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 Table of Contents  
CASE SERIES
Year : 2022  |  Volume : 24  |  Issue : 2  |  Page : 195-199

Post-COVID Neurological Complication; A Case Series and Review of the Literature


1 Department of Medicine, Army Hospital, Delhi, India
2 Department of Medicine, Base Hospital, Delhi, India
3 Department of Neurology, Command Hospital (CC) Lucknow, Uttar Pradesh, India

Date of Submission09-Oct-2021
Date of Decision28-Nov-2021
Date of Acceptance29-Nov-2021
Date of Web Publication01-Apr-2022

Correspondence Address:
Rahul Soni
Base Hospital Delhi Cantt, Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmms.jmms_132_21

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  Abstract 


Introduction: There are certain post-coronavirus disease (COVID) neurological syndromes which have been reported such as cerebrovascular diseases, cerebral venous thrombosis, peripheral neuropathy, encephalitis, encephalopathy, cerebellar ataxia, facial palsy, and myositis. However, most of these are isolated case reports. In this case series, we discuss the post-COVID neurological complications such as facial palsy, lateral rectus palsy, cerebellar ataxia, peripheral neuropathy, and stroke which occurred within 2 weeks after complete recovery from COVID. Methods: This multicentric case series is from three large tertiary care hospitals in northern and central India. We have reviewed seven patients with recent-onset neurological symptoms who had recovered from COVID infection within 2 weeks. We have retrospectively studied the clinical profile and radiological imaging during COVID infection. Results: Three out of these seven patients had received steroids during COVID treatment. None of our cases had any neurological manifestations during their COVID infection. The likelihood of neurotransmission through the cribriform plate via the olfactory bulb was low, as none of our patients had anosmia. None of the patients in the case series showed features of systemic hyperinflammatory syndrome, making the possibility of macrophage activation syndrome less likely. Conclusion: We hypothesize that antibodies against the coronavirus post recovery from COVID are responsible for these post-COVID neurological complications. Higher likelihood of these complications after rapid tapering off steroids may further corroborate this mechanism, as the antibody levels rise after steroid withdrawal. Titers of antibodies to SARS COV-2 virus in the postinfection period in these cases may have further helped prove our hypotheses which can be considered in future studies on the subject.

Keywords: Coronavirus disease, hemophagocytic lymph histiocytosis, lower motor neuron cranial nerve palsy, pancerebellar syndrome, stroke, systemic hyperinflammatory syndrome


How to cite this article:
Mamidi S, Soni R, Dhull P, Singh S, Muthukrishan J. Post-COVID Neurological Complication; A Case Series and Review of the Literature. J Mar Med Soc 2022;24:195-9

How to cite this URL:
Mamidi S, Soni R, Dhull P, Singh S, Muthukrishan J. Post-COVID Neurological Complication; A Case Series and Review of the Literature. J Mar Med Soc [serial online] 2022 [cited 2022 Dec 1];24:195-9. Available from: https://www.marinemedicalsociety.in/text.asp?2022/24/2/195/342374




  Introduction Top


Coronavirus disease (COVID) infection is known to cause neurological symptoms such as headaches, anosmia, and ageusia. Severe neurological complications are also well-documented during the COVID illness such as cerebrovascular disease, cerebral venous thrombosis, peripheral neuropathy, encephalitis, encephalopathy, cerebellar ataxia, facial palsy, and myositis.[1] Even in patients who have been cured of primary infection COVID infection, the virus remains latent and able to reactivate and trigger central nervous system (CNS) disease.[2] Post-COVID neurological complications can also occur due to residual inflammation of the CNS, other organ damage, prolonged ventilation, and pre-existing comorbid illness such as diabetes and hypertension. However, there is limited information regarding this available scientific literature. In this case series, we encountered the post-COVID neurological complications, facial palsy, lateral rectus palsy, cerebellar ataxia, stroke, and peripheral neuropathy, which occurred within 2 weeks after complete recovery from COVID. It is also important to look for prognostic inflammatory markers during SARS-CoV such as D-dimer, interleukin 6 (IL-6), lactate dehydrogenase(LHD), or serum ferritin and their correlation in delayed neurological complications.


