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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 68
| Issue : 3 | Page : 560-572 |
Spectrum of Neurological Manifestations in Covid-19: A Review
Ravindra K Garg
Department of Neurology, King George Medical University, Lucknow, Uttar Pradesh, India
| Date of Web Publication | 6-Jul-2020 |
Correspondence Address:
Dr. Ravindra K Garg
Department of Neurology, King George Medical University, Lucknow, Uttar Pradesh - 226 003
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.289000
COVID-19, in most patients, presents with mild flu-like illness. Elderly patients with comorbidities, like hypertension, diabetes, or lung and cardiac disease, are more likely to have severe disease and deaths. Neurological complications are frequently reported in severely or critically ill patients with comorbidities. In COVID-19, both central and peripheral nervous systems can be affected. The SARS-CoV-2 virus causes the disease COVID-19 and has the potential to invade the brain. The SARS-CoV-2 virus enters the brain either via a hematogenous route or olfactory system. Angiotensin-converting enzyme two receptors, present on endothelial cells of cerebral vessels, are a possible viral entry point. The most severe neurological manifestations, altered sensorium (agitation, delirium, and coma), are because of hypoxic and metabolic abnormalities. Characteristic cytokine storm incites severe metabolic changes and multiple organ failure. Profound coagulopathies may manifest with ischemic or hemorrhagic stroke. Rarely, SARS-CoV-2 virus encephalitis or pictures like acute disseminated encephalomyelitis or acute necrotizing encephalopathy have been reported. Nonspecific headache is a commonly experienced neurological symptom. A new type of headache “personal protection equipment-related headache” has been described. Complete or partial anosmia and ageusia are common peripheral nervous system manifestations. Recently, many cases of Guillain-Barré syndrome in COVID-19 patients have been observed, and a postinfectious immune-mediated inflammatory process was held responsible for this. Guillain-Barré syndrome does respond to intravenous immunoglobulin. Myalgia/fatigue is also common, and elevated creatine kinase levels indicate muscle injury. Most of the reports about neurological complications are currently from China. COVID-19 pandemic is spreading to other parts of the world; the spectrum of neurological complications is likely to widen further.
Keywords: Coronavirus, encephalitis, encephalopathy, Guillain-Barré syndrome, myalgia
Key Messages: COVID-19 is caused by the SARS-COV-2 virus. Several neurological manifestations have been reported. Headache, myalgia, anosmia, and ageusia are common. Cases of encephalitis have been reported but the virus has infrequently been isolated from cerebrospinal fluid. Guillain-Barré syndrome is a postinfectious immune-mediated complication of virus infection.
How to cite this article:
Garg RK. Spectrum of Neurological Manifestations in Covid-19: A Review. Neurol India 2020;68:560-72 |
Coronavirus disease 2019 (COVID-19) is a potentially serious condition caused by a novel coronavirus termed as “severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)”. COVID-19 is clinically characterized by respiratory system involvement. COVID-19 disease was first seen in Wuhan, China, in December 2019, when a series of patients presented with pneumonia of unknown etiology. COVID-19 has very rapidly spread worldwide and on March 11, 2020, the World Health Organization officially announced COVID-19 a pandemic.[1]
The majority of patients suffering from COVID-19 have mild to moderate respiratory symptoms. Lungs are the most severely affected organ. Many COVID-19 patients have neurological manifestations as well. Neurological manifestations are common in advanced stages of the disease. In severe COVID-19, systemic disorders like hypoxia, sepsis respiratory and metabolic acidosis, hypercoagulable states, and disseminated intravascular coagulation (DIC) are largely responsible for most of the clinical manifestations, including neurological. Neurological manifestations can also be caused by prolonged stays in the intensive care unit and drug toxicities. The central and peripheral nervous system, both, can be affected in COVID-19. For this article, an extensive literature search was done and all neurological manifestations, seen in COVID-19 patients, were reviewed.
