Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research
  Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login  
  Home Print this page Email this page Small font sizeDefault font sizeIncrease font size Users Online: 381       

   Table of Contents      
REVIEW ARTICLE
Year : 2020  |  Volume : 152  |  Issue : 1  |  Page : 41-47

Neurological manifestations of COVID-19: A brief review


1 Department of Neurology, Medipulse Hospital, Jodhpur, Rajasthan, India
2 Department of Pulmonary Medicine, Medipulse Hospital, Jodhpur, Rajasthan, India
3 Department of Pulmonary, Critical Care & Sleep Medicine, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
4 Department of Vasundhara Hospital & Infertility Centre, Jodhpur, Rajasthan, India

Date of Submission20-Apr-2020
Date of Web Publication17-Sep-2020

Correspondence Address:
Dr Nitesh Gupta
Department of Pulmonary, Critical Care & Sleep Medicine, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi 110 029
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmr.IJMR_1395_20

Rights and Permissions
   Abstract 

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been predominantly a respiratory manifestation. Currently, with evolving literature, neurological signs are being increasingly recognized. Studies have reported that SARS-CoV-2 affects all aspects of the nervous system including the central nervous system (CNS), peripheral nervous system (PNS) and the muscular system as well. Not all patients have reverse transcription-polymerase chain reaction positive for the virus in the cerebrospinal fluid, and diagnosing the association of the virus with the myriad of neurological manifestations can be a challenge. It is important that clinicians have a high-index of suspicion for COVID-19 in patients presenting with new-onset neurological symptoms. This will lead to early diagnosis and specific management. Further studies are desired to unravel the varied neurological manifestations, treatment, outcome and long-term sequel in COVID-19 patients.

Keywords: COVID-19 - CSF - encephalopathy - intracranial pressure - ischaemic stroke - nervous system diseases - neuronal cells - SARS-CoV-2 - venous thromboembolism


How to cite this article:
Sachdev K, Agrawal S, Ish P, Gupta N, Raheja K. Neurological manifestations of COVID-19: A brief review. Indian J Med Res 2020;152:41-7

How to cite this URL:
Sachdev K, Agrawal S, Ish P, Gupta N, Raheja K. Neurological manifestations of COVID-19: A brief review. Indian J Med Res [serial online] 2020 [cited 2021 Apr 18];152:41-7. Available from: https://www.ijmr.org.in/text.asp?2020/152/1/41/293260

Classical neurotropic viruses include herpes, Japanese encephalitis, polio, coxsackie, measles, mumps, rabies and influenza[1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a betacoronavirus which is a 29,903 bp single-stranded RNA virus that targets the angiotensin-converting enzyme (ACE)-2 receptors to gain entry into the host cells. The ACE-2 receptor is widely present in capillaries of respiratory and nervous systems[2]. SARS-CoV-2 has been documented to cause both central and peripheral nervous system (CNS and PNS) involvement. The current review is aimed to highlight the myriad of neurological manifestations due to SARS-CoV-2 infection.


   Pathogenesis Top


Several theories have been put forward for the pathogenesis of neurological manifestations. These include direct entry of the virus through ACE-2 receptor, haematogenous spread and neuronal spread. The indirect mechanisms are inflammatory response, immune response and cytokine storm[2],[3],[4]. Among the proposed mechanisms, the emerging literature emphasizes the importance of cytokine storm in multi-organ manifestations. Cytokine storm syndrome and secondary haemophagocytic lymphohistiocytosis can occur in a subgroup of patients leading to hyperinflammatory syndrome. Clinically, this is characterized by unremitting fever, cytopenia, hyperferritinemia and acute respiratory distress syndrome (ARDS). The cytokine profile shows increased interleukins (IL-2 and IL-7), granulocyte colony-stimulating factor, interferon-gamma inducible protein-10 and tumour necrosis factor-alpha. This can cause stroke, encephalopathy and skeletal muscle injury[4].

