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 Table of Contents  
Year : 2022  |  Volume : 12  |  Issue : 3  |  Page : 231-234

Neurological manifestations of coronavirus disease 2019 hospitalised patients in Punjab, India

1 Department of Neurology, Mogamedicity Superspeciality Hospital Punjab, Moga, Punjab, India
2 Department of Neurology, SKIMS, Srinagar, Jammu and Kashmir, India

Date of Submission28-Mar-2021
Date of Acceptance10-May-2021
Date of Web Publication02-Sep-2022

Correspondence Address:
Dr. Zahoor Ahmad Parry
Mogamedicity Superspeciality Hospital Punjab, Moga, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aihb.aihb_74_21

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Introduction: Coronavirus disease 2019 (COVID-19), the disease linked to severe acute respiratory syndrome coronavirus-2, is a widespread infectious disease. Coronaviruses cause multiple systemic infections, but neurological involvement has been reported very rarely. Materials and Methods: The present study is a single-centre prospective study conducted during the COVID-19 pandemic from November 2020 to April 2021, at Mogamedicity Superspeciality Hospital, Punjab, India. All COVID-19 patients with de novo neurologic manifestations were eligible to take part in the study. A total of 810 confirmed COVID-19 patients were enrolled for the study. Demographic features and initial clinical manifestations were noted, and patients were followed up during the hospital stay for the development of any new neurological signs and symptoms. For analytical purposes, neurological presentations were grouped into the central nervous system, peripheral nervous system and musculoskeletal system manifestations. Appropriate laboratory testing was employed as required on a case-to-case basis. Results: In this study, the mean age of the patients was 46.6 ± 15.5 years. Five hundred and fifty two (66.9%) patients were male, while 268 (33.1%) were female. Neurological illness was a primary manifestation in 48 (6%) cases. These included encephalopathy (n = 30), ischaemic stroke (n = 4), Guillain–Barre syndrome, (n = 2), facial nerve palsy (n = 4) and encephalitis (n = 1). The most common neurological symptoms were headache (284 [35%]) and hyposmia (78 [9.6%]), followed by encephalopathy (68 [8.3%]). More serious complications such as seizures (14 [0.7%]) and stroke (18 [2.2%]) were also seen. Conclusion: COVID-19 can present with a neurological illness, and we should remain vigilant to the possibility of neurological presentation of COVID-19 that can be thrombo-embolic, inflammatory or immune-mediated.

Keywords: COVID-19, neurological, pandemic

How to cite this article:
Parry ZA, Khanday BI, Khwaja ZA. Neurological manifestations of coronavirus disease 2019 hospitalised patients in Punjab, India. Adv Hum Biol 2022;12:231-4

How to cite this URL:
Parry ZA, Khanday BI, Khwaja ZA. Neurological manifestations of coronavirus disease 2019 hospitalised patients in Punjab, India. Adv Hum Biol [serial online] 2022 [cited 2022 Dec 5];12:231-4. Available from: https://www.aihbonline.com/text.asp?2022/12/3/231/355555

  Introduction Top

Coronavirus disease 2019 (COVID-19), the disease linked to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a widespread infectious disease, with the first cases reported in China in December 2019.[1] The virus has continued to spread since then, and on 11 March 2020, the World Health Organization characterised COVID-19 as a pandemic. The common manifestations of the disease include respiratory tract and associated systemic manifestations, but neurologic manifestations including headaches, dizziness, anosmia, encephalopathy and stroke have been reported in cohort studies.[2],[3] Coronaviruses cause multiple systemic infections. Some of them can adapt fast and cross the species barrier, such as in the cases of SARS-CoV and the Middle East respiratory syndrome-CoV, which cause epidemics or pandemics. However, infection, specifically in humans, often leads to severe symptoms, which may lead to a high mortality rate. Therefore, for COVID-19, several studies have described many other clinical manifestations, which include respiratory symptoms, myalgia, fatigue and characteristic laboratory findings and lung computed tomography (CT) scan abnormalities, but neurological involvement has been reported very rarely.[4] The potential pathogenesis of SARS-CoV-2 in the central nervous system (CNS) remains unclear,[5] and the range of neurologic disorders associated with COVID-19 is not fully defined. The COVID-19 virus can cross the blood–brain barrier, which can invade the brain. The SARS-CoV-2 virus enters the brain either via the olfactory system or it may use the hematogenous route. Endothelial cells, which are located on the cerebral vessels containing angiotensin-converting enzymes, are thought to be a possible entry point for the virus. The most severe neurological manifestations which were observed were agitation, coma and delirium, which result from hypoxic and metabolic abnormalities. In many cases, haemorrhagic or ischaemic strokes occurred due to profound coagulopathies. In a few cases, encephalitis, acute disseminated encephalomyelitis and acute necrotising encephalopathy were also reported.[6] The most common complication experienced was a non-specific headache. In a few recent studies, a new type of 'personal protection equipment'-related headache has been described.

