aihb_74_21_R2_OA

Original Article
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4 Neurological Manifestations of Coronavirus Disease 2019 4
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Hospitalised Patients in Punjab, India 5
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AQ81,2 Zahoor Ahmad Parry1, Binafsha Irshad Khanday2, Zubair Ahmad Khwaja 3
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A Q3 1)Consultant Neurologist, Department of Neurology,Mogamedicity Superspeciality Hospital Punjab, Moga, Punjab,India.
9 2)Medical officer, Department of neurology, Mogamedicity Superspeciality Hospital, Moga Punjab, India.
10 3)Senior resident, department of neurology, Neurology, SKIMS, Srinagar, Jammu and Kashmir, India
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11 10
12 11
13 Abstract
AQ4 12
14 Introduction: Coronavirus disease 2019 (COVID‑19), the disease linked to severe acute respiratory syndrome coronavirus‑2, is a widespread 13
15 infectious disease. Coronaviruses cause multiple systemic infections, but neurological involvement has been reported very rarely.
16 Materials and Methods: The present study is a single‑centre prospective study conducted during the 15
17 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 16
18 the study. Demographic features and initial clinical manifestations were noted, and patients were followed up during the hospital stay for the 17
19 development of any new neurological signs and symptoms. For analytical purposes, neurological presentations were grouped into the central 18
20 nervous system, peripheral nervous system and musculoskeletal system manifestations. Asppropriate laboratory testing was employed as 19
21 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%) 20
22 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). 21
23 The most common neurological symptoms were headache (284 [35%]) and hyposmia (78 [9.6%]), followed by encephalopathy (68 [8.3%]). 22
24 More serious complications such as seizures (14 [0.7%]) and stroke (18 [2.2%]) were also seen. Conclusion: COVID‑19 can present with a 23
25 neurological illness, and we should remain vigilant to the possibility of neurological presentation of COVID‑19 that can be thrombo‑embolic, 24
26 inflammatory or immune‑mediated. 25
27 Keywords: COVID‑19, neurological, pandemic
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28 27
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29 29
humans, often leads to severe symptoms, which may lead
30 INTRODUCTION to a high mortality rate. Therefore, for COVID‑19, several
30
31 C or on a vi r us di se a se 2019 ( C O V I D ‑ 1 9 ) , t he 31
studies have described many other clinical manifestations,
32 disease linked to severe acute respiratory syndrome which include respiratory symptoms, myalgia, fatigue 32
33 coronavirus‑2 (SARS‑CoV‑2), is a widespread infectious and characteristic laboratory findings and lung computed 33
34 disease, with the first cases reported in China in December tomography (CT) scan abnormalities,but neurological involvement
AQ4 has
35 2019.[1] The virus has continued to spread since then, and on
36 11 March 2020, the World Health Organization characterised been reported very rarely.
37 COVID‑19 as a pandemic. The common manifestations of .[4] The potential pathogenesis of 36
the disease include respiratory tract and associated systemic
38 manifestations, but neurologic manifestations including SARS‑CoV‑2 in the central nervous system (CNS) remains 37
[5]
39 headaches, dizziness, anosmia, encephalopathy and stroke unclear, and the range of neurologic disorders associated 38
40 have been reported in cohort studies.[2,3] Coronaviruses cause 39
41 multiple systemic infections. Some of them can adapt fast and Address for correspondence: Dr. Zahoor Ahmad Parry, 40
cross the species barrier, such as in the cases of SARS‑CoV Mogamedicity Superspeciality Hospital Punjab, Moga, Punjab, India. 41
42
E‑mail: drzahor@gmail.com
43 and the Middle East respiratory syndrome‑CoV, which cause 42
44 epidemics or pandemics. However, infection, specifically in Submitted: 10‑May‑2021 Revised: 23‑Mar‑2022 43
45 Accepted: 24‑Mar‑2022 Published: *** 44
46 Access this article online 45
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DOI:
51 10.4103/aihb.aihb_74_21 50
How to cite this article: Parry ZA, Khanday BI, Khwaja ZA. Neurological
52 manifestations of coronavirus disease 2019 hospitalised patients in Punjab, 51
India. Adv Hum Biol 2022;XX:XX‑XX. 52
© 2022 Advances in Human Biology | Published by Wolters Kluwer - Medknow 1
 Parry, et al.: Neurological manifestations of COVID‑19 hospitalised patients