Solomon et al[5] reported neuropathological findings from autopsies of 18 consecutive patients with SARS-CoV-2 infection. Microscopic examination demonstrated acute hypoxic injury in the forebrain (cerebrum) and brainstem (cerebellum), with loss of neurons in the cerebral cortex, hippocampus and cerebellar Purkinje cell layer in all the patients. However, there were no thrombi or vasculitis documented. Foci of perivascular lymphocytes (in 2 patients) and focal leptomeningeal inflammation (in 1 patient) were rare findings. Noteworthy was the absence of microscopic abnormalities in the olfactory bulbs or tracts. Paniz-Mondolfi et al[6] established the presence of the SARS-CoV-2 in capillary endothelial and neural cells in the frontal lobe of the brain in an autopsy specimen. The viral particles were specifically present in small vesicles of these endothelial cells.


   Clinical features Top


The prototype symptoms of COVID-19 are fever, non-productive cough, sore throat, difficulty in breathing along with abdominal pain, diarrhoea and conjunctivitis. The potential mechanisms of neurological manifestations of COVID-19 include direct viral infection (blood-brain barrier, infected leukocytes or neuronal transport), hypoxic brain injury (vasodilation, hypercarbia and aerobic metabolism leading to metabolite accumulation), immune mediated (cytokine storm or cell/antibody mediated) and vascular (direct involvement or coagulopathy, endothelial dysfunction, thrombotic microangiopathy and vasculitis)[7].

The neurological manifestations can broadly be categorized into CNS and PNS. The neurological manifestations are commonly observed in older age and critically ill patients. Varatharaj et al[8] reported clinical data of 125 patients with COVID-19 over a three-week period showcasing neurological or psychiatric disease. Notably, cerebrovascular event in 77 (62%) patients, ischaemic stroke in 57 (46%), intracerebral haemorrhages in nine (7%) and CNS vasculitis in one (<1%) patients were documented. This study also reported altered mental status in 31 per cent of patients, encephalopathy (13%) and neuropsychiatric diagnosis (18%)[8].

The involvement of PNS manifests as altered smell and taste dysfunction (68 and 71%, respectively) as reported by Yan et al[9] and Bagheri et al[10] (48.23 and 83.38%, respectively). Guillain-Barre syndrome (GBS) has been documented in eight cases[11], and skeletal muscle damage has been reported by Mao et al[12] in 19.3 per cent of patients in the severely ill and 4.8 per cent of patients in the non-severe group. The various studies on neurological manifestations in COVID-19 patients are summarized in [Table 1][13],[14],[15],[16],[17].
Table 1: Summary of various studies on neurological manifestations in coronavirus disease 2019 (COVID-19) patients

Click here to view



   Investigations Top


Cerebrospinal fluid (CSF) analysis

For intracranial invasion of COVID-19, the definitive test is to demonstrate COVID RNA in CSF by lumbar puncture, but practically, this remains difficult, especially in severely affected patients with multi-organ dysfunction who are on ventilatory support and in the presence of thrombocytopenia and raised prothrombin time. It has been seen that COVID-19 patients with neurological manifestations may not always have the reverse transcription-polymerase chain reaction (RT-PCR) positive in CSF[16],[17].

Imaging findings

The neuroimaging and neurological findings in COVID-19 presented in a systematic review of 116 patients demonstrated normal imaging in 37 (41%) patients, whereas abnormal findings included acute cerebrovascular events (ischaemic and haemorrhagic types), demyelinating disorders (acute disseminated encephalomyelitis), myelitis, meningitis and encephalitis[18]. Magnetic resonance imaging (MRI) of brain may show features of raised intracranial pressure, multifocal infarcts or, in extreme cases, bilateral thalamic involvement in haemorrhagic necrotizing encephalopathy. In a study of 235 intensive care unit (ICU) patients of SARS-CoV-2, around 50 per cent had neurological symptoms and in 54 per cent patients neuroimaging was done[19]. Cortical signal abnormality in fluid-attenuated inversion recovery was found in 37 per cent, and cortical diffusion restriction, cortical blooming artefact and leptomeningeal enhancement were also seen in a few cases. Major differential diagnosis included infectious or autoimmune encephalitis, postictal state and hypoglycaemic and hypoxic encephalopathy[19]. MRI of a COVID-19 patient reported by Poyiadji et al[20] revealed haemorrhagic rim-enhancing lesion in bilateral thalami, subinsular region and medial temporal region. A study done by Palmer[21] in a young COVID-19-infected male with anosmia found normal olfactory bulb volume and signal, but he suggested that hybrid imaging (single-photon emission computed tomography-MRI with nasal thallium-21 and magnetization prepared gradient echo sequence) may demonstrate the abnormality.