  Materials and Methods Top

The present study aimed to provide a comprehensive overview of neurologic manifestations associated with SARS-CoV-2 infection and to describe the clinical course and outcomes of COVID-19 patients with neurologic manifestations. This study was conducted between November 2020 and April 2021. All confirmed cases presenting during the study period were included. A confirmed case was defined after a positive result on real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of nasopharyngeal swabs. We excluded patients with no diagnosis of COVID-19, patients in whom neurological illness was not temporally related to COVID-19 and patients with exacerbations of chronic neurologic diseases. The study design was reviewed and approved by the ethics committee of the hospital (MMEC No. Rs/1019/1). Fully informed consent was obtained in all cases either from the patient or from the next of kin if the patient himself was not considered capable of doing so because of impaired conscious level. Confidentiality was ensured. Detailed data forms were filled out by the attending physicians. Demography, history, examination findings and complementary tests were recorded and updated regularly by the attending physicians. A trained neurologist reviewed and confirmed the positive findings. For analytical purposes, neurological manifestations were divided into three groups as follows: the CNS, peripheral nervous system and musculoskeletal manifestations. IBM SPSS Statistics for Windows (Version 20.0. Armonk, NY: IBM Corp) software was used for statistical analysis. The study was carried out as per the 'Declaration of Helsinki'.

  Results Top

The study population comprised 810 COVID-19 hospitalised patients. Baseline characteristics and comorbidities are summarised in [Table 1]. The mean age of the patients was 46.6 ± 15.5 years and ranged from 15 to 71 years; Five hundred and forty two (66.9%) patients were male, whereas 268 (33.1%) were female. The most common comorbidities were hypertension (276 [34%]), diabetes mellitus (126 [15.5%]), ischaemic heart disease (74 [9.1%]) and cerebrovascular disease (36 [4.4%]).
Table 1: Clinical characteristics of the patients with coronavirus disease 2019

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The most common presenting manifestations were fever in 700 (86.4%) patients, cough in 596 (73.5%) and dyspnoea in 418 (51.6%) patients. As many as 342 (42.2%) patients exhibited neurological symptoms [Table 2] and [Table 3]. The most common were headache (284 [35%]) and dizziness (92 [11.3%]). This was followed by hyposmia (78 [9.6%]) and encephalopathy or altered sensorium (68 [8.3%]). It is important to note that 30 (3.7%) of these patients presented with encephalopathy, whereas 38 (4.6%) developed encephalopathy during the hospital stay.
Table 2: Central nervous system manifestations

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Table 3: Peripheral nervous system and musculoskeletal manifestation

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There were 18 cases of acute cerebrovascular events in our study population. Fourteen patients developed ischaemic stroke during the illness. All of them had at least two comorbidities. Whereas four patients, one 42 years of age and the other 46 years of age, presented with ischaemic stroke as the index presentation. These two patients had no known comorbidities or vascular risk factors. Besides, it is important to note that they did not have any systemic manifestation of COVID-19 at the time of presentation. However, a CT scan of the chest showed bilateral ground-glass appearance with peripheral opacities in the lungs (CORADS 6), and C-reactive protein and lactate dehydrogenase were mildly elevated. D-dimers were raised in all cases with ischaemic stroke (range of 0.5–1.7 mg/L), more so in cases who developed ischaemic stroke during the course of illness.

There were six cases of intracranial haemorrhage, all of which had at least two comorbidities and were on prophylactic anti-coagulation due to the severe disease. The coagulation profile was mildly deranged in four cases (66% of the cases).

A total of 14 cases of seizures (1.7%) were seen in our study population. Seizures were the cause of presentation in 6 (0.7%) cases. Two patients were known cases of epilepsy, well controlled on anti-epileptic drugs. They had breakthrough seizures despite good compliance. Two patients had new-onset refractory status epilepticus. Yet another two patients were diagnosed with encephalitis based on neuroimaging and cerebrospinal fluid (CSF) analysis. These five patients were diagnosed with COVID-19 on routine screening as they had no systemic manifestation of the disease.

Peripheral nervous system manifestations were present in 48 (5.9%) patients. The most frequent symptom was hyposmia (42 [5.1%]), although it was revealed only on direct questioning. Four patients presented with isolated facial nerve palsy and two with Guillain–Barre syndrome (GBS). In all patients with facial nerve palsy, it was the presenting symptom, and COVID was diagnosed later when they developed symptoms. However, the course of the disease was mild in all of them. The patients with GBS had been diagnosed with COVID 2 weeks back and had mild disease.

Neuropsychiatric manifestations were found in 96 (11.8%) patients. The most common was anxiety, followed by insomnia, depression and psychosis. These were not associated with any other comorbidities.