1 with COVID‑19 is not fully defined. The COVID‑19 virus 1

Table 1: Clinical characteristics of the patients with
2 can cross the blood–brain barrier, which can invade the brain.
coronavirus disease 2019 2
3 The SARS‑CoV‑2 virus enters the brain either via the olfactory 3
4 system or it may use the hematogenous route. Endothelial Characteristics n (%)
4
5 cells, which are located on the cerebral vessels containing Age
5
6 angiotensin‑converting enzymes, are thought to be a possible <50 478 (59)
6
entry point for the virus. The most severe neurological >50 332 (40.9)
7
7 manifestations which were observed were agitation, coma Gender
8 and delirium, which result from hypoxic and metabolic Male 542 (66.9) 8
9 abnormalities. In many cases, haemorrhagic or ischaemic Female 268 (33.1) 9
10 strokes occurred due to profound coagulopathies. In a few Comorbidities 10
Hypertension 276 (34.0) 11
11 cases, encephalitis, acute disseminated encephalomyelitis and
Diabetes mellitus 126 (15.5)
12 acute necrotising encephalopathy were also reported.[6] The 12
Ischaemic heart disease 74 (9.1)
13 most common complication experienced was a non‑specific Cerebrovascular disease 36 (4.4)
13
14 headache. In a few recent studies, a new type of ‘personal Malignancy 8 (0.9) 14
15 protection equipment’‑related headache has been described. Chronic kidney disease 62 (7.6) 15
16 Others 68 (8.3) 16
17 MATERIALS AND METHODS 17
18 52
The present study aimed to provide a comprehensive overview comorbidities were hypertension (276 [34%]), diabetes
19 of neurologic manifestations associated with SARS‑CoV‑2
20 infection and to describe the clinical course and outcomes
21 of COVID‑19 patients with neurologic manifestations.
22 This study was conducted between November 2020 and
23 April 2021. All confirmed cases presenting during the study
24 period were included. A confirmed case was defined after a
25 positive result on real‑time reverse transcriptase‑polymerase
26 chain reaction (RT‑PCR) analysis of nasopharyngeal swabs.
We excluded patients with no diagnosis of COVID‑19,
27
28 patients in whom neurological illness was not temporally
related to COVID19 and patients with exacerbations of
chronic
29
neurologic diseases. The study design was reviewed and
30 approved by the ethics committee of the hospital (MMEC
31 No. Rs/1019/1). Fully informed consent was obtained in
32 all cases either from the patient or from the next of kin if
33
the patient himself was not considered capable of doing
34 so because of impaired conscious level. Confidentiality
35 was ensured. Detailed data forms were filled out by the
36 attending physicians. Demography, history, examination
37
findings and complementary tests were recorded and updated
38 regularly by the attending physicians. A trained neurologist
39 reviewed and confirmed the positive findings. For analytical
purposes, neurological manifestations were divided into three
40 groups as follows: the CNS, peripheral nervous system and
41 musculoskeletal manifestations. IBM SPSS Statistics for
AQ6
Windows, Version 20.0. Armonk, NY: IBM Corp. software
was used for statistical analysis. The study
42
was carried out as per the ‘Declaration of Helsinki’.
44
45 RESULTS
46 The study population comprised 810 COVID‑19 hospitalised
47
patients. Baseline characteristics and comorbidities are
48 summarised in Table 1. The mean age of the patients
49 was 46.6 ± 15.5 years and ranged from 15 to 71 years;
50 Five hundred and forty two (66.9%) patients were male,
51 whereas 268 (33.1%) were female. The most common
2 Advances in Human Biology ¦ Volume XX ¦ Issue XX ¦ Month 2022
mellitus (126 [15.5%]), ischaemic heart disease (74 [9.1%]) 18
and cerebrovascular disease (36 [4.4%]). 19
20
The most common presenting manifestations were fever in 21
700 (86.4%) patients, cough in 596 (73.5%) and dyspnoea in 22
418 (51.6%) patients. As many as 342 (42.2%) patients exhibited
neurological symptoms [Tables 2 and 3]. The most common 23
were headache (284 [35%]) and dizziness (92 [11.3%]). This
24
was followed by hyposmia (78 [9.6%]) and encephalopathy 25
or altered sensorium (68 [8.3%]). It is important to note that 26
30 (3.7%) of these patients presented with encephalopathy, 27
whereas 38 (4.6%) developed encephalopathy during the 28
hospital stay. 29
30
There were 18 cases of acute cerebrovascular events in our
31
study population. Fourteen patients developed ischaemic stroke
during the illness. All of them had at least two comorbidities.
32
Whereas four patients, one 42 years of age and the other 33
46 years of age, presented with ischaemic stroke as the index 34
presentation. These two patients had no known comorbidities 35
or vascular risk factors. Besides, it is important to note that they 36
did not have any systemic manifestation of COVID‑19 at the 37
time of presentation. However, a CT scan of the chest showed 38
bilateral ground‑glass appearance with peripheral opacities 39
in the lungs (CORADS 6), and C‑reactive protein and lactate 40
dehydrogenase were mildly elevated. D‑dimers were raised 41
in all cases with ischaemic stroke (range of 0.5–1.7 mg/L), 42
more so in cases who developed ischaemic stroke during the 43
course of illness. 44
There were six cases of intracranial haemorrhage, all of which 45
had at least two comorbidities and were on prophylactic 46
anti‑coagulation due to the severe disease. The coagulation 47
profile was mildly deranged in four cases (66% of the cases). 48
A total of 14 cases of seizures (1.7%) were seen in our 49
study population. Seizures were the cause of presentation in 50
6 (0.7%) cases. Two patients were known cases of epilepsy, 51
well controlled on anti‑epileptic drugs. They had breakthrough 52

