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.

Encephalopathy in COVID-19 Patients.

- 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

Ischemic Stroke in COVID-19 Patients

- 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

Smith College

Syracuse University

Boston University

Even in the absence of typical respiratory symptoms such as fever, cough, and shortness of breath, various patients diagnosed with COVID-19 have presented neurological symptoms, such as:

- acute cerebrovascular diseases

- impaired consciousness

-  skeletal muscle injury

- encephalopathy (symptoms: ischemic stroke)

- loss of smell (anosmia) and taste (ageusia)

- stroke

- cranial nerve deficits

- delirium

- meningitis

- paralysis

- seizures

- neuroinflammatory syndromes

- high pressure CSF

- muscle stiffness

The list below includes less-common neurological symptoms of COVID-19:
- Guillain–Barré syndrome (GBS)
- Multisystem Inflammatory Syndrome in Children (MIS-C)

Neurological symptoms Presented in COVID-19 Patients

Fotuhi, M., Mian, A., Meysami, S., & Raji, C. A. (2020). Neurobiology of COVID-19. Journal of Alzheimers Disease, 76(1), 3-19. doi:10.3233/jad-200581
https://content.iospress.com/articles/journal-of-alzheimers-disease/jad200581

Neurobiology of COVID-19

Mao et.al study finds that 36.4% of the COVID-19 patients surveyed presented neurologic symptoms, such as acute cerebrovascular events, impaired consciousness and skeletal muscle injury. Neurologists conducted a study (Jan. 16 - Feb. 19) (n=214, from 3 designated Wuhan hospitals) by retrospectively reviewing patient charts. Nervous system symptoms were found to be more prevalent in severe patients, affecting them disproportionately to their counterparts with regards to CNS function and muscle injury.

Increased neurologic symptoms in severely infected COVID-19 patients

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

- Multisystem Inflammatory Syndrome in Children (MIS-C)
- Guillain-Barré Syndrome
- Loss of smell (hyposmia/anosmia) and taste (hypogeusia/ageusia)
- Serious damage to cranial nerves, peripheral nerves, and muscles


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

It was found early on that population with respiratory problems is at greater risk but risk factors include pre-existing diagnoses such as dementia, subarachnoid hemorrhage and epilepsy.  Increased risk is found when the acute care uses sedation, ventilation and delirium. 


Who is likely to suffer from neurocognitive symptoms

Up to 20% of COVID-19 patients who enter the intensive care unit (ICU) with neurological issues or deficits have a higher mortality risk. Even after recovering and leaving the ICU, patients may develop long-term neurological conditions such as depression, obsessive compulsive disorder, psychosis, Parkinson’s disease, and Alzheimer’s disease. ICU patients who take numerous medications or have pre-existing medical conditions can develop memory loss, slow processing speed, delirium, or even coma. Patients with multiple sclerosis, amyotrophic lateral sclerosis, and respiratory dysfunction may struggle to survive ICU hospitalization, and those on immunosuppressive medications may decline faster.


Effects of ICU Admission on COVID Patients with Neurological Issues

Effects on the nose, cranial nerves and brain
1) Anosmia and ageusia caused by inhibition of nasal and gustatory epithelial cells
2) Vessel occlusion in cerebral arteries caused by activation of cytokines and hypercoagulation pathways in the blood
3) Blood clots in the cerebral veins leading to cerebral venous thrombosis.
4) Seizures and/or encephalopathy from high levels of cytokines in the cerebral vessels damaging the blood-brain barrier, infiltrating the brain, and damaging neurons and glia 
5) Meningitis from artery damage
6) Cranial nerve damage from formation of auto-antibodies (molecular mimicry)

Figure 2. Pathophysiology of Neurological Abnormalities in COVID-19

Most researchers believe the neurological effect of the virus are an indirect result of either oxygen starvation to the brain (the “happy hypoxia” exhibited by many patients), or the byproduct of the body’s inflammatory response (the famed “cytokine storm”).  A pateints MRI brain scan showed signs of viral meningitis (inflammation of the brain), and a lumbar puncture detected Sars-CoV-2 in his cerebrospinal fluid.  Another patient had viral particals detected in the  endothelial cells lining the blood vessels of the brain itself. In fact, some scientists now suspect that the virus causes respiratory failure and death not through damage to the lungs but through damage to the brainstem.

How COVID-19 can damage the brain

- Stage I: anosmia, ageusia

- Stage II: blood clots, PNS damage

-Stage II: seizures, coma, encephalopathy


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