Electroencephalogram

In a retrospective review of 36 COVID-19 patients, pathological EEGs recorded did not reveal any specific patterns in these patients. The abnormal patterns were similar to other critically ill patients or brain pathologies[22].


   Treatment Top


Neurological manifestations have to be dealt with in accordance with the usual therapy; for example, GBS with intravenous immunoglobulin[23],[24], raised intracranial pressure by mannitol along with other measures and seizures with various anti-epileptic drugs (AEDs) keeping in mind specific renal and hepatic side effects of each drug. Patients should continue their AEDs as before as these drugs do not pose an increased risk for developing COVID-19 infection except for adrenocorticotrophic hormone (given specifically in tuberous sclerosis).

In patients with ischaemic stroke, anticoagulation is recommended. A study from China[25] reported a patient who had limb ischaemia along with bilateral infarcts in the brain and on evaluation was found to have raised antiphospholipid antibodies. These antibodies can get transiently elevated in certain infections and critical illness just like acute-phase reactants and can cause multifocal thrombosis[25]. In patients of intracranial haemorrhage, optimal blood pressure control should be targeted[12].

Attention must be paid regarding prophylaxis of venous thromboembolism in critically ill patients. There are various risk factors including infection, immobilization, mechanical ventilation, respiratory failure and indwelling central venous catheter. Compression stockings, intermittent pneumatic compression and cautious use of anticoagulants are recommended[26]. The Association of British Neurologists[27] has formulated guidelines to deal with the patients with various neurological illnesses who are at an increased risk of developing COVID-19. The risk is divided into three categories - low, moderate and high. Mild-to-moderate forms of common neurological diseases such as Parkinson's disease (PD), multiple sclerosis and epilepsy do not confer any increased risk as long as swallowing and breathing mechanisms are normal. Patients with these neurological conditions falling into low or normal risk are considered at high-risk if concomitant lung or kidney disease is also present. Diseases causing weakness of bulbar and respiratory muscles are considered high-risk and need special attention[27]. These include motor neuron disease, myasthenia gravis, myopathies and GBS. Those patients who are on immunosuppressive drugs such as azathioprine, mycophenolate mofetil or methotrexate are at a high-risk for COVID-19. The use of any of these with prednisolone 20 mg daily or higher is considered high-risk. The risk-benefit ratio should be assessed, and decision should be individualized in each patient[27].

Patients with advanced PD are at a high-risk for COVID-19 as there is respiratory muscle rigidity along with impairment of cough reflex. PD patients have reduced number of ACE-2 receptors on dopaminergic neurons, and COVID-19 infection worsens the symptoms leading to increased requirement of the dopaminergic drug. Patients with advanced disease who underwent deep brain stimulation or were on levodopa, were more vulnerable and had mortality close to 50 per cent[28].

Thus, there is a multitude of neurological manifestations of COVID-19 with various plausible pathophysiologies as summarized in [Table 2][29],[30],[31],[32]. The ongoing studies relevant to prevalence, pathology and treatment are summarized in [Table 3].
Table 2: Neurological manifestations of COVID-19 and their possible aetiology

Click here to view
Table 3: Ongoing trials for COVID-19 and neurological manifestations

Click here to view



   Regional differences in neurological manifestations Top


In a study from Wuhan in China in 214 patients[13], 36.4 per cent had nervous system manifestations. CNS manifestations were more common than PNS and skeletal muscle injury. Dizziness (16.8%) and headache (13.1%) were the most common CNS manifestations. Taste and smell impairment was noted in 5.6 and 5.1 per cent, respectively[13]. In the UK, a large cross-specialty surveillance study of acute neurological and psychiatric complications was conducted in 125 patients which found stoke as the most common CNS manifestation (62%), followed by encephalopathic symptoms in 31 per cent[8]. In a multicentre European study by Lechien et al[33] on COVID-19 patients, 85.6 per cent had abnormality of smell and 88.8 per cent showed gustatory abnormality, and smell and taste abnormality was more prevalent in Europeans than in Chinese.