| » Virus | |  |
The novel coronavirus SARS-CoV-2 was first isolated from the lower respiratory tract, in patients having unexplained pneumonia.[2] Coronaviruses are a group of RNA viruses that dominantly affect the vertebrates. There have been two novel coronavirus outbreaks in the past. In 2002–2003, an outbreak of severe acute respiratory syndrome (SARS) took place that was caused by SARS-CoV. Another outbreak of SARS took place between 2012 that was termed as the Middle East respiratory syndrome (MERS). MERS was caused by MERS-CoV. The current SARS, which is termed as COVID-19, is caused by SARS-CoV-2.[1]
Epidemiology
As per the latest World Health Organization report, globally there were 4534731 confirmed COVID-19 cases along with 307537 deaths. COVID-19 has now been reported from 216 countries. India, so far, reported 90727 confirmed cases of COVID-19.[3]
According to the latest meta-analysis (published on April 14, 2020) that analyzed data of 47,344 patients, noted sex ratio (male to a female) of 1.06 and an average age of an affected person was more than 40 years. Diabetes, hypertension, cardiovascular disease, and malignancies were common comorbidities.[4] Another large study, describing data of 5700 hospitalized patients from New York, USA, reported a median age of 63 years (range 1–107 years). There were 40% of females. Common comorbidities were hypertension, obesity, and diabetes. Among patients who were discharged or died (n = 2634), 14% required intensive care management. Approximately, 12% of patients needed mechanical ventilation. In total, 21% of patients had died.[5]
Pathogenesis
The SARS-CoV-2 virus is a novel coronavirus, consisting of a single-strand positive-sense RNA genome, virus genome lies within a helical nucleocapsid, that is, surrounded by lipid bilayer capsule. SARS-CoV-2 virus entry, into the host cells, is a complex process. After binding to the receptor present on the host cell, the enveloped virus fuses its envelope with the host cell membrane; subsequently, the virus delivers its nucleocapsid into the host cell cytoplasm. In the host cell, viral RNA multiplies and viral proteins are synthesized. Viral proteins reassemble with the viral genome, forming new virus particles. New virus particles are released in new uninfected cells, thus, virus spread takes place.
The SARS-CoV-2 virus utilizes the angiotensin-converting enzyme 2 receptor for entry into the host cell. These receptors are profusely expressed on lung tissues and arterial and venous endothelial cells. Angiotensin-converting enzyme 2 receptors are also expressed in the brain, particularly, in endothelial cells of cerebral capillaries.[6] A unique spike glycoprotein receptor binding domain of SARS-CoV-2 confers affinity of virus for an angiotensin-converting enzyme two receptor.[7] A unique furin-like cleavage site, on the spike protein, plays a crucial role in viral cell entry.[8] Earlier versions of the SARS-CoV virus do not possess a furin-like cleavage site. Transmembrane protease, serine 2 (TMPRSS2) enzyme, is needed to activate the spike protein. A serine protease enzyme inhibitor blocks viral entry into the host cell. This phenomenon can be exploited for developing a treatment of COVID-19, in the future.[6]
Qi and colleagues assessed the expression level of angiotensin-converting enzyme two receptor and TMPRSS2 enzyme in various body organs. Angiotensin-converting enzyme two receptor and TMPRSS2, in the brain, were highly expressed in the oligodendrocyte precursor cells and astrocytes of the substantia nigra and cortex.[9]
Central nervous system (CNS) invasion and crossing of the blood–brain barrier
Available pieces of evidence suggest that the SARS-CoV-2 virus can break the blood–brain barrier and enter into the brain. The virus, possibly, travels to the brain by a hematogenous route. The virus can also enter trans-neuronally to the brain via the olfactory system, across the cribriform plate.[10] Angiotensin-converting enzyme 2 receptors that are present on endothelial cells of cerebral vasculature act as cell entry points for virus.[11] Paniz-Mondolfi and co-workers, in an autopsy-based study, demonstrated the presence of the SARS-CoV-2 virus in neural and capillary endothelial cells of the frontal lobe of the brain. The viral particles were specifically present in small vesicles of endothelial cells. Neurons or microglia did not have angiotensin-converting enzyme two receptors.[12] Comorbidities, like diabetes and hypertension, enhance the angiotensin-converting enzyme 2 receptor expression in the brain and neurotropism of the SARS-CoV-2 virus.[13]
In COVID-19, alterations in blood pressure control are another proposed mechanism that has been suggested to explain the increased risk of cerebral vascular complications. Ordinarily, angiotensin-converting enzyme 2 signaling lowers blood pressure.[14] Competitive blockage of angiotensin-converting enzyme 2 by the SARS-CoV-2 virus down-regulates angiotensin-converting enzyme 2 expression leading to uncontrolled blood pressure and the enhanced possibility of cerebrovascular accidents.
