Introduction
The December 2019 emergence of the now recognized SARS-CoV-2 novel coronavirus fundamentally altered the lens through which 21st-century public health, epidemiology, and medicine will be addressed.1 With an estimated R0 of 1.5 to 3.5, SARS-CoV-2 otherwise known as COVID-19 is considered a highly infectious agent.2 Transmissible mainly through inhalation or contact with infected droplets, COVID-19 is responsible for a series of symptoms that range from mild to deadly. The most common symptoms are pyrexia, dyspnea, cough, anosmia, aguesia, and fatigue.2 In some cases, the disease may progress to lower respiratory disease and respiratory failure.3 Commonly, the aged and those with comorbid conditions are at risk to develop the catastrophic complications of the disease. Though many individuals experience symptoms, there are also COVID-19 patients that present with no symptoms. These asymptomatic individuals can also contribute to the spread of COVID-19.3
With a total of 179,241,734 confirmed global cases including 3,889,723 deaths as reported by the World Health Organization (WHO), the RNA virus COVID-19 has evoked considerable international comradery toward developing a solution.4 In perhaps the most groundbreaking research campaign of the century, several vaccinations for COVID-19 have been developed and distributed to date. As of June 24, 2021, 2,624,733,776 vaccine doses have been administered to the general public with the United States accounting for over 317 million.4 Fig. 10.1 depicts a population-adjusted image of the current international COVID-19 vaccination efforts.5 Because of the aggressive international vaccination efforts, the rate of morbidity and mortality related to the virus has seemingly begun to decrease. There also seem to be several novel variants that have emerged over the past year. As of now, there is limited evidence on the effectiveness of vaccination toward all potential variants.6
Fig. 10.1 Cumulative vaccine doses administered per 100 individuals. Population adjustment accounts for the scale of vaccine rollout.5 https://figshare.com/articles/software/A_global_database_of_COVID-19_vaccinations/14387702
COVID-19 and the Nervous System
Though the most common symptoms of COVID-19 are related to respiratory illness, there are also several others that suggest involvement of the nervous system. Neurological complications of SARS-CoV-2 include encephalopathy, ataxia, hypogeusia, hyposmia, neuralgia, and seizures.7 The existence of these symptoms allows for several questions. What are both the acute and chronic neurological manifestations of COVID-19, when in COVID-19 disease progression do neurological symptoms manifest, and how long do they last? While some, like Nalbandian et al, in the journal Nature note that lingering or permanent neurological deficits of COVID-19 fall under the umbrella postacute COVID-19, wherein persistent complications exist beyond 4 weeks from onset of COVID-19-related symptoms, others state neurological complications appear concurrently with other symptoms.8 Fig. 10.2 depicts the postulated timeline for postacute COVID-19 along with related symptoms.8
Understanding the timeline underlying COVID-19-related neurological manifestations further delineates whether the relationship between the two is causal. In other words, does COVID-19 directly cause neurological manifestations or are they simply a by-product? As will be discussed, research indicates that it seems to be a combination. Since December 2019, a robust amalgam of evidence has arisen that confirms the relationship between COVID-19 and nervous system involvement. Having recognized the types of symptoms and when they occur, the various potential mechanisms that allow the SARS-CoV-2 virus to infiltrate the nervous system and produce neurological symptoms will also be discussed.
COVID-19–Related Neurological Symptoms
Neurological manifestations related to SARS-CoV-2 or COVID-19 have been shown to begin as early as disease onset. As more literature related to COVID-19 is amassed, patterns indicate that the neurological manifestations can emerge in many different ways. While the manifestations can be neurological complications of the systemic disease, they can also be direct effects of the virus on the nervous system, parainfectious, or postinfectious immune-related disease.9 Examples of parainfectious diseases include: Guillain-Barré syndrome (GBS), transverse myelitis, and acute disseminated encephalomyelitis.10 Regardless of the mechanism, however, emergent studies demonstrate that the most frequent neurological symptoms are short term like cephalagia, muscle aches, dizziness, anosmia, and ageusia. In severe cases, other, more direct manifestations of the virus in the central nervous system (CNS) can also occur (Fig. 10.3).7
Fig. 10.3 Approximate timeline for COVID-19-related neurological symptom presentation. Blue bars present periods where viral RNA or antibodies can be detected via diagnostic testing. Red bars indicate duration of systemic and/or pulmonary symptoms. Green bars indicate potential neurological disease causing mechanisms.9 https://creativecommons.org/publicdomain/mark/1.0/
In one study, involving 214 patients, neurological manifestations occurred in 36.4% of individuals. The investigation indicated that those with more severe COVID-19 demonstrated increasing severity of neurological symptoms including acute cerebrovascular diseases, depressed levels of consciousness, and skeletal muscle injury.11 Recently, a retrospective study of a large database containing 81 million patients of which 237,379 were diagnosed with COVID-19, 33.6% developed new-onset neuropsychiatric symptoms in the 6 months after the onset of the disease.12,13 Interestingly, of the COVID-19 patients that were admitted to intensive care units, 46.42% diagnosed with neurological manifestations and 62.34% with encephalopathy, indicating that the more severe COVID-19 cases were, in fact, coupled with an increased incidence of neurological manifestations.13 In the cohort of COVID-19 patients that were admitted to the ICU, the estimated incidences were as follows: 2.66% for intracranial hemorrhage, 6.92% for ischemic stroke, 0.26% for parkinsonism, 1.74% for dementia, 19.15% (17.90–20.48) for anxiety disorder, and 2.77% for psychotic disorder13 (Fig. 10.4).