  Methods Top


This case series is derived from three large tertiary care centers in north and central India. We have studied seven patients with new-onset neurological symptoms within 2 weeks recovery from COVID. We have retrospectively studied the patient's clinical profile, hematological and biochemical parameters, and inflammatory markers such as IL-6, D-dimer, ferritin, and LDH. We have categorized patients into mild, moderate, and severe COVID disease based on existing criteria [Table 1].
Table 1: Clinical profile, past relevant medical history, and treatment received by COVID-19 patients

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  1. Mild COVID: Patients were those patients who had never had hypoxia (SpO2 of between more than 95% at room air) and were managed at home with symptomatic treatment
  2. Moderate COVID: Patients were those patients who had hypoxia (SpO2 of between 80% and 95% at room air) and required oxygen supplementation and were hospitalized
  3. Severe COVID: Patients are those who have severe hypoxia (SpO2 <80% at room air) and require noninvasive or invasive ventilatory support.


Relevant investigations to diagnose the neurological condition and underlying etiology were done including computed tomography (CT)/magnetic resonance imaging (MRI) of the brain, cerebrospinal fluid (CSF) study, and electrophysiological studies and immunological parameters [Table 2].
Table 2: Clinical profile, investigation, and management of neurological symptoms in post-COVID patient

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  Results Top


Out of seven patients, two patients were male and five were female. The mean age of our patents was 47.2 years. Three patients had moderate and four had mild COVID infection. None of our patents had severe COVID disease. Three patients with moderate infections were hospitalized and managed with oxygen support. Rest four patients were managed with oral medication in home quarantine. Three patients were managed with steroids, one was given, one was given favipiravir, and one was given ivermectin. Inflammatory convalescent plasma markers were not raised in any patient. None of our cases had any neurological manifestations during their COVID illness infection [Table 1].

Four of our patients developed lower motor neuron (LMN) facial nerve palsy, one each had LMN abducens nerve palsy, pancerebellar syndrome, stroke, and peripheral neuropathy. The mean duration of onset of neurological symptoms from the recovery from COVID infection was 8.71 days. Cranial nerve palsy patients were treated with oral prednisolone for 2 weeks on tapering dosages. Stroke patients were thrombolysed with IV tenecteplase, while pancerebellar syndrome was managed with injection methylprednisolone and intravenous (IV) immunoglobulin. Five patients had good recovery [Table 1].


  Discussion Top


Tabacof et al. found that the most common post-acute COVID-19 symptoms were excessive fatigue, followed by loss of concentration or recent memory, generalized weakness, headache, and dizziness.[3] These neurological symptoms may persist for more than 6 weeks after the onset of acute symptoms. SARS-CoV-2 virus crosses the blood–brain barrier by three routes, either transneuronal to the brain or via the olfactory bulb across the cribriform plate.[4] Hematogenous spread to the CNS is by angiotensin-converting enzyme 2 receptors, which are more expressed in endothelial cells of the brain vasculature.[5] Viruses can infect the various peripheral nerve terminals and spread along the nerves by trans axonal or trans-synaptic routes.[6] Available literature also suggests that post-COVID neurological complications are either due to direct viral toxicity by crossing the blood–brain barrier, or secondary to hypercoagulability, or are immune mediated due to systemic inflammatory response.[7]

Facial palsy is commonly associated with viral infections such as the human immunodeficiency virus, herpes simplex virus, herpes zoster virus, Epstein–Barr virus, pregnancy-induced hormonal changes, and traumatic and idiopathic causes. Few case reports link cranial nerve palsy to COVID-19. The most common cranial nerve involvement is the facial nerve.[8] In our series, we had three patients with isolated LMN facial nerve palsy. None of these three had involvement of any other cranial nerves, or any other focal neurological symptoms. One patient had undergone MRI of the brain, and that was normal, which suggested that there was no direct involvement of the CNS.