© 2022 Advances in Human Biology | Published by Wolters Kluwer - Medknow 1

 Parry, et al.: Neurological manifestations of COVID‑19 hospitalised patients

1 of illness. This was less than the frequency of 57.4% (P = 0.09) 1

Table 2: Central nervous system manifestations
2 AQ7 2
reported by Romero - Sanchez et al.[7] from Spain and higher than 37.4%
Clinical features n (%) AQ8 3
3 reported by Mao et al. from Wuhan, China[2] (P = 0.037).
Headache 284 (35) 4
4 There are three possible mechanisms underlying the
Dizziness 92 (11.3)
5 pathogenesis of neurological involvement. The first is 5
Encephalopathy 68 (8.3)
6 Ischaemic stroke 18 (2.2) diffuse cerebral dysfunction as a consequence of systemic 6
7 Haemorrhagic stroke 6 (0.7) disturbances namely cytokine storm, hypoxia, sepsis and 7
8 Seizures 14 (1.7) multiorgan dysfunction. Second is the immune‑mediated 8
9 Encephalitis 2 (0.2) mechanism that is also implicated in the complications of 9
10 Neuropsychiatric symptoms 96 (11.8) many other viral illnesses. The third and the most important 10
11 factor is neuroinvasion or neurotropism that is well known 11
12 with other human coronaviruses such as 229E, OC43 and 12
13 Table 3: Peripheral nervous system and musculoskeletal SARS‑COV‑1[5,8] and certain other respiratory viruses such 13
14 manifestation as measles.[10] Anosmia or hyposmia, which is an initial 14
15 Clinical features n (%) presentation in many cases of COVID‑19, depicts the
neuroinvasive potential of SARS‑COV‑2. The affinity of this 15
Hyposmia 39 (9.6) 16
16 Neuropathy 2 (0.4) virus to angiotensin‑converting enzyme 2 (ACE‑2) receptor
17 can be a potential underlying mechanism, as ACE‑2 receptors
17
GBS 1 (0.2)
18 Myositis 2 (0.4) are expressed both in respiratory epithelium and neuronal 18
19 GBS: Guillain‑Barre syndrome [8]
cells. As far as the CNS is concerned, the virus can reach there 19
20 either by retrograde transfer through peripheral nerves [10,11] 20
21 seizures despite good compliance. Two patients had new‑onset or by direct hematogenous spread after blood–brain barrier 21
22 refractory status epilepticus. Yet another two patients were [12]
disruption by inflammatory mediators. And, theoretically, 22
23 diagnosed with encephalitis based on neuroimaging and if brainstem‑mediated complications develop,[13] they can be 23
24 cerebrospinal fluid (CSF) analysis. These five patients were devastating. This direct involvement of CNS has been proven 24
25 diagnosed with COVID‑19 on routine screening as they had by the presence of viral particles in frontal lobe neurons[14] and 25
26 no systemic manifestation of the disease. positive RT‑PCR for SARS‑COV‑2 in CSF.[15] 26
27 Peripheral nervous system manifestations were present Now, focusing on individual neurological manifestations in 27
28 in 48 (5.9%) patients. The most frequent symptom was this cohort, about one‑third (35%) of the patients complained 28
29 hyposmia (42 [5.1%]), although it was revealed only on direct of headaches that is significantly more than the frequency of 29
AQ4
30 questioning. Four patients presented with isolated % described by Mao et al. Interestingly, the head ache 30
