More than two years after the global COVID-19 pandemic, it is clear that infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called post-acute COVID syndrome or long COVID. Neurological symptoms in patients with long COVID are the most frequent, persistent and disabling symptoms in long COVID patients. These symptoms include headaches, visual and olfactory dysfunction, gait disturbances, paresthesia, coordination problems, and cognitive impairments, such as concentration and memory problems and confusion. The spectrum of neurological symptoms in patients with long COVID results in a long-term impairment of functional ability.
Recent studies have identified subdivision of long COVID on subacute or persistent symptomatic COVID-19, which includes symptoms and abnormalities that persist for 4 to12 weeks following acute COVID-19, and chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities that persist for more than 12 weeks following acute COVID-19. Data shows that 43% of people infected with SARS-COV2 worldwide can develop long COVID. Patients with long COVID suffer from a wide range of organ dysfunctions and clinical symptoms. Neurological and neuropsychiatric symptoms are the most frequent, persisting and disabling. Symptoms of long COVID can last for several months or longer.
It should be noted that studies have extensively mapped the spectrum of neurological sequelae in patients with long COVID, but, there has been no significant progress in understanding the underlying mechanisms.
Studies on neurological symptoms in patients with long COVID
Italian investigators reported on their one year experience at a center for neurological manifestations of long COVID. Their study included 103 patients. Most of these patients previously had a mild form of COVID-19. The average time between acute COVID-19 infection and the first outpatient clinic visit was 243 days.
Results showed that the spectrum of neurological symptoms in patients with long COVID included fatigue, cognitive impairment, and olfactory and gustatory dysfunctions. Asthenia was present in more than half of the patients, determining chronic fatigue, one of the most common manifestations of long COVID, even more than dyspnea. Olfactory and gustatory dysfunctions were present in the acute disease (56%), but also in the long COVID (39%). Tremor, a new-onset headache and the worsening of a pre-existing headache after COVID-19 resolution have also been reported.
Cognitive impairments were among the most common persistent neurological symptoms. Neuropsychological testings showed that memory was the most impaired cognitive ability, with a prevalence of 37%.
The authors concluded that neurological symptoms do not appear to be due to virus-specific pathophysiological changes, as the evidence of the presence of SARS-CoV-2 in the cerebrospinal fluid and neurological tissues is scarce. They suggested that the pathophysiological processes of long COVID may include residual immune activation, autoimmunity, continuous endothelial activation, a vascular dysfunction, and residual injuries after acute disease.
The study by Xu E et al investigated the risk of developing a long-term neurological disorders one-year after the acute SARS-CoV-2 infection in a large cohort of 154,068 participants. The study also included 5,638,795 contemporary controls and 5,859,621 historical controls, representing a total of 14,064,985 persons.
Results showed that after the first 30 days of infection, people with COVID-19 have an increased risk of developing a variety of neurological disorders, including stroke (both ischemic and hemorrhagic), cognition and memory disorders, peripheral nervous system disorders, episodic disorders, extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders and sensory disorders.
Moreover, the results showed the increased risk of developing Guillain–Barré syndrome and encephalitis/encephalopathy.
Xu E. Nature Medicine, September 2022. https://www.nature.com/articles/s41591-022-02001-z
The study by Apple AC et al analyzed immune activation in cerebrospinal fluid of adults reporting postacute cognitive sequelae after the mild COVID-19. The study included 22 adults with postacute cognitive sequelae and 10 controls.
Results showed dysregulated immune activation in cerebrospinal fluid of patients with cognitive sequelae, but not in control subjects. 69% of participants with postacute cognitive sequelae had an abnormal profile of oligoclonal bands compared to 0% in control subjects.
Spanos et al studied the presence of biomarkers of brain injury (glial fibrillary astrocytic protein and neurofilament light chain) in patients with long-term neurological symptoms after SARS-CoV-2 infection. Glial fibrillary astrocyte protein is an astrocyte biomarker, elevated during neuronal injury, glial activation, and scarring. The neurofilament light chain is an intraaxonal structural protein, elevated following traumatic brain injury.
Results showed that these markers remained significantly elevated in patients with long-term neurological symptoms one year following SARS-CoV-2 infection.
Spanos et al. iScience 25, 104833. August 19, 2022 https://doi.org/10.1016/j.isci.2022.104833
Finally, there is the first task-activated blood-oxygenation-level-dependent functional MRI (BOLD-fMRI) study in the post-COVID participants with neuropsyhiatric symptoms. The authors evaluated whether participants with a post-COVID condition and neuropsychiatric symptoms have an abnormal brain activation during a working memory task.
Results showed that suboptimal functioning in the normal network, but increased brain activation in the contralateral hemisphere during working memory tasks. Several brain regions that showed lower activation in post-COVID participants than in controls included regions in the left hemisphere. At the same time, on the NIHTB battery for motor function, the post-COVID-19 participants performed worse than controls for endurance, locomotion and the dexterity of the dominant hand.
In contrast, all brain regions with higher activation on 2-back task in the post-COVID group than in the controls were in the right hemisphere. The authors concluded that BOLD-fMRI was sensitive to detect a process of brain reorganization in the post-COVID participants with neuropsychiatric symptoms. https://discovermednews.com/patients-with-post-covid-syndrome-and-neuropsychiatric-symptoms-have-different-brain-activation-during-the-working-memory-task/
Studies have extensively mapped the spectrum of neurological symptoms in patients with long COVID, but, there has been no significant progress in understanding the underlying mechanisms. Since SARS-CoV-2 causes various neurological sequelae, various mechanisms may be involved, so, several theories have been proposed.
The direct neuroinvasiveness and neurotropism of SARS-CoV-2 has been demonstrated in experiments with animals and CNS organoids, with detrimental effect on infected and neighboring neurons. However, evidence of direct primary infection of brain cells with SARS-CoV-2 is limited. Post-mortem examination of brain in COVID-19-positive patients found that viral RNA levels were very low or undetectable, and were not correlated with significant histopathological changes, such as hypoxic/ischemic changes, hemorrhagic infarctions, and microglial activation with microglial nodules, especially in the brainstem and periventricular subcortical white matter.
It seems that most neurological complications of long COVID may include neuroinflammation, autoimmunity, vascular dysfunction, and residual injuries after acute disease.