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

Support for indirect over direct causes of neurological symptoms:
- Cerebralspinal fluid (CSF) samples in some CoV-2 patients have shown the presence of SARS-CoV-2 antibodies (anti-S1 IgM) and increased multiple cytokines, suggesting a possible CoV-2 direct infection of the CNS (Benameur et. al). However, this coupled with low levels of CSF and plasma viral RNA in patients, suggests that the neurological symptoms present may be a result of autoimmune responses, rather than direct infection.

Support for autoimmunity:
- the anti-neuronal and anti-glial autoantibodies presence in CSF and serum lends support of a causal relationship between autoimmunity and neurological clinical symptoms (Franke et. al)
- transcriptomic data from COVID-19 patients, control samples, and mice studies, reveal evidence of virus-driven cell lysis (Ray et. al)

COVID-19 Neurological Effects as a Result of Autoimmunity in the PNS

Some COVID-19 patients have presented with peripheral neurological symptoms. Although it is not a common complication of COVID-19, it is worth investigating all possible causes of the neurological symptoms that arise.

Smith College

University of Michigan - Ann Arbor

Current studies show that many organs that are heavily affected by COVID-19 have a high expression level of ACE2.

- Cardiovascular system
- Central nervous system (CNS)
- Gastrointestinal tract (GI)
- Kidney
- Liver 
- Lungs (Respiratory System)
- Peripheral nervous system (PNS)
- Testis

Organs and Organ Systems Affected by COVID-19

The peripheral nervous system are all nerve components (nerve, ganglia) outside of the brain and spinal cord. The word "peripheral" describes its function in connecting limbs and organs to the central nervous system. It is functionally divided into two components:
- somatic nervous system
- autonomic nervous system

Peripheral Nervous System

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

It has been observed that many COVID-19 patients develop renal conditions, including acute kidney injury.  Older patients or those who have kidney conditions are more likely to die from COVID-19 while hospitalized.  Kidneys are known to have a greater level of ACE 2 expression than the lungs.  Kidney disease caused by COVID-19 is directly related to ACE2 expression: a study confirmed by electron microscopy that viral particles have been found in the glomerulus of COVID-19 patients. 

Effects of COVID-19 on the Kidney

Liver injury has been observed in a percentage of COVID-19 patients.  Cholangiocytes, the epithelial lining cells of the bile ducts of the liver, are known to have a high level of ACE 2 expression.  Overall, the liver has a greater expression level of ACE 2 than the lungs.  However, no studies have shown that SARS-CoV-2 can infect hepatic cells.  

Effects of COVID-19 on the Liver

Because as many as 10% of COVID-19 patients have the symptom of diarrhea, it is hypothesized that SARS-CoV-2 can infect gastrointestinal cells.  Symptoms such as loss of appetite and nausea have been commonly found with patients as well. It is known that the GI tract overall has a high expression level of ACE 2, with the duodenum and small intestine having an especially high level of expression. Viral RNA has been found in both the sputum and feces of COVID-19 patients.  

Effects of COVID-19 on the Gastrointestinal (GI) Tract

A main feature of symptomatic COVID-19 disease is respiratory infection. Severe damage to the lungs during respiratory distress may cause pulmonary fibrosis, necessitating lung transplants. Lasting damages to the lungs may occur even in recovering patients with mild infections. SARS-CoV-2 targets the following cell types:

- Type I pneumocytes (AT1) 
- Type II pneumocytes (AT2) 
- alveolar macrophages

ACE2 expression is primarily seen in AT2 cells which have been shown to be involved in the reproduction and transmission of the virus.  Viral targeting of alveolar macrophages is evidenced by N antigen expression.

Effects of COVID-19 on the Lungs

Patients with COVID-19 are likely to experience symptoms that can be attributed to  the virus affecting the cardiovascular system. Common complications to the system include arrhythmia, cardiac injury, fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation. Severe cases of COVID-19 may lead to lasting cardiac damage and those with pre-existing cardiac issues are likely to have worse prognoses. 

Effects of COVID-19 on the Cardiovascular System 

Impaired male fertility is a known symptom of COVID-19.  It is thought that the testes' high expression level of ACE2 and immunoactivity could contribute to this manifestation of the disease.  

Effects of COVID-19 on the Testis   

COVID-19 patients have shown symptoms of direct and indirect neurological effects, from changes in taste and smell, to immunologic factors in cerebral spinal fluid (CSF).  It is unknown whether these phenomena are the result of neurological damage, of SARS-CoV-2 infection, and/or of indirect effects of the immune response. Furthermore, studies in mice have shown that neurons are susceptible to infection, suggesting that cells of the CNS may contribute to the deteriorating breathing and respiratory function of COVID-19 patients. The image below is an early hypothesized mechanism of viral entry through nasal and oral mucosa cells, though there is not yet any evidence to support this hypothesis.

Effects of COVID-19 on the Central Nervous System

Effects of COVID-19 on the Peripheral Nervous System

- SARS-CoV-2 can be blocked by physical barriers in the placenta, such as densely branched microvilli and cytoskeletal network
- placenta can attack the virus with the following 3 molecular pathways: type III IFN signaling, secreted miRNAs triggering autophagy, and NF-κB pathway
- immunomodulation can be employed after viral infection to alleviate cytokin storm

Effects of COVID-19 on the Placenta

- There have been two reports of COVID-19 positive patients with conjunctivitis or conjunctival congestion
- Ocular secretions were seen in those with the SARS-CoV-2 positive serology
- This presents the possibility that the SARS-CoV-2 virus can cause conjunctivitis
- However, this relationship is not very clear at this point due to a lack of studies comparing the two
- It has also been suggested that the ocular system is a potential route of transmission of the virus

Effects of COVID-19 on the Ocular System

The autonomic nervous system (ANS) is a subset of the peripheral nervous system. The word "autonomic" describes its role in regulating involuntary and unconscious bodily function, such as heart rate, respiratory rate, and sexual arousal. The system consists of motor neurons (ganglia) and its axonal connections, and is functionally divided into three components:
- sympathetic nervous system
- parasympathetic nervous system 
- enteric nervous system

Autonomic Nervous System

The somatic nervous system is a part of Peripheral Nervous System. It controls the voluntary functions of the body through skeletal muscles. There are two types of nerves in the somatic nervous system: afferent (sensory) nerves and efferent (motor nerves). Afferent nerves relay information from the body to the central nervous system. It primarily relays sensory information like pain. smell, etc. Efferent nerves relay information from the central nervous system to the body. Somatic Nervous System consists of two parts: cranial nerves and spinal nerves. Cranial nerves are responsible for carrying information to and fro from the brain stem. Spinal nerves carry information to and fro from the spinal cord. 

Somatic Nervous System

Affective scientists can measure the peripheral nervous system to make inferences about one's emotional state. For example, they can measure eye movements, blood pressure and volume, heart rate, and electrodermal activities to infer one' emotional states (e.g. fear, anxiety, anger, etc.)

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