   Predictors of neurological dysfunction Top


There is an overlap among the predictors of COVID-19 and stroke, namely age, cardiovascular disease, cardiac arrhythmia diabetes mellitus, smoking and coronary artery disease. Patients with pre-existing neurological disorders, viz. multiple sclerosis and autoimmune syndromes such as neuromyelitis optica, angiitis, myasthenia gravis and inflammatory polyneuropathies, are on a large variety of immunosuppressive agents. These therapies can hamper the host immune response to COVID-19. Furthermore, pre-existing neurodegenerative disease in patients makes them vulnerable to infection. The therapy during COVID-19 management such as hydroxychloroquine sulphate, anticoagulants and remdesivir can also be associated with new-onset neurological manifestations[34].


   Conclusion Top


The neurological manifestations in patients with COVID-19 are varied and can emerge standalone or during the clinical course. Upholding a high-index of suspicion for COVID-19 in patients presenting with new-onset neurological symptoms will expedite an early diagnosis. Further studies are desired to unravel these varied neurological manifestations, treatment, outcome and long-term sequelae in COVID-19 patients.

Financial support & sponsorship: None.

Conflicts of Interest: None.

 
   References Top

1.
Ludlow M, Kortekaas J, Herden C, Hoffmann B, Tappe D, Trebst C, et al. Neurotropic virus infections as the cause of immediate and delayed neuropathology. Acta Neuropathol 2016; 131 : 159-84.  Back to cited text no. 1
    
2.
Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: Tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 2020; 11 : 995-8.  Back to cited text no. 2
    
3.
Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun 2020; 87 : 18-22.  Back to cited text no. 3
    
4.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395 : 1033-4.  Back to cited text no. 4
    
5.
Solomon IH, Normandin E, Bhattacharyya S, Mukerji SS, Keller K, Ali AS, et al. Neuropathological features of COVID-19. N Engl J Med 2020. pii: NEJMc2019373.  Back to cited text no. 5
    
6.
Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2). J Med Virol 2020; 92 : 699-702.   Back to cited text no. 6
    
7.
Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, et al. Neurological associations of COVID-19. Lancet Neurol 2020. pii: S1474-4422(20)30221-0.  Back to cited text no. 7
    
8.
Varatharaj A, Thomas N, Ellul MA, Davies N, Pollak TA, Tenorio EL, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: A UK-wide surveillance study. Lancet Psychiatry 2020. pii: S2215-0366(20)30287-X.  Back to cited text no. 8
    
9.
Yan CH, Faraji F, Prajapati DP, Boone CE, DeConde AS. Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms. Int Forum Allergy Rhinol 2020; 10 : 806-13.  Back to cited text no. 9
    
10.
Bagheri SH, Asghari AM, Farhadi M, Shamshiri AR, Kabir A, Kamrava SK, et al. Coincidence of COVID-19 epidemic and olfactory dysfunction outbreak. medRxiv 2020. doi: 10.1101/2020.03.23.20041889.  Back to cited text no. 10
    
11.
Ahmad I, Rathore FA. Neurological manifestations and complications of COVID-19: A literature review. J Clin Neurosci 2020; 77 : 8-12.  Back to cited text no. 11
    
12.
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020; 77 : 1-9.  Back to cited text no. 12
    
13.
Mao L, Wang M, Chen S, He Q, Chang J, Hong C, et al. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: A retrospective case series study. medRxiv 2020. doi: 10.1101/2020.02.22.20026500.  Back to cited text no. 13
    
14.
Li Y, Li M, Wang M, Zhou Y, Chang J, Xian Y, et al. Acute cerebrovascular disease following COVID-19: A single center, retrospective, observational study. Stroke Vasc Neurol 2020. pii: svn-2020-000431.  Back to cited text no. 14
    
15.
Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med 2020; 382 : 2268-70.  Back to cited text no. 15
    
16.
Giacomelli A, Pezzati L, Conti F, Siano M, Oreni L, Rusconi S, et al. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: A cross-sectional study. Clin Infect Dis 2020; 71 : 889-90.  Back to cited text no. 16
    
17.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou LQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 : 1708-20.  Back to cited text no. 17
    
18.
Katal S, Balakrishnan S, Gholamrezanezhad A. Neuroimaging and neurologic findings in COVID-19 and other coronavirus infections: A systematic review in 116 patients. J Neuroradiol 2020. pii: S0150-9861(20)30204-2.  Back to cited text no. 18
    
19.
Kandemirli SG, Dogan L, Sarikaya ZT, Kara S, Akinci C, Kaya D, et al. Brain MRI findings in patients in the intensive care unit with COVID-19 infection. Radiology 2020; 201697.  Back to cited text no. 19
    
