key: cord-0783544-v666xzjj authors: Abboud, Hilal; Abboud, Fatima Zahra; Kharbouch, Hanane; Arkha, Yasser; Abbadi, Najia El; Ouahabi, Abdessamad El title: COVID-19 and SARS-Cov-2 Infection: Pathophysiology and Clinical Effects on the Nervous System. date: 2020-05-28 journal: World Neurosurg DOI: 10.1016/j.wneu.2020.05.193 sha: e410c19e6a2e6987ea3f8e8a5ca9cd4c26e2456d doc_id: 783544 cord_uid: v666xzjj Coronavirus disease 19 (COVID-19) is an infectious disease caused by SARS-Cov-2, resulting in severe acute respiratory syndrome, with high potential of spreading and infecting humans worldwide. Since January 2020, when the virus was identified in humans, the literature on COVID-19 has grown exponentially, and extra respiratory symptoms including neurological symptoms are increasingly highlighted. These neurological disorders are grouped into several categories, ranging from non-specific and moderate symptoms such as headache, myalgia and hyposmia to severe symptoms including cerebrovascular disease and intracranial infections. Severe neurological symptoms such as acute cerebrovascular disease occur only in a minority of patients with usual risk factor, and are associated with poor outcome. However, most COVID-19 patients exhibit only minor or mild neurological symptoms. Given the high and increasing number of publications reporting neurological involvements of SARS-Cov-2, we think providing an update for neurological complications of COVID-19 could be useful for physician and especially young trainees in neurology and neurosurgery. Indeed, in this review we discuss several neurological aspects reported in the literature to date, including the evidence and pathways of the neuro-invasion in COVID-19, and the main neurological disorders reported in the literature to date, as well as the future perspectives and the potential long term consequence of current neuro-infection in COVID-19 patients. The clinical course of COVID-19 ranges from asymptomatic infection to severe acute respiratory distress with multi-organ involvement and death. The disease can cause extra pulmonary complications such as neurological disorders which are increasingly reported in the literature. Understanding the nervous system involvement pathways and neurological manifestations can be very useful in improving assessment and management of SARS-Cov-2 patients. Indeed, these disorders may interfere with the prognosis or require treatment modification. Although pneumonia is the most frequent manifestation of COVID-19, many other extrapulmonary involvements including nervous system have been reported [1] . Given high rates of COVID-19 infection in the general population, coincidental occurrence of neurological events is likely. However, currently there is convincing evidence that SARS-Cov-2 can involve the nervous system, and its neurotropic potential is increasingly well established: Genomic analysis shows that SARS-CoV-2 is in the same beta-coronavirus (βCoV) clade as MERS-CoV and SARS-CoV, and shares highly homological sequence with SARS-CoV [2] . In addition, the entry of SARS-CoV-2 into human host cells has been identified to use the same receptor as SARS-CoV [3] [4] . A growing body of evidence shows that neurotropism is one common feature of CoVs, which share a similar viral structure and infection pathway [5] , and therefore, the infection mechanisms and neurotropism previously found for other CoVs may also be applicable for SARS-CoV-2. Previous autopsy studies identified the SARS-CoV in the brain tissue from both patients with significant central nervous system symptoms and experimental animals [6] [7] . Recently, a Japanese team reported a young patient with convulsion and unconsciousness; he was diagnosed with aseptic encephalitis with SARS-CoV-2 RNA in cerebrospinal fluid [8] . SARS-CoV-2 have been also identified in the CSF of a 56 year old male who developed COVID-19 in China [9] , this case remains unpublished in peer-reviewed literature, but was cited by other papers [26] . Note that viral particles were also identified in brain tissue from post-mortem examination of a SARS-CoV-2 infected patient [10] . Published case series of other corona respiratory viruses like MERS-CoV and SARS-CoV in prior years have listed many neurological complications including intracranial haemorrhage, ischemic stroke, polyneuropathy, encephalitis, and Guillain Barre Syndrome [11-12-13] . Dissemination across the cribriform plate of the ethmoid bone during the infection can lead to cerebral invasion; this was reported in SARS-CoV [14] . Altered sense of smell and/or taste in uncomplicated early stage COVID-19 patients is suggestive