Coagulopathies
Severe COVID-19 is characterized by profound coagulopathy. In the patients of severe COVID-19, coagulopathies are important detrimental factors that are invariably associated with poor outcomes. The hallmark coagulopathy abnormalities in COVID-19 are elevated prothrombin time, raised D-dimer level, and mild thrombocytopenia, but without hypofibrinogenemia. DIC is the severest form of coagulopathy in COVID-19. DIC is characterized by thrombocytopenia, prolonged prothrombin time, and increased D-dimer and markedly elevated D-dimer.[15],[16] Coagulopathies in COVID 19 predispose to stroke and other prothrombotic events.[17],[18],[19]
Cytokine storm
Cytokines are crucial mediators of the inflammation in COVID-19. Severe COVID-19 is characterized by markedly elevated levels of proinflammatory cytokines, lymphopenia, an increased number of neutrophils. This kind of cytokine profile is termed as “cytokine storm.” Interleukin 6 is a key element of the cytokine storm. Other proinflammatory cytokines that are elevated in cytokine storm are interleukin-1β, interleukin-2, interleukin-8, interleukin-17, chemokine ligand 3, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, the human interferon-inducible protein, and tumor necrosis factor-alpha. Cytokine storm is associated with enhanced vascular hyperpermeability, coagulopathies, and multisystem dysfunction.[20] Approximately, 5% of COVID-19 patients develop acute respiratory distress syndrome, septic shock, and/or multiple organ dysfunction. A cytokine storm is held responsible for the pathogenesis of all the complications of severe COVID-19.[21],[22]
The SARS-CoV-2 virus infection can trigger hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis is a rare hyperinflammatory condition that is characterized by a severe hypercytokinaemia with multiorgan failure. The cytokine profiles of severe COVID-19 and hemophagocytic lymphohistiocytosis syndrome are largely similar.[23],[24]
Autoimmunity
Postinfectious autoimmune reactions can affect neuronal cells. The SARS-CoV-2 virus epitopes bear a structural resemblance to several human proteins. Molecular mimicry between virus epitope and myelin basic protein results in autoimmune postinfectious demyelinating syndromes.[25] Dysregulation of the angiotensin-converting enzyme 2 receptor also contributes to the pathogenesis of experimental autoimmune encephalomyelitis.[26],[27] Spike surface glycoprotein plays a crucial role in immunopathology.
Phases in pathogenesis
The pathogenesis of COVID-19 evolves in three phases. In the early infection phase, the inflammatory response is localized to the mucosa of the upper respiratory tract. During this phase, the patient is infected and transmits the disease to others. In the next pulmonary phase, the virus proliferates and invades the lungs. There are lung damage, hypoxemia, and cardiovascular dysfunction. In the last, inflammatory response phase, there is a cytokine storm. In the last phase, multiple body organs, including the nervous system, are likely to be affected.[28]
Common clinical features
The incubation period for COVID-19 ranges from 4 to 14 days. The average time to hospitalization, after first symptoms, on an average is 7 days. Fever is the most frequent symptom. Fatigue, dry cough, anorexia, myalgia, dyspnea, and expectoration are other common initial symptoms.
According to the severity, Covid-19 is categorized into mild, severe, and critical categories. In mild disease, patients have no pneumonia or mild pneumonia. In severe cases, patients have severe dyspnea (respiratory rate >30/min) and hypoxemia, needing intensive care unit care. At that stage, bilateral pulmonary infiltrates are seen on chest imaging. Critical patients either have respiratory failure requiring mechanical ventilation, septic shock, and/or multiple organ dysfunction.[29],[30] Comorbid conditions, cardiovascular disorders, diabetes mellitus, hypertension, chronic lung disease, systemic malignancies, and chronic renal failure are crucial.