20.
Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: Imaging features. Radiology 2020; 296 : E119-20.  Back to cited text no. 20
    
21.
Palmer WJ. Brain images show olfactory impact in patient with early stage COVID-19 infection. Diagnostic Imaging. Available from: https://www.diagnosticimaging.com/covid-19/brain-images-show-olfactory-impact-patient-early-stage-covid-19-infection, accessed on April 14, 2020.  Back to cited text no. 21
    
22.
Petrescu AM, Taussig D, Bouilleret V. Electroencephalogram (EEG) in COVID-19: A systematic retrospective study. Neurophysiol Clin 2020; 50 : 155-65.  Back to cited text no. 22
    
23.
Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P, Cuzzoni MG, et al. Guillain-Barré syndrome associated with SARS-CoV-2. N Engl J Med 2020; 382 : 2574-6.  Back to cited text no. 23
    
24.
Gutiérrez-Ortiz C, Méndez A, Rodrigo-Rey S, Pendro-Murillo ES, Bermejo-Guerrero L, Gordo-Manas R, et al. Miller Fisher syndrome and polyneuritis cranialis in COVID-19. Neurology 2020; 95 : e601-5.  Back to cited text no. 24
    
25.
Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with COVID-19. N Engl J Med 2020; 382 : e38.  Back to cited text no. 25
    
26.
Wang T, Chen R, Liu C, Liang W, Guan W, Tang R, et al. Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19. LancetHaematol 2020; 7 : e362-3.  Back to cited text no. 26
    
27.
Association of British Neurologists Guidance on COVID-19 for People with Neurological Conditions, their Doctors and Carers-Prepared by the ABN Executive in Association with Subspecialist Advisory Groups. Version 3. Available from: https://cdn.ymaws.com/www.theabn.org/resource/collection/6750BAE6-4CBC-4DDB-A684-116E03BFE634/ABN_Neurology_COVID-19_Guidance_22.3.20.pdf, accessed on May 6, 2020.  Back to cited text no. 27
    
28.
Antonini A, Leta V, Teo J, Chaudhuri KR. Outcome of Parkinson's disease patients affected by COVID-19. Mov Disord 2020; 35 : 905-8.  Back to cited text no. 28
    
29.
Ish P, Sachdev K, Agrawal S, Gupta N. Neurological manifestations of COVID-19 - continually evolving and perplexing. Ann Indian Acad Neurol 2020; 23 : 361-2.  Back to cited text no. 29
    
30.
Yadav SR, Kumar R, Kumar A, Ish P, Gupta N, Chakrabarti S. Sleepless in COVID-19: How not to lose sleep in lockdowns. Monaldi Arch Chest Dis 2020; 90 : 10.4081/monaldi.2020.1364.  Back to cited text no. 30
    
31.
Ish P, Sen MK, Gupta N. In reference to anosmia and ageusia: Common findings in COVID-19 patients. Laryngoscope 2020. pii: 10.1002/lary.28832.  Back to cited text no. 31
    
32.
Gupta N, Ish P, Agstam S. Angiotensin-converting enzyme inhibitors and angiotensin receptor blocker in coronavirus disease 2019: Safe and possibly beneficial. Lung India 2020; 37 : 352-3.  Back to cited text no. 32
    
33.
Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): A multicenter European study. Eur Arch Otorhinolaryngol 2020; 277 : 2251-61.  Back to cited text no. 33
    
34.
Tsivgoulis G, Palaiodimou L, Katsanos AH, Caso V, Köhrmann M, Molina C, et al. Neurological manifestations and implications of COVID-19 pandemic. Ther Adv Neurol Disord 2020; 13 : 1756286420932036.  Back to cited text no. 34
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]


This article has been cited by
1 Covid-19 Manifestation in The Adult and Paediatric Eyes.
Clinical Journal of Ophthalmology and Eye Care. 2020; : 1
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Pathogenesis
   Clinical features
   Investigations
   Treatment
    Regional differe...
    Predictors of ne...
   Conclusion
    References
    Article Tables

 Article Access Statistics
    Viewed3026    
    Printed173    
    Emailed0    
    PDF Downloaded643    
    Comments [Add]    
    Cited by others 1    

Recommend this journal