of a movement of the virus to the brain via the olfactory bulbe which could enables the virus to reach and affect the brain [15] . SARS-Cov-2 has been shown to use the ACE2 receptor fo cell entry [16] , this receptor has been also detected over glial cells and neurones, which make it a potential target for COVID-19 [17] . Moreover, SARS-CoV-2 spike protein could interact with ACE2 expressed in the capillary endothelium; the virus may also damage the blood-brain barrier and enter the CNS by attacking the vascular system [17] . When a virus replicates and proliferates in pneumocytes, it causes diffuse alveolar and interstitial inflammatory exudate, and the formation of membranes in most severe forms. This, in turn, leads to alveolar gas exchange disorders causing hypoxia in the CNS, increasing the anaerobic metabolism in brain cells, inducing cellular and interstitial edema, obstruction of cerebral flow blood as well as ischemia and vasodilation in the cerebral circulation [18] . SARS-Cov-2 binds to ACE2 with a high affinity compared to SARS-CoV [19] , the ACE2 is known to be a cardio-cerebral vascular protection factor, playing a major role in regulating blood pressure and anti-atherosclerosis mechanisms. Binding to ACE2, the above-mentioned viruses may cause abnormally elevated blood pressure and increase the risk of cerebral haemorrhage and ischemic stroke. In addition, patients with COVID-19 often suffer from coagulopathy and prolonged prothrombin time [20] [21] , both of which are also contributing factors to secondary cerebral haemorrhage. The immune response can also play a role. Some patients with COVID-19 have died from hyperinflammatory syndrome (cytokine storm) and multi-organ failure [22] . Coronaviruses have the ability to infect macrophages, as well as glial cells. Experimental models have shown that glial cells are capable of secreting pro-inflammatory factors, such as interleukin-6, interleukin-12, Interleukin-15 and tumor necrosis factor alpha, after coronavirus infection [23] . The usual lack of permeability of cerebral blood vessels represents a barrier to virus invasion, but also a barrier to viruses' elimination in case of brain invasion. Given the lack of major histocompatibility complex antigen in nerve cells, the elimination of viruses is limited and depends on the role of cytotoxic T-cells and apoptosis of infected neurones [24] . The above mentioned characteristics contribute to the chronic existence of viruses, and may facilitate exacerbation of neurological damage. Note that neuronal degeneration has been identified in SARS-CoV infected patients, and viral particles were identified in human brain tissue and CSF in Multiple sclerosis patients [25] . A previous study in Wuhan when the pandemic was first described, demonstrated that 36% of 214 patients hospitalised for COVID-19 developed neurological symptoms or secondary cerebral events. Others studies reported several categories of central and peripheral neurological disorders in COVID-19 patients. Here; we highlight the main neurological disorders observed in COVID-19 patients to date: Headache, myalgia, dizziness and fatigue are the most common non-specific symptoms seen in COVID-19 patients. These symptoms range from 30 to 45.5%, and are more common as the disease is severe. Headache: The most reported neurological symptom in COVID-19 patients. Several studies showed headache as a symptom occurred in 8 to 34% of patients, and the intensity is often described as mild [26] [27] . Myalgia: Has been commonly reported during the infection process. Some patients showed fatigue, muscle soreness and elevated muscle enzyme levels, which may be related to the inflammation and muscle damage caused by the virus [28] . Hyposmia or anosmia and, less commonly, disturbed taste would be very common in patients with COVID-19, even in the absence of nasal symptoms, and may be initial and appear suddenly [29] . In a study reporting 417 patients with mild to moderate COVID-19 patients, 85.6% and 88% of the patients respectively described disturbances of smell and taste, and olfactory dysfunction was the initial symptom in 12% of the cases [30] . Other moderate nervous symptoms including deficit in visual function and neuralgia were also reported, however, electrophysiology report of COVID-19 with peripheral nervous system symptoms is still lacking [1] . Infectious toxic encephalopathy, also known as acute toxic encephalitis, is a reversible brain dysfunction syndrome caused by factors such as systemic toxemia, metabolic disorders, and hypoxia during the process of acute infection [31] . The basic pathological changes include cerebral