In 48 (6%) patients, neurological manifestation was the reason for the presentation. These included encephalopathy (30 [3.7%]), seizures (6 [0.7%]), facial nerve palsy (4 [0.4%]), ischaemic stroke (4 [0.4%]), headache (4 [0.4%]), GBS (2 [0.2%]) and encephalitis (2 [0.2%]).

  Discussion Top

Our results highlight the broad spectrum of neurologic manifestations associated with SARS-CoV-2 infection. Our results showed that neurological manifestation was the presenting feature in 48 (6%) cases, and at least 42% of the patients developed neurological involvement during the course of illness. This was less than the frequency of 57.4% (P = 0.09) reported by Romero-Sanchez et al.[7] from Spain and higher than 37.4% reported by Mao et al. from Wuhan, China[2] (P = 0.037).

There are three possible mechanisms underlying the pathogenesis of neurological involvement. The first is diffuse cerebral dysfunction as a consequence of systemic disturbances namely cytokine storm, hypoxia, sepsis and multiorgan dysfunction. Second is the immune-mediated mechanism that is also implicated in the complications of many other viral illnesses. The third and the most important factor is neuroinvasion or neurotropism that is well known with other human coronaviruses such as 229E, OC43 and SARS-COV-1[5],[8],[9] and certain other respiratory viruses such as measles.[10] Anosmia or hyposmia, which is an initial presentation in many cases of COVID-19, depicts the neuroinvasive potential of SARS-COV-2. The affinity of this virus to angiotensin-converting enzyme 2 (ACE-2) receptor can be a potential underlying mechanism, as ACE-2 receptors are expressed both in respiratory epithelium and neuronal cells.[8] As far as the CNS is concerned, the virus can reach there either by retrograde transfer through peripheral nerves[10],[11] or by direct hematogenous spread after blood–brain barrier disruption by inflammatory mediators.[12] And, theoretically, if brainstem-mediated complications develop,[13] they can be devastating. This direct involvement of CNS has been proven by the presence of viral particles in frontal lobe neurons[14] and positive RT-PCR for SARS-COV-2 in CSF.[15]

Now, focusing on individual neurological manifestations in this cohort, about one-third (35%) of the patients complained of headaches that is significantly more than the frequency of 13.1% described by Mao et al. Interestingly, the head ache was the presenting complaint in four patients where it was so severe that they were immediately sent for CT of brain to rule out subarachnoid haemorrhage. It has been postulated that cytokines and chemokines released by macrophages trigger nociceptive sensory neurons, resulting in headaches.[16] Apart from encephalitis, a preliminary report of patients with posterior reversible encephalopathy syndrome-like features on neuroimaging has emerged from Italy.[17],[18]

Poyiadji et al.[19] from Detroit also reported a case of acute necrotising haemorrhagic encephalopathy in a middle-aged female.

Skeletal muscular injury was found in 4 (0.4%) patients, all of which had significantly raised serum creatinine kinase levels, but as these patients had severe respiratory disease, it cannot be reliably determined if it represented direct or indirect injury.

We had two cases of encephalitis that presented with seizures and had bilateral temporal hyperintensities on magnetic resonance imaging of the brain. The CSF examination revealed mild pleocytosis. However, it should be kept in mind that magnetic resonance imaging and CSF analysis were not done in all patients with encephalopathy, especially where encephalopathy seemed to be secondary to severe disease or multiorgan dysfunction. Thus, there is a possibility that some cases of encephalitis might have been missed. Cases of encephalitis and optic neuritis have already been reported from other parts of the world as an inflammatory complication of COVID-19.[7]

Concerning ischaemic stroke in patients with COVID-19, a frequency of 2.5% was reported from Italy,[20] while a higher frequency of 5% has been reported from China.[21] We observed ischaemic stroke in 2.2% of the patients in our study population. The lower incidence here could be the result of the overall younger age of the cohort. Although most of the ischaemic strokes were seen in severely ill patients with multiple comorbidities, two cases of acute ischaemic stroke were relatively young patients with no known comorbidities, indicating that for a subset of patients, there is a true neurological impact of COVID-19. A study in New York has also reported stroke in COVID patients younger than 50 years of age.[22] Cases of acute ischaemic strokes have also been previously reported with SARS-COV-1.[23] The underlying pathogenesis follows Virchow's triad as evidenced by direct endothelial damage by the virus resulting in endothelitis and altered blood flow and hypercoagulability triggered by cytokine release.[24],[25],[26],[27]

  Conclusion Top

Our study highlights the broad spectrum of neurologic manifestations associated with SARS-CoV-2 infection, which is probably related to different pathogenic pathways. We would also emphasise that many COVID patients who presented with vascular and inflammatory neurological diseases, such as stroke, GBS and facial nerve palsy, had mild or no respiratory symptoms. Thus, we recommend that all patients presenting with acute neuro-logical illness should be screened for COVID-19 during the pandemic.

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3]


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