The Norwegian Study of Nervous System Manifestations and Sequelae After COVID-19

Corona virus (CoV) may have deleterious effects on the nervous system. As the number of
individuals infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is
increasing, more and more neurological, neuropsychological and neuropsychiatric symptoms are
being reported in COVID-19 patients. Neurologists and psychiatrist, in turn, may increasingly
find themselves involved in caring for patients with the novel virus.

Sars-CoV-2 usually enter the body via the enzyme angiotensin converting enzyme 2 (ACE2) in
alveolar cells in the lungs. However, ACE2 is expressed in a number of other tissues and
cells, such as mucous membranes of the eyes, nose and oral cavity, neurons, glia cells and
endothelial cells, including those in the brain, making it a potential target of the virus.

There are several possible mechanisms for nervous system affection in COVID-19. Firstly,
transneuronal transport of viruses through the olfactory nerve to the brain can induce direct
injury. Sars-CoV-2 has been detected in cerebrospinal fluid in patients with encephalitis and
meningitis. A second type of injury may result from an excessive immune response in the form
of a "cytokine storm". Cytokines can cross the blood-brain barrier and are associated with
acute necrotizing encephalopathy. A third mechanism of nervous tissue damage results from
unintended host immune response effects after an acute infection. Examples of this type of
indirect CNS injury are Guillain-Barré syndrome (GBS) and brain and spine demyelination. A
fourth mechanism is an indirect viral injury that results from the effects of systemic
illness, hypoxia and in some cases hypercoagulability, a prominent feature of severe
COVID-19. Most cases of COVID-19-related neurologic complications appear to fall into this
category. Severely ill patients in the intensive care unit may develop neurologic symptoms
such as encephalopathy, critical illness myopathy, and neuropathy. This is common in both
COVID-19 and in other diseases.

There have been several reports of nervous system manifestations in COVID-19. In a
retrospective study from Wuhan China with 214 consecutive hospitalized patients, 1/3 had
neurologic manifestations and nearly one half of those with severe infection. Common central
nervous system (CNS) symptoms were dizziness, headache, and impaired consciousness or
symptoms of acute cerebrovascular disease. The most common peripheral nervous system (PNS)
symptoms included impaired taste, smell, or vision, and nerve pain. Skeletal muscular injury
symptoms were also frequently reported. COVID-19 patients with CNS symptoms had lower
lymphocyte levels and platelet counts and higher blood urea nitrogen levels compared to their
counterparts without CNS symptoms. This may be indicative of immunosuppression in patients
with COVID-19 and CNS symptoms or it may be manifestations coexisting in the same patient.
Systematic brain imaging and measurements of neuron- or brain-specific biomarkers may
increase the knowledge regarding nervous system manifestations in COVID-19 but were not
performed in this study. Case report series with types of CNS or PNS manifestations, such as
ischemic or hemorrhagic stroke, Guillain Barré syndrome, encephalitis, meningitis and toxic
hemorrhagic necrotizing encephalopathy have been described. Furthermore, post infection
surveillance will be necessary to identify possible post-COVID neurologic syndromes.

Moreover, COVID-19 is a significant psychological stressor, which may in addition to the
neurological manifestations contribute to neuropsychiatric and neuropsychological sequela.
Past respiratory viral pandemics have been associated with neuropsychiatric symptoms that may
arise acutely or after variable periods of time. The long-term effect on neuropsychological
functioning and the prevalence of neuropsychiatric symptoms due to COVID-19 are currently
unknown. However, patients with COVID-19 are at risk of developing delirium that may cause
long term cognitive impairment. Furthermore, Sars-CoV-2 proteins have been shown to interact
with human proteins in multiple aging-related processes and CNS symptoms in patients with
COVID-19 may put them at risk of neurocognitive complications. Given the global burden of
COVID-19, long term neurocognitive complications are of importance to recognize.

Previously anxiety, depression and trauma related symptoms have been associated with CoV
outbreaks. In survivors of SARS-CoV-1 active psychiatric illnesses were diagnosed in more
than 40%, (PTSD (54%), depression (39%), somatoform pain disorders (36%), panic disorder
(32%) and OCD (15%)) post-infection compared to pre-infection prevalence of less than 3%, and
more than 27% had fatigue symptoms. Moreover, antibodies against CoV have been found in both
psychoses and affective disorders. However, it is not known to which extent
neuropsychological and psychiatric symptoms and disorders after COVID-19 are related to the
psychological stressor or to CNS sequela after Covid-19 or to both.

Our hypotheses in this project are:

1. Nervous system manifestations and neurological sequelae are common after COVID 19.

2. Biomarkers in blood can be used to assess neurological manifestations and sequelae in
COVID-19 patients at 6- and 12-months follow-up.

3. Severe COVID-19 infection predicts neurological manifestations and sequelae at 6- and
12-months follow-up.

4. Psychiatric disorders, especially anxiety and depressive disorders, but also psychotic
and somatoform disorders are common after COVID-19, either due to CNS sequelae or
manifestation or to perceived distress/strain.

5. Neuropsychological sequelae are common after COVID-19 either due to CNS sequelae or
manifestation or to perceived distress/strain.

6. Biomarkers and imaging findings can be used to predict neuropsychiatric manifestations
after Covid-19 at 6- and 12- months follow up.

7. Biomarkers in blood and imaging findings can be used to predict neuropsychological
manifestations after Covid-19 at 6- and 12- months follow up.

8. Severe COVID-19 infection predicts neuropsychiatric and psychiatric disorders at 6- and
12-months follow-up.

9. Severe COVID-19 infection predicts neuropsychological sequelae at 6- and 12-months
follow-up.