edema, with no evidence of inflammation on cerebrospinal fluid analysis. Its clinical symptoms are complex and diverse, including headache, dysphoria, mental disorder, and delirium. Some rare severe forms may experience disorientation, loss of consciousness, coma, and paralysis [32] . Epilepsy as well as paralysis and consciousness disorder is a symptom associated with many underlying intracranial lesions, and has been reported in COVID-19 patients. It may result from hypoxia, multi-organ failure, or metabolic and electrolyte derangements. This symptom may require specific medication and neurological assessment. Hence, it is plausible to expect clinical or subclinical acute symptomatic seizures and status epilepticcus to happen in these patients Several categories of cerebrovascular events (Intra-cerebral haemorrhage, Ischemic stroke, Cerebral venous thrombosis) were recently reported in COVID-19 patients. Intra cerebral haemorrhage: Several cases have been reported in elderly COVID-19 patients with usual risk factors such as hypertension, diabetes, and underlying cardiac disease. Binding to ACE2 which is known to be cerebrovascular protective factor, SARS-Cov-2 may cause abnormally elevated blood pressure. This hypertension, associated with the presence of thrombocytopenia and bleeding disorders, is a factor that may contribute and increase the risk of intra-cerebral haemorrhage in patients with COVID-19 [34] [35] . Ischemic stroke: SARS-Cov-2 infection has been suggested to cause stroke. Current evidence suggests that COVID-19 patients commonly had neurological symptoms manifested as acute stroke in 2.8% to 6%, and most (80%) were ischemic [36] [37] . A number of potential mechanisms by which COVID-19 might increase ischemic stroke risk have been reported. These include hypercoagulability as evidenced by raised D-dimer levels, exaggerated systemic inflammation (cytokines storm), and cardio embolism from virus-related cardiac injury [37] . Acute Necrotizing Encephalopathy: ANE is a rare disorder leading to brain dysfunction, which was reported recently in COVID-19 patients, it results in seizures, liver problems, and mental disorientation [9] . The disease is characterized by multifocal symmetric lesions in the brain, which affect the brain stem, thalami, cerebellum, and cerebral white matter. ANE is characterized by neuro-inflammation resulting from a cytokine storm mediated mainly by the production of the interleukin-6 (IL-6). This systemic inflammation causes severe encephalopathy in the patient, and that may lead even to stroke. The first case of COVID-19 with encephalitis was reported in Beijing, China. He presented with convulsions and persistent hiccups. Neurological examination revealed bilateral ankle clonus, bilateral positive Babinski sign and meningeal irritation. The patient had a normal CT-scan. A lumbar puncture showed an increased opening pressure of 330 mm H2O, normal biochemical and cytological parameters with a positive PCR for SARS-CoV-2 [28] . Another case of meningitis associated with Coronavirus was recently reported in Japan, in a young patient without medical history, with negative nasopharyngeal swab. The SARS-Cov-2 RNA was detected in CSF [8] . Note that symptoms of meningitis or encephalitis may be the first symptom as well as the respiratory symptoms. A case of GBS associated with SARS-CoV-2 infection has been described in a 62-year-old patient who presented motor weakness in the lower extremities, and clinical symptoms of COVID-19 a week later. The cerebrospinal fluid study showed a hyperproteinorachia (124 mg / dL) and absence of cells. Neurophysiological examination revealed an increase in distal latencies and an absence of F-waves, pointing to a demyelinating form of GBS. The authors suggest that the patient was infected with SARS-CoV-2 at the onset of GBS symptoms, as she had lymphopenia and thrombocytopenia [38] . Given the chronic neuro-inflammation and neuronal degeneration reported in SARS-CoV patients as well as the viral particles found in Multiple sclerosis patients [24] [25] , and considering that human neurodegenerative diseases often involve a gradual process that evolves, in some cases, over several decades, we think that current COVID-19 patients, especially with neurological symptoms, may develop late and long term neurological complications. Hence, they should be closely followed up, and futures studies should consider late neurological complications such as demyelinating and degenerative disorders in these patients (e.g., Poly-neuropathies, Parkinson disease, Multiple sclerosis...). 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