Literature suggests that peripheral nervous system involvement in such cases was due to a systemic inflammatory response with macrophage activation secondary to hemophagocytic lymphohistiocytosis (HLH).[9] None of our patients with facial palsy had symptoms of anosmia and all were hemodynamically stable. Hence, the possible CNS transmission via the olfactory bulb and the inflammatory response secondary to HLH were less likely. However, there is a possibility that the SARS-COV2 virus caused inflammation of the facial nerve, causing edema and compression of the facial nerve in the facial canal, which is the narrowest part on the route of facial nerve.[8] The SARS COV2 infection exhibits neurotropism after the febrile illness settles down or steroids are withdrawn.[10]

Isolated lateral rectus palsy is usually caused due to neoplastic, myasthenia gravis, thyroid ophthalmopathy, trauma, preexisting strabismus, and vascular involvement. Recent studies suggest that most patients with COVID-19 present with diplopia followed by headache.[11] They usually have abducens nerve palsy accompanied with oculomotor nerve palsy.[12] The mechanism is unknown. Patient developed Post COVID lateral rectus palsy. He presented with diplopia while horizontal gaze towards left temporal side. He developed these symptoms after the steroid tapping period in the first 7 days. He presented with headache followed by diplopia. There were no previous neurological symptoms. CSF analysis suggested increased protein (70 mg/dl) and culture grew Aspergillus flavus. Noncontrast computed tomography of the head with paranasal sinuses was suggested fungal rhinosinusitis. However, MRI of the brain and orbits was normal. The causes of lateral rectus palsy were either due to a fungal invasion into the ocular structures or into the brain; however, this was not clear from the imaging available.

Peripheral nervous system involvement is increasingly being noted during COVID-19 along with other neurological manifestations.[1] We had one patient with post-COVID peripheral neuropathy who presented with tingling and numbness in the upper limbs. There was no history suggestive of motor or autonomic nerve involvement. Electrophysiological studies suggested involvement of sensory small myelinated fibers. Peripheral neuropathy is due to a sudden strong inflammatory response syndrome that is triggered during the infectious process with activation of macrophage and pro-inflammatory cytokine secondary to HLH.[9] Guillain–Barre syndrome is one of the most common syndromes reported.

Viral infections due to herpes, varicella, mumps, and Epstein–Barr are known to cause acute cerebellitis. MRI is the best imaging modality in the diagnosis of acute cerebellitis, but in 15%–20% of patients, it may be normal. Cerebellar ataxia secondary to COVID-19 has been reported.[13] Cerebellar Purkinje fibers are most sensitive to hypoxic injuries. Patients with severe hypoxia during acute pneumonia can have such a sequel.[14] Our case presented with cerebellar symptoms within 1 week of tapering of steroids. Her MRI of the brain was normal. The patient had mild COVID disease with normal serum inflammatory markers. In cases of postinfectious cerebellar ataxia, MRI of the brain may be normal.[6] Our patient developed pancerebellar syndrome as a result of a delayed humoral or cellular immune response cross-reactive to cerebellar autoantigens. She responded to immunomodulation therapy in the form of IV immunoglobulin.

Strokes in COVID infections are due to either hypercoagulability or are immune mediated due to either hyperinflammatory state or cytokine storm. Endothelial dysfunction is caused by cytokines which lead to dysregulation of the coagulation system and formation of microthrombi and microbleeds in the brain.[15] Cytokines cross the blood–brain barrier causing immune-mediated tissue damage. High levels of cytokine and glutamate receptors causing lesions in the corpus callosum have been documented in COVID patients who present with encephalopathy. COVID infection causes myocardial damage which may lead to the formation of clots, and it can also destabilize or rupture of a preexisting atherosclerotic plaque. Our patient was a known case of primary hypertension with good control antihypertensives, and she developed stroke 2 weeks after recovering COVID [Figure 1] and [Figure 2], which corroborated with her D-dimer, ferritin, IL6, and LDH which were not raised significantly during her illness. We presume that the inflammatory response due to COVID, with underlying hypertension, contributes to her risk of stroke.
Figure 1: Diffusion-weighted magnetic resonance imaging of the brain showing diffusion restriction in the left thalamus

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Figure 2: Apparent diffusion coefficient magnetic resonance imaging of the brain showing reduced ADC values in the left thalamus

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Post-COVID neurological involvement is a lesser known entity, and more and more data are being collected the world over. Our series is a step in this direction from this subcontinent. We have included varying types of neurological complications which have occurred within 2 weeks of recovery from COVID. RT-PCR for SARS CoV-2 virus in CSF would have been further confirmatory of the etiological mechanism of the neurological syndrome in four of our patients where we did not perform CSF studies. However, since all our patients had completely recovered from acute illness and their RT-PCR for the virus from nasal mucosa was negative, we hypothesize that these complications are autoimmune mediated against CNS and prolonged cytokines dysregulation. This will require further studies of large number of patients to confirm.