Diagnosis
Common laboratory findings include lymphopenia, increased neutrophil count, eosinopenia along with prolonged prothrombin time, raised lactate dehydrogenase, raised alanine aminotransferase, raised aspartate aminotransferase, a high troponin and markedly elevated D-dimer, and C-reactive protein levels. Increased ferritin level is an indicator of the imminent cytokine storm.[31],[32]
Reverse transcription-polymerase chain reaction (RT-PCR) is the gold standard diagnostic procedure for confirming SARS-CoV-2 virus infection. RT-PCR testing is done on nasopharyngeal swabs. RT-PCR test has a specificity that is close to 100%, but the sensitivity is inadequate at 79%. If the results are negative, the RT-PCR test needs to be performed after 3 days.[33],[34]
Recently, IgM and IgG antibody tests to detect antibodies, against SARS-COV-2 infection in human blood, serum/plasma, have been made available. These tests are valuable as they can be used for screening purposes in a large population. However, the World Health Organization has some doubts about the reliability of these tests. IgM and IgG antibody tests need further validation to establish their accuracy.[35]
Neurologic manifestations
In COVID-19, a variety of neurological complications have been reported. Headache, myalgia, and malaise are common initial neurological symptoms. Severe neurological complications are either because of direct viral invasion, immunological reaction, or hypoxic metabolic changes. In COVID-19, both the CNS and peripheral nervous system (PNS) are affected [Table 1] and [Figure 1].[36],[37] | Table 1: Neurological manifestation in COVID-19: review of published original data from two studies, which included patients in large numbers
Click here to view |
 | Figure 1: Flow diagram depicts common and uncommon central nervous system (CNS) and peripheral nervous system complications on COVID-19
Click here to view |
Helms and co-workers recorded neurological manifestations in 58 severely ill patients. The median age of these patients was 63 years. Agitation was the most frequent neurological complication (69%; 40/58). On examination, diffuse pyramidal signs were recorded in 39 (67%) patients. A dysexecutive syndrome, consisting of inattention, disorientation, or poorly organized movements, was common sequelae among one-third of the survivors.[36]
In another retrospective study, Mao and co-workers from China noted that among 214 severely affected patients, 78 (36.4%) had neurological complications. CNS involvement was noted in 53 (24.8%) patients. In total, 19 (8.9%) patients had peripheral nervous system involvement. Rest, 23 (10.7%) had skeletal muscle injury. The commonest CNS manifestations were dizziness and headache. More serious CNS manifestations included acute cerebrovascular disease 6 (5 ischemic stroke and 1 hemorrhage). Impaired consciousness was recorded in 16 patients. The majority of serious patients had multiple organ dysfunction. The commonest peripheral manifestations were anosmia and ageusia. Three patients had vision impairment, and five patients had neuralgic pain. Muscle injuries were associated with elevated creatine kinase levels.[37]
| » Central Nervous System | | |
Encephalopathy
Altered sensorium, in severe COVID-19, ranges from confusion, delirium, stupor to coma. Delirium is often associated with systemic inflammation and prolonged hypoxia. Middle-aged and older adults with severe disease are more likely to be affected.[37] Metabolic alterations in an isolated case manifested with posterior reversible encephalopathy syndrome. Kaya and colleagues reported a 38 man, who presented with cortical blindness and MRI hyperintensities in the visual cortex. Both blindness and imaging abnormalities resolved soon after stopping chloroquine and starting corticosteroids.[38] Altered sensorium, in COVID-19, is associated with an increased risk of death.[39]
Encephalitis
The SARS-CoV-2 virus has the potential to enter the brain. Xiang and co-workers, in Beijing, China, claimed to isolate the first SARS-CoV-2 virus in cerebrospinal fluid (CSF).[40] So far seven additional cases of SARS-CoV-2 associated encephalitis, encephalopathy, or meningitis have been reported. Four cases presented with features were consistent with encephalitis. Only in two patients, the SARS-CoV-2 virus in CSF was isolated; in one such case, the SARS-CoV-2 virus was not identified in a throat swab. Neuroimaging, usually, in patients with SARS-CoV-2 encephalitis is normal. In a case of COVID-19-associated encephalitis, MRI revealed the involvement of the limbic system. It was likely that the SARS-CoV-2 virus travelled down from nasal mucosa to olfactory bulb then spreading to the piriform cortex. In the majority of patients with encephalitis, computed tomography (CT) thorax demonstrated the ground-glass appearance of the lungs. The majority of the patients had recovered completely.[41],[42],[43],[44],[45],[46],[47],[48],[49] Patients also presented with corticosteroid-responsive encephalopathy, acute disseminated encephalomyelitis, and immune-mediated acute hemorrhagic necrotizing encephalopathy.[50],[51],[52],[53] In the case with hemorrhagic necrotizing encephalopathy, hemorrhagic lesions in thalamus were noted [Table 2].[50] | Table 2: Encephalitis/meningitis in COVID-19: review of all published isolated cases
