory loses, while other right hemisphere changes correlated with smell loss. 

Post-Infection Cerebral Changes in COVID-19 Patients

- Impact of COVID-19 on Outcomes in Ischemic Stroke Patients in the United States
- COVID-19 Is an Independent Risk Factor for Acute Ischemic Stroke
- Prevalence and Outcomes of Acute Ischemic Stroke Among Patients ≤50 Years of Age With Laboratory Confirmed COVID-19 Infection
- Characteristics and Comparison of 32 COVID-19 and Non-COVID-19 Ischemic Strokes and Historical Stroke Patients
- Characteristics and Outcomes in Patients With COVID-19 and Acute Ischemic Stroke

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