31 facial nerve palsy and two with Guillain–Barre syndrome was the presenting complaint in four patients where it was 31
(GBS). In all patients with facial nerve palsy, it was the so severe that they were immediately sent for CT of brain to 32
presenting rule out subarachnoid haemorrhage. It has been postulated 33
32 symptom, and COVID was diagnosed later when they developed that cytokines and chemokines released by macrophages 34
33 symptoms. However, the course of the disease was mild in all of trigger nociceptive sensory neurons, resulting in headaches.[16] 35
34 them. The patients with GBS had been diagnosed with COVID Apart from encephalitis, a preliminary report of patients with 36
35 2 weeks back and had mild disease. posterior reversible encephalopathy syndrome‑like features 37
36 Neuropsychiatric manifestations were found in 96 (11.8%) on neuroimaging has emerged from Italy.[17,18] 38
37 patients. The most common was anxiety, followed by insomnia, Poyiadji et al.[19] from Detroit also reported a case of acute 39
38 depression and psychosis. These were not associated with any necrotising haemorrhagic encephalopathy in a middle‑aged 40
39 other comorbidities. female. 41
40 In 48 (6%) patients, neurological manifestation was the reason for Skeletal muscular injury was found in 4 (0.4%) patients, all of 42
41 the presentation. These included encephalopathy (30 [3.7%]), which had significantly raised serum creatinine kinase levels, 43
42 seizures (6 [0.7%]), facial nerve palsy (4 [0.4%]), ischaemic but as these patients had severe respiratory disease, it cannot 44
44 stroke (4 [0.4%]), headache (4 [0.4%]), GBS (2 [0.2%]) and be reliably determined if it represented direct or indirect injury. 45
45 encephalitis (2 [0.2%]). 46
We had two cases of encephalitis that presented with seizures
46 47
and had bilateral temporal hyperintensities on magnetic
47 DISCUSSION resonance imaging of the brain. The CSF examination revealed 48
48 Our results highlight the broad spectrum of neurologic 49
mild pleocytosis. However, it should be kept in mind that
49 manifestations associated with SARS‑CoV‑2 infection. 50
magnetic resonance imaging and CSF analysis were not
50 Our results showed that neurological manifestation was the 51
done in all patients with encephalopathy, especially where
51 presenting feature in 48 (6%) cases, and at least 42% of the encephalopathy seemed to be secondary to severe disease 52
52 patients developed neurological involvement during the course

4 Advances in Human Biology ¦ Volume XX ¦ Issue XX ¦ Month 2022

 Parry, et al.: Neurological manifestations of COVID‑19 hospitalised patients

1 or multiorgan dysfunction. Thus, there is a possibility that 6. Parry ZA, Bumb SS, Kumar S, Bhatt R, Irfan M, Bhatt P. Neurological 1
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2 some cases of encephalitis might have been missed. Cases India. Bangladesh Journal of Medical Science, 20(5), 155–161. AQ12 2
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AQ9
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