Click here to view |
SARS-CoV-2 virus-associated medullary respiratory center dysfunction is now held responsible for respiratory distress. Many experts noted that patients of COVID-19 lacked dyspnea; instead, these patients had marked tachypnoea and tachycardia.[54] Li and colleagues argue that the SARS-CoV-2 virus spreads to the medulla oblongata and contributes to the pathogenesis of acute respiratory failure.[55]
In an interesting isolated case, SARS-CoV-2 virus-associated brainstem encephalitis has been described. MRI showed hyperintense signal changes in the brainstem and the upper cervical cord. Clinical manifestations indicated dysfunction of the medulla, pons as well as the midbrain. The patient had marked hepatic insufficiency. Virus possibly travelled from olfactory mucosa to brainstem.[56]
Myelitis
Spinal cord involvement is uncommon. Zhao and co-workers described acute myelitis in a 66-year-old patient. The patient developed acute flaccid paraplegia with spinal sensory level at T10 and urinary incontinence. The patient was treated with intravenous immunoglobulin and corticosteroids, and he responded well to the treatment. The cytokine storm and exaggerated inflammatory changes resulted in acute transverse myelitis.[57]
Stroke
In COVID-19, coagulopathies enhance the risk of cerebral arterial and venous thrombosis. Li and co-workers, in a retrospective study, noted that out of 221, 11 patients had an acute ischemic stroke. One patient each had cerebral venous thrombosis and cerebral hemorrhage. Majority stroke patients were elderly and were suffering from severe COVID-19. Comorbidities were common.[58] Beyrouti and co-workers, in a report of six severely affected patients with large cerebral infarcts, noted elevated D-dimer levels (≥1000 μg/L), indicating a coagulopathy.[59]
COVID-19-related strokes happen in young patients as well. Oxley and colleagues, from New York, USA, described five cases of large-vessel infarct in young (>50; 33–49 years). Three patients had prior risk factors (diabetes and hypertension). National Institutes of Health Stroke Scale scores, on hospitalization, ranged from 13 to 19. On follow up, all five patients deteriorated. In four patients, either the endovascular intervention or thrombolysis was done. Covid-19-associated coagulopathy and vascular endothelial dysfunction were plausible mechanisms.[60] In patients of stroke, the SARS-CoV-2 virus could not be demonstrated in CSF.[61]
Administration of exogenous soluble angiotensin-converting enzyme 2 receptors (human recombinant soluble angiotensin-converting enzyme 2 receptors), in experimental conditions, found to prevent SARS-CoV-2 virus infection of engineered human blood vessels. Soluble angiotensin-converting enzyme 2 acts as a virus trap. This treatment has the potential to prevent multiorgan failure and stroke.[19],[62]
Seizures
Seizures are not common manifestation in COVID-19. Mao and co-workers noted that among 214 patients admitted in intensive care units, the seizure was recorded only in one patient.[37] A multicentric Chinese retrospective study noted that among 304 COVID-19 patients (108 with severe disease) in none of the patients acute symptomatic seizures or status epilepticus were observed despite the presence of severe metabolic alterations.[63] In many case reports, authors had described new-onset seizures that were triggered by the SARS-CoV-2 virus infection. Even convulsive and nonconvulsive status epilepticus triggered by SARS-CoV-2 virus infection has also been described. Status epilepticus patients had responded well to parenteral levetiracetam.[64],[65]
Vollono and colleagues published a report of nonconvulsive status epilepticus triggered by Covid-19, in an elderly patient. Electroencephalography showed intermittent epileptiform discharges over the left temporal area. MRI brain revealed extensive gliosis and atrophy of left temporo-parietal lobe. After the resolution of fever, the patient had improved.[66] Dugue and co-workers, from the USA, described a six-week-old child, who presented with an acute episode of seizure. His CSF examination and neuroimaging were normal. The child initially had a fever; authors considered this episode as a manifestation of febrile seizures.[67]
Sporadic electroencephalographic epileptiform discharges, in acutely ill patients of COVID-19, have been described. Epileptiform discharges were dominantly localized to frontal lobes. These patients never had a definite seizure episode. Electroencephalography was done either because the patient had encephalopathy or had some seizure-like event.[68]
