Research

Neurological Manifestations of COVID-19

Saad Umar


Abstract

The coronavirus disease 2019 (COVID-19) is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It typically presents with cough, fever, and difficulty in breathing, but can affect the central and peripheral nervous system.  The neurological manifestations can include minor symptoms such as headache, altered mental status, confusion, loss of smell, and taste sensations. However, some patients can have serious complications due to life-threatening neurological emergencies such as ischemic and hemorrhagic strokes, cerebritis and encephalitis, seizure disorder, and acute inflammatory demyelinating polyneuropathy resulting in paralysis.  Therefore, it is important to watch for any neurological signs and symptoms in these patients to prevent long term disability and mortality. 

 

Introduction 

The coronavirus, SARS‐CoV‐2, was first reported in December 2019 in Wuhan, China [1].  It has very rapidly spread around the world resulting in a pandemic [1]. The spread of COVID-19 to the nervous system occurs via the hematogenous route or by retrograde axonal transport (RAT). The RAT of COVID-19 may be possible through some of the cranial nerves, such as the olfactory nerve or the trigeminal nerve. This virus can affect both the central nervous system (CNS) and the peripheral nervous system (PNS) due to its directly toxic effect on nerve cells or because of a neuroinflammatory response. Some resulting neurological manifestations can be from the effects of the virus on other body systems and related complications such as sepsis and disseminated intravascular coagulation (DIC) [2-6]. However, the exact mode of entry to the nervous system and the mechanism of CNS toxicity is not clear.

The mild neurological manifestations of the disorder include headache, nausea, altered mental status, confusion, anosmia (loss of smell) and ageusia (loss of taste sensation).  The impairment or loss of smell, or taste sensation, could be a marker for identifying infected COVID-19 patients, who do not yet exhibit any other symptoms. The most serious effects of the virus are on the brain and peripheral nerves, resulting in life-threatening complications such as stroke, seizures, and acute inflammatory demyelinating polyneuropathy (AIDP), requiring intensive care unit (ICU) care.  The time before developing serious neurological complications in COVID-19 patients varies, but the average time from infection to onset of cerebrovascular manifestations is about 12 days [2-6]. This article will mainly focus on ischemic and hemorrhagic strokes, seizure disorder, and AIDP related with COVID-19 infection (Figure 1). 

 

Ischemic Stroke

Ischemic stroke results from a blockage in the cerebral blood vessels.  There are two main types of ischemic strokes: (i) large vessel strokes and (ii) small vessel strokes.  Large vessel strokes result from an occlusion of cerebral vessels, such as the internal carotid and middle cerebral arteries. Small vessel stroke results from a blockage in the lenticulostriate blood vessels in the brain. COVID-19 can potentially result in both small and large vessel strokes, but one of the most dramatic manifestations of the virus are large vessel occlusions in young adults. The exact mechanism by which COVID-19 causes blockage of these blood vessels is unknown. The currently proposed mechanisms include vasculitis, arteriopathy, and hypercoagulable condition, as the virus can cause inflammation and impair coagulation mechanisms.  The inflammation of blood vessels may result in blood clot formation, causing the blockage of blood vessels and blood supply cut-off to the brain.  COVID-19 infection can result in cardiomyopathy, leading to the formation of blood clots in the heart and cardioembolic strokes. It has been reported that COVID-19 patients with stroke have an elevated white blood count, C reactive protein, and D-dimer levels, indicating enhanced immune response and inflammation. [3, 4]. These stroke patients can have an involvement of the bilateral thalami and the temporal lobes. However, some of these patients also develop associated hemorrhage, as discussed in the next section. The cases of cerebral venous sinus thrombosis, resulting in venous infarcts, have also been reported in a single-center retrospective observational study [3, 4].

