Neurological complications in post-COVID care
October 10, 2023
A post-COVID world
The COVID-19 pandemic has brought forth myriad challenges, one significant area being the extensive range of neurological implications observed in patients. Since the initial identification of neurological symptoms in 36.4% of COVID-19 patients from Wuhan, there has been a global endeavour to explore the potential post-COVID conditions of the disease. Efforts span from global registries to diverse case series, crucial for enhancing clinical understanding as the disease proliferates. Despite fairly uniform case definitions of neurological symptoms and syndromes internationally, there’s significant heterogeneity in case ascertainment due to the chaotic nature of the pandemic, leading to opportunistic patient recruitment and variances in patient location and disease severity. This has resulted in a wide range of reported prevalences for neurological presentations, between 7% and 77.8%, illustrating the diverse and extensive spectrum of neurological complaints associated with COVID-19, like the varying reported prevalences of headaches, ranging from as high as 41.1% to as low as 4.3%. Anosmia, dysgeusia, and headache are common, while others like seizures and Guillain–Barré syndrome are rare. The diverse and opportunistic nature of the collected data due to the pandemic chaos reflects discrepancies in reported prevalence across various studies.
Pathogenesis
The pathogenesis of neurological symptoms in COVID-19 is diverse and multifactorial, involving various potential mechanisms of nervous system dysfunction and damage during SARS-CoV-2 infection. These mechanisms, which often occur concurrently, include direct neurological invasion and damage by the virus, suggesting possible invasion to the central nervous system (CNS). This is given prevalent symptoms of anosmia and dysgeusia, which are linked to high viral loads in the nasopharynx and olfactory bulb and nerve involvement. Studies using models and post-mortem examinations have provided varied evidence on direct viral presence in CNS, with some identifying the virus and others not. However, extrapolating findings from animal studies to humans is challenging due to differences in ACE2 receptor expressions. Given this, primary invasion of CNS by the virus seems rare, likely happening when the virus moves across a disrupted blood–brain barrier in pro-inflammatory conditions.
Additionally, immune dysregulation and para-infectious autoimmune responses against the nervous system can occur, arising due to factors such as the loss of self-tolerance of the adaptive immune system activated by a virus, molecular mimicry, or as a byproduct of antiviral inflammatory responses. Another mechanism is vascular injury stemming from endothelial dysfunction and disruptions in normal coagulation characterised in severe COVID-19 cases, which results in thrombotic complications and endotheliitis identified in various brain regions. This is evidenced by biomarkers like elevated D-dimer levels indicating microangiopathic changes.
Finally, toxic effects due to severe systemic COVID-19 disease, like hypoxia and heightened inflammatory states or “cytokine storms,” can cause potential CNS injury. This has been evidenced by post-mortem examinations showing widespread inflammation and microglial activation in the brain, independent of endotheliitis or direct viral injury. These changes, however, aren’t unique to COVID-19, as similar pathological CNS changes are seen in severe sepsis cases.
While these mechanisms aren’t mutually exclusive and can often coexist, understanding them is critical for delineating the neurological manifestations of COVID-19, even though they pose complexities and variances in clinical presentations and studies.
Post-COVID inflammatory conditions
Headache is frequently reported as an early symptom in COVID-19, sometimes being the first symptom in 26% of patients, with the majority of COVID-19-related headaches lasting no more than two weeks. It’s most commonly bifrontal or holocephalic and is associated with migraine symptoms, such as photophobia and phonophobia. The cause of headache in COVID-19 is debated, but a multifactorial origin is likely, involving various inflammatory and molecular mechanisms, including alterations in calcitonin gene-related peptide (CGRP) and interleukin (IL)-6 levels, which play a role in migraine pathogenesis. A more in-depth understanding of headache in COVID-19 may elucidate the pathology of other headache disorders.
Peripheral nervous system involvement in COVID-19 primarily falls into two categories: rare inflammatory events and critical illness neuropathy or myopathy due to severe illness. The former involves conditions like brachial plexitis and is likely related to systemic inflammatory response, while the latter is associated with severe illness requiring prolonged inpatient care and ventilation, manifesting as critical illness myopathies or symmetrical sensory-motor axonal neuropathies. Additionally, small fibre neuropathy has been recognized predominantly post-COVID-19, presenting as new onset paraesthesia and autonomic dysfunction, although a direct causal relationship has not been established. Moreover, isolated autonomic dysfunction is frequently reported in post-COVID-19 syndrome, aligning with symptoms of chronic fatigue and other central sensitization syndromes.
Seizures in COVID-19 are relatively uncommon and are typically due to either pre-existing CNS pathology, including epilepsy, or new intracranial pathology induced by COVID-19. Electroencephalogram (EEG) changes are predominantly abnormal background rhythm or intermittent slowing, with the risk of long-term seizures being associated with pre-existing conditions or structural CNS lesions rather than the severity of the SARS-CoV-2 infection or acute illness seizures. This indicates that long-term antiseizure medications are seldom required for managing seizures in the context of COVID-19.
Immune-mediated conditions
Encephalitis in COVID-19 is recognized as a significant, albeit rare condition and typically manifests late, around two weeks post-onset of COVID-19 symptoms. The common clinical presentation includes altered consciousness and seizures, with imaging often revealing specific or broad changes in different brain regions. Autoimmune encephalitis syndromes, including limbic encephalitis and N-methyl-D-aspartate receptor (NMDAR) autoimmune encephalitis, have been specifically documented post-SARS-CoV-2 infection, often responding to various immunotherapies. Observations of encephalitis post-COVID-19 provide a vital perspective into the pathogenesis of immune-mediated central nervous system disease.
Guillain–Barré syndrome (GBS) is another recognized manifestation of COVID-19. There is, however, debate around whether COVID-19 has a causal effect on GBS’s onset, with varying studies providing contradictory evidence on the relationship between GBS incidence and COVID-19. For instance, studies from the United Kingdom reported a decrease in GBS incidence during the pandemic and refuted a causal link between GBS and COVID-19. Conversely, several studies from Italy and Spain demonstrated an increased incidence of GBS in COVID-19 patients, suggesting a potential causal link. Interestingly, a unique phenotype of GBS associated with COVID-19 seems to be emerging, with higher rates of demyelinating pathology and prevalent involvement of cranial nerves. Due to these varying findings and the observed specific phenotype, it’s concluded that GBS could be a rare complication of SARS-CoV-2 infection, emphasising the need for continued monitoring and study of the relationship between GBS and COVID-19.
What comes next for primary care
Cognitive complaints are frequent in post-COVID-19 conditions, often complicated by varied definitions of abnormal cognition and the influence of other factors like fatigue, mood changes, and anxiety. Some studies show a correlation between cognitive dysfunction and the severity of the disease, with certain cognitive functions remaining below baseline levels even after recovery from severe illness.
Research suggests that the SARS-CoV-2 infection could predispose individuals to various neurological conditions, including migraines and more severe disorders like Alzheimer’s disease, sometimes manifesting up to a year after infection. There’s speculation that COVID-19 might reveal previously undiagnosed neurodegenerative diseases and may be linked to certain inflammatory conditions. However, there’s also the consideration that the diagnosis of other health conditions may simply be more likely to occur after any significant health event. In summary, there are many unknowns at present, and much more research and longitudinal data is required to accurately predict the outcomes given the extraordinary number of people potentially affected by post-COVID conditions.
Wesselingh, R. (2023), Prevalence, pathogenesis and spectrum of neurological symptoms in COVID-19 and post-COVID-19 syndrome: a narrative review. Med J Aust, 219: 230-236. https://doi.org/10.5694/mja2.52063