Headache
In many meta-analyses, headache has now been recognized as one of the common initial symptom of COVID-19. In these meta-analyses and systematic reviews, the incidence of headache ranged from 10% to 15% [Table 3].[69],[70],[71],[72] A recent European study noted a different clinical profile of younger (median 37 years) COVID-19 patients. In 1,420 mild-to-moderate Covid-19 patients, headache (70%) was the most prevalent symptom. Other common neurological symptoms were loss of smell (70%), asthenia (63%), myalgia (63%), and loss of taste (54%). A fewer number of patients reported a reduction in visual acuity (n = 6), vertigo (n = 6), and tinnitus (n = 5). Fever was not a common symptom and was reported only by 45% of patients.[73] Exact reasons for headache remained unexplained. Increased mental stress, excessive anxiety, and changes in lifestyle are possible reasons for early headaches. Pre-existing migraine may get worse because of COVID-19-related stress.[74] Belvis in a recent communication opined that COVID-19-associated acute headaches can be because of systemic viral infection, primary cough headache, and tension-type headache. Early headaches respond well to acetaminophen. Headaches appearing between the 7th and the 10th days of illness can be related to cytokine storm.[75] | Table 3: The most common presenting symptoms of COVID-19: review of three meta-analysis analyzing large number of patients
Click here to view |
Personal protection equipment (PPE) can because of new-onset headaches. Ong and co-workers, among hospital staff performing Covid-19 related duties, described a new kind of PPE-associated headache. In a cross-sectional study, the authors noted that most healthcare workers had either PPE-associated headache or there was the aggravation of their pre-existing headaches. In a questionnaire-based study, 81% (128/158) respondents experienced de novo PPE-associated headaches. The majority (42/46) of participants with pre-existing headaches experienced that prolonged PPE usage triggered the disabling headache.[76]
Subjective neurological symptoms
Frequently, the neurological symptoms that patients complain are subjective. Liguori and colleagues assessed 103 patients with SARS-CoV2 virus infection and noted that 91.3% of participants had one or more subjective neurological complaints. Sleep disturbances were the most common complaint. Other complaints were dysgeusia, headache, hyposmia, depression, dizziness, numbness/paraesthesia, daytime sleepiness, and muscle ache. These subjective neurological complaints were more common in females.[77]
Neuroimaging brain
In critically ill patients of Covid-19, a variety of neuroimaging abnormalities of the brain has been described. Kandemirli and co-workers demonstrated nonspecific T2/FLAIR cortical, subcortical, and deep white-matter signal abnormalities in 37% (10/27) critically ill patients. One patient each had transverse sinus thrombosis and right middle cerebral artery infarct. In patients with neuroimaging abnormalities, CSF protein levels (range 59.9 – 109.7 mg/dL) were elevated. The SARS-CoV-2 virus in CSF was not demonstrated.[78]
Coleen and co-workers performed MRI in 19 deceased patients of severe COVID-19, within 24 h after death. White-matter cortical abnormalities were noted in four deceased patients. These changes were intracranial vasculopathy, subcortical micro- and macrobleeds, and changes similar to posterior reversible encephalopathy syndrome.[79]
| » Peripheral Nervous System | | |
Loss of smell and taste
A complete or partial loss of smell sensation (anosmia) and taste sensation (ageusia) is the most frequent neurological manifestation of COVID-19. Anosmia and ageusia are common even in mild to moderate cases.[80] Smell sensation is more severely affected than a taste sensation. In a French study, Lechien and co-workers reported that out of 417 mild-to-moderate COVID-19 patients, 86% and 88% of patients, respectively, reported anosmia and ageusia. Anosmia in many patients was the first manifestation of Covid-19.[81] Beltrán-Corbellini and co-workers noted that anosmia and ageusia were more frequent in Covid-19 than in influenza. The SARS-CoV-2 virus utilizes angiotensin-converting enzyme 2 receptors, presents in the olfactory epithelium, to enter into the neuronal cells, and then via the olfactory nerve, it spreads to the olfactory bulb.[82]
Other cranial nerves
Isolated cranial neuropathies are rare in COVID-19. Wei and co-workers described a case of acute unilateral isolated oculomotor nerve palsy in a severely ill patient. CT chest demonstrated multiple ground-glass opacities of the lungs. The inflammatory reaction against the SARS-CoV-2 virus and inflammation of vessels supplying to nerve trunk was a possible reason for cranial nerve damage.[83]