  Conclusion Top


We hypothesize that antibodies against the coronavirus post recovery from COVID are responsible for these post-COVID neurological complications. Higher likelihood of these complications after rapid tapering off steroids may further corroborate this mechanism, as the antibody levels rise after steroid withdrawal. Titers of antibodies to SARS COV-2 virus in the postinfection period in these cases may have further helped prove our hypotheses which can be considered in future studies on the subject. We tried to find out associated risk factors during COVID infection for the development of neurotological complications. Rapid steroid reduction is one of the risk factors in post-COVID patients with neurological complications. We could not find any co-relation between inflammatory markers during COVID and neurological complications after recovering from COVID.

Key message: There should be close monitoring of patients who recover from COVID, especially 2 weeks. Steroid tapering should be gradual to avoid any immune-mediated neurological complications. Prolong use of anticoagulants and antiplatelets can reduce the chances of these vascular complications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Andalib S, Biller J, Di Napoli M, Moghimi N, McCullough LD, Rubinos CA, et al. Peripheral nervous system manifestations associated with COVID-19. Curr Neurol Neurosci Rep 2021;21:9.  Back to cited text no. 1
    
2.
Monroy-Gómez J, Torres-Fernández O. Effects of the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) on the nervous system. What can we expect from SARS -CoV-2? Biomedica 2020;40:173-9.  Back to cited text no. 2
    
3.
Tabacof L, Tosto Mancuso J, Wood J, Cortes M, Kontorovich A, McCarthy D, et al. Post-acute COVID-19 syndrome negatively impacts health and wellbeing despite less severe acute infection. medRxiv 2020;1:48.  Back to cited text no. 3
    
4.
Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 2021;24:168-75.  Back to cited text no. 4
    
5.
Bastola A, Sah R, Nepal G, Gajurel BP, Rajbhandari SK, Chalise BS, et al. Bell's palsy as a possible neurological complication of COVID-19: A case report. Clin Case Rep 2021;9:747-50.  Back to cited text no. 5
    
6.
Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care 2020;24:422.  Back to cited text no. 6
    
7.
Fenrich M, Mrdenovic S, Balog M, Tomic S, Zjalic M, Roncevic A, et al. SARS-CoV-2 dissemination through peripheral nerves explains multiple organ injury. Front Cell Neurosci 2020;14:229.  Back to cited text no. 7
    
8.
Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med 2021;27:601-15.  Back to cited text no. 8
    
9.
McGonagle D, Ramanan AV, Bridgewood C. Immune cartography of macrophage activation syndrome in the COVID-19 era. Nat Rev Rheumatol 2021;17:145-57.  Back to cited text no. 9
    
10.
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. 10
    
11.
Dinkin M, Gao V, Kahan J, Bobker S, Simonetto M, Wechsler P, et al. COVID-19 presenting with ophthalmoparesis from cranial nerve palsy. Neurology 2020;95:221-3.  Back to cited text no. 11
    
12.
Falcone MM, Rong AJ, Salazar H, Redick DW, Falcone S, Cavuoto KM. Acute abducens nerve palsy in a patient with the novel coronavirus disease (COVID-19). J AAPOS 2020;24:216-7.  Back to cited text no. 12
    
13.
Waseem D, Maqbool W, Arjimand Y, Ravouf A, Adnan R, Feroze M, et al. Para-infectious cerebellar ataxia post covid 19 infection. Neurol Asia 2021;26:197-8.  Back to cited text no. 13
    
14.
Werner J, Reichen I, Huber M, Abela IA, Weller M, Jelcic I. Subacute cerebellar ataxia following respiratory symptoms of COVID-19: A case report. BMC Infect Dis 2021;21:298.  Back to cited text no. 14
    
15.
Bhaskar S, Sinha A, Banach M, Mittoo S, Weissert R, Kass JS, et al. Cytokine storm in COVID-19-immunopathological mechanisms, clinical considerations, and therapeutic approaches: The REPROGRAM Consortium Position Paper. Front Immunol 2020;11:1648.  Back to cited text no. 15
    


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