Patients with ischemic stroke are treated with tissue plasminogen activator (t-PA) if indicated or with other blood thinners such as aspirin. However, in some cases of large vessel strokes and elevated D-dimer levels, stronger blood thinners such as heparin and Factor Xa inhibitors may be indicated. [3, 4]. The healthcare professionals will likely need to individualize treatment for each case, to document the reasons for selecting a particular  approach for the patient and be sure to have the patient/care-giver assent to such an approach knowing there is clinical equipoise. 

 

Hemorrhagic Strokes

Hemorrhagic Strokes result from the rupture of blood vessels.  COVID-19 seems to cause damage and necrosis of blood vessels resulting in acute necrotizing encephalopathy (ANE). This is a rare complication of some viral infections and is thought to be related to severe immune response and cytokine storm in the brain.   The blood vessel wall becomes very leaky, risking brain bleed, or intracerebral hemorrhage.  The cases of ANE have also been reported with COVID-19.  The commonly affected areas in these patients include the bilateral thalami, brain stem, cerebral white matter, and cerebellum [3, 4].

Computerized tomography (CT) scan of the brain and magnetic resonance imaging (MRI) brain can help determine if a patient has an ischemic or hemorrhagic stroke. Some of these patients also need special imaging studies of cerebral blood vessels, including a CT angiogram or MR angiogram. Blood thinners are not used in hemorrhagic stroke patients, with some exceptions.  This discussion is beyond the scope of this article.  

 

Seizure Disorder

Patients with CNS involvement are prone to develop abnormal brain activity and seizure spells. This can result in altered mental status and unresponsiveness. If there are concerns about abnormal brain activity in COVID-19 patients, electroencephalography (EEG) should be considered. This can help to determine if a patient has any ongoing subclinical seizure activity, also known as subclinical status epilepticus.  This might require aggrieve management and treatment with anti-epileptic drugs to prevent any ongoing seizure activity and potential brain damage [4].  

 

Acute Inflammatory Demyelinating Polyneuropathy

Acute Inflammatory Demyelinating Polyneuropathy (AIDP) is a post-viral immune-mediated complication also known as Guillain-Barré syndrome (GBS).  This results in the demyelination of peripheral nerves and ultimately causes muscle weakness of upper and lower extremities. This may also involve the diaphragm, causing difficulty breathing, which might require intubation and mechanical ventilation. Intubation can prolong patients’ critical care unit stay and can increase the risk of other complications like ICU myopathy [5-6].

 

At-Risk Patients

The neurological manifestations of COVID-19 are relatively rare or under-reported at this time but should be considered when taking care of these patients to avoid any potential complications and poor outcomes.  Older patients with multiple comorbidities such as hypertension, diabetes, and immunocompromised status are more prone to have cerebrovascular complications of COVID-19. The potential mechanism of poor outcome in some of these patients may be related to angiotensin-converting enzyme-2 (ACE2) activation as it helps the virus easily enter the cells by attaching to ACE2.  Therefore, special attention should be paid to older patients with vascular disorders and other risk factors as mentioned above [4,7].

 

Treatment

There is no definite treatment of COVID-19 at this time. However, different drugs such as antimalarials, antivirals, and immunotherapies are currently being considered and tried currently. Researchers are also working on a vaccine against COVID-19 but it is not conclusive as to when it will be available for public use [1].  

 

Conclusion
COVID-19 patients with severe infection are more likely to develop neurological manifestations such as ischemic and hemorrhagic strokes. This is especially the case if they have other comorbidities, including cardiovascular risk factors. COVID-19 may enter the CNS through the hematogenous or retrograde neuronal route. The damage to the nervous system may be from the direct toxic effects of the virus, a neuroinflammatory response, and/or a cytokine storm. The key neurological manifestations involve CNS, PNS, and skeletal muscles. The mainstay of clinical treatment consists of symptomatic management and oxygen therapy. Several antiviral, antimalarial, and immunotherapy drugs are being tested, but none have been specifically approved for COVID-19. The safety and efficacy of new vaccines is further being assessed via clinical trials. Developing a working vaccine is now the most important matter for addressing the pandemic.


References


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Saad Umar

Saad Umar


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