Guillain-Barré syndrome
Guillain-Barré syndrome is a frequently encountered neurological complication of COVID-19. Zhao and co-workers described the first patient of Guillain-Barré syndrome in a patient with COVID-19.[84] After this, 18 more patients, of Guillain-Barré syndrome in COVID-19, have been described. All patients presented with classical clinical manifestations – acute symmetric flaccid, areflexic quadriparesis. CSF examination, in the majority, revealed albumin-cytologic dissociation. Treatment with intravenous immunoglobulins led to complete or partial recovery, in the majority. Few patients needed ventilatory support.[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98]
Miller Fisher syndrome is a variant of Guillain-Barré syndrome and is characterized by ophthalmoplegia, ataxia, and areflexia. Miller Fisher syndrome has also been described in patients with Covid-19. An albumin-cytologic dissociation in CSF and positive GD1b-IgG antibodies indicated an inflammatory pathology.[99],[100] A postinfectious immune-mediated mechanism was the putative mechanism proposed for the pathogenesis of COVID-19 associated Guillain-Barré syndrome and Miller Fisher syndrome [Table 4]. | Table 4: Guillain-Barré syndrome in COVID-19: review of all published isolated cases
Click here to view |
Muscles
General muscle pain or myalgia and fatigue are common initial symptoms of COVID-19. Several meta-analyses noted that myalgia, muscle soreness, and fatigue occurred in up to 35% of patients [Table 3].
Mao and co-workers noted muscle injury in 10% (23/214) of COVID-19 patients. Muscle involvement was much more common in severe cases. Creatine kinase levels were elevated in all patients with muscle disease. Rhabdomyolysis, a life-threatening disorder, has been described in Covid-19. Rhabdomyolysis is clinically characterized by myalgia, fatigue, and haemoglobinuria. If not recognized and treated promptly, acute renal failure may set in.[37],[101] Rhabdomyolysis can be a heralding manifestation of COVID-19. A COVID-19 patient, presenting with localized muscle pain or generalized weakness, a high index of suspicion for rhabdomyolysis should be kept.[102],[103] It has been hypothesized that via angiotensin-converting enzyme 2 receptor, virus enter in the muscles and can cause muscle injury.[104]
Beydon and co-workers recently described myositis in a critically ill patient of COVID-19. The patient presented with acute myalgias, difficulty in waking, and proximal weakness. Creatine kinase level (25384 IU/L) was markedly elevated. Four days later, the patient became febrile and tested positive for the SARS-CO-V-2 virus. A thoracic CT scan revealed ground-glass opacities of lungs. Limb MRI revealed external obturator muscle and quadricipital edema, suggesting myositis.[105]
Drugs
Drugs that have been repurposed for use in COVID-19 have the potential to cause neurological toxicities.[106] Hydroxychloroquine-associated retinal toxicity is well recognized and can occur in up to 7.5% of patients.[107] Hydroxychloroquine myopathy/myositis is another rarely encountered neurological condition. Hydroxychloroquine induced myositis is clinically characterized by proximal muscle weakness and normal creatinine kinase levels. Electron microscopy of biopsied muscle tissue demonstrates vacuolar changes and curvilinear bodies.[108],[109],[110] Hydroxychloroquine myopathy should be clinically and pathologically considered in the differential diagnosis of Pompe disease and other limb-girdle muscle disorders.[111] In isolated instances, hydroxychloroquine has also been implicated as a trigger for seizure.[112],[113]
Treatment
Currently, no drug has proven efficacy in the treatment of COVID-19.
Patients with mild disease are usually treated at home. The clinical condition of the patient should be keenly monitored. Severe and critically ill patients require intensive care treatment and mechanical ventilation. The focus is on prevention of transmission of the virus to the others.
| » Conclusions | | |
Information regarding SARS-CoV-2-related neurological manifestations is available in the form of a few large studies and case series, but bulk information is available only in the form of case reports. Neurological manifestations of the SARS-CoV-2 are seen in severe cases of Covid-19. Reports on SARS-CoV-2 encephalitis are in the form of isolated reports, and virus in CSF is not readily demonstrated. Guillain-Barré syndrome is another common complication of COVID-19. Several newly developed vaccines are currently in various phases of clinical trial. Vaccines are always at risk of inciting neurological complications. Even newer drugs, that are being tried, can have neurological complications.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4]
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