Fig. 10.4 Kaplan-Meier estimates for major COVID-19-related neurological symptoms compared with other respiratory tract infections (RTI) based symptoms.13 http://creativecommons.org/licenses/by/4.0/ (Continued)
Fig. 10.4 (Continued) Kaplan-Meier estimates for major COVID-19-related neurological symptoms compared with other respiratory tract infections (RTI) based symptoms.13 http://creativecommons.org/licenses/by/4.0/
One of the first COVID-19 positive cases with neurological signs that was reported (April 2020) described a patient with severe cognitive impairment, bilateral ankle clonus, positive Babinski, and meningeal signs. In this patient, the computed tomography (CT) scan was unremarkable and the viral genome was not present in the patient’s cerebrospinal fluid (CSF).14
Though COVID-19 is incredibly complex, as mentioned above, it causes considerable comprehensive risk to the entire nervous system. The manifestations can, however, be categorized by CNS involvement or peripheral nervous system (PNS) involvement. Examples of COVID-19-related CNS disease include encephalopathy, acute disseminated encephalomyelitis, encephalitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis.15 Examples of COVID-19-related PNS disease are GBS, anosmia, chemosensory dysfunction, skeletal muscle damage, neuralgia, and epilepsy among others16 (Fig. 10.5).
Fig. 10.5 Mechanisms of SARS-CoV-2 neuropathogenesis on the nervous system. Creative Commons License.17
Central Nervous System Manifestations
Encephalopathy and Neuroinflammatory Diseases (Encephalitis)
Among neurological manifestations of COVID-19, encephalopathy and encephalitis are considered to be serious.16 Encephalopathy, collectively, is defined as alterations in mental status including disorientation, confusion, agitation, and somnolence or sleepiness.18 These symptoms are common in elderly patients who also present with associated comorbidities or immunodeficiencies. Clinical manifestations can also include fever, headache, epilepsy, and/or impaired consciousness and is visible in magnetic resonance imaging (MRI) as altered cortical and subcortical T2/FLAIR signals.19 In a study with 214 patients from Wuhan, China, 53 (25%) had CNS symptoms, including 36 (17%) patients with dizziness,11 13% with headache, and 16 (7%) with impaired consciousness.9 In another study, a series of 58 intensive care patients were analyzed and 49 (84%) had neurological complications with 40 (69%) presenting with encephalopathy.9
While the vast majority of patients with encephalopathy and encephalitis do not show evidence of the presence of SARS-CoV-2 in their CSF, some patients were found to have SARS-CoV-2 in their CSF.20 There is therefore limited evidence suggesting that entry to CSF is what causes encephalopathy and encephalitis.
Though altered mental status rarely impacts COVID-19 patients seeking care for respiratory illness, it impacts the majority of critically ill COVID-19 patients with ARDS or acute respiratory distress syndrome.18 Importantly, the distinction between altered mental status as a result of encephalopathy caused by systemic illness or as a result of encephalitis directly caused by the SARS-CoV-2 virus itself must be made.
Encephalitis refers to inflammatory lesions caused by either pathogenic infection or the body’s immune defenses.21 Without direct brain inflammation, detection of SARS-CoV-2 in CSF does not provide definitive diagnosis of encephalitis.9 Clinical presentation of encephalitis includes irritability, confusion, reduced consciousness, and sometimes seizures.9
Interestingly, SARS-CoV-2 can also promote postinfectious neurological complications. These delayed effects can impact both the CNS and the PNS. In the CNS, an example includes acute necrotizing hemorrhagic encephalopathy.12 The first case of acute necrotizing hemorrhagic encephalopathy was reported in a 58-year-old woman with a 3-day history of cough, fever, and altered mental status (Fig. 10.6).22 Though the CSF fluid showed no evidence of SARS-CoV-2, evidence of the acute necrotizing hemorrhagic encephalopathy could be observed via MRI.1,22
Fig. 10.6 An example of acute necrotizing hemorrhagic encephalopathy, computed tomography (CT) chest (a) demonstrating bilateral peripheral ground glass opacities of a 68-year-old woman who presented with severe COVID-19-associated respiratory failure. Her hospital course was complicated by coma and stupor 30 days postadmission. Magnetic resonance imaging (MRI) of the brain (b-h) (diffusion-weighted imaging, axial sections) showing diffuse hyperintensities in multiple areas of the brain. Creative